用于治療狼瘡腎炎的組合物和方法

專利名稱：用于治療狼瘡腎炎的組合物和方法
技術領域：
總的說來，本發明涉及核酸和多肽，更具體地，涉及編碼用于檢測和治療狼瘡腎炎，以及鑒定用于治療狼瘡腎炎的治療劑的多肽的核酸和多肽。
背景技術：
狼瘡腎炎是″經典的″自身免疫性疾病的實例，其中患者的免疫系統攻擊其自身的器官。已經估計45-75％的狼瘡患者總會患某些形式或其它的腎臟損傷。從需要極少介入的輕微病例直至重要器官，例如肺、腎臟、心臟和腦發生顯著損傷并最終可能致命的病例，狼瘡的嚴重程度有很大的不同。狼瘡主要是女性疾病，女性與男性比率約是9∶1。在北美，估計每500個年齡在20至40歲的女性中就有一個1個受到影響。
針對狼瘡的治療還是未知的。治療一般旨在控制癥狀以希望使疾病的癥狀緩解。最近，已經證明抗生素雷帕霉素在該疾病的鼠模型中對于治療狼瘡腎炎有效。
發明概述本發明部分地是基于名稱為BFLP0169基因的發現，其在患有狼瘡腎炎的小鼠腎臟組織中表達增加；然而，該基因的表達水平不隨雷帕霉素治療而顯著降低。這個表達圖譜表明，當施用這個抗生素以改善狼瘡腎炎的癥狀時，BFLP0169基因的產物與雷帕霉素相互作用。當缺乏雷帕霉素時，該基因產物是游離的，以造成患病狀態，并且其影響可能包括活化為導致該患病狀態所需要的基因。當存在雷帕霉素時，BFLP0169基因產物是失活的并且使患病狀態減弱。因此，BFLP0169蛋白質可用作鑒定在治療狼瘡腎炎癥狀中類似雷帕霉素的有用的試劑的靶。
在一個方面，本發明提供包括編碼BF40169基因產物的核苷酸序列的分離核酸分子。在優選的實施方案中，該核苷酸序列包括SEQ IDNO1的序列，或其片段、同系物、類似物或衍生物。該核酸可包括例如，編碼與包括SEQ ID NO2的氨基酸序列的多肽至少70％、例如80％、85％、90％、95％、98％，甚至99％或以上相同的多肽的核酸序列。該核酸可以是例如，基因組DNA片段或cDNA分子。
本發明也包括包含一種或多種在此所描述的核酸的載體，和包含所述載體或核酸的細胞。
本發明也針對用包括如上所述的任何核酸分子的載體轉化的宿主細胞。
在另一個方面，本發明包括包含BFLP0169核酸和藥物學上可接受的載體或稀釋劑的藥物組合物。
在進一步的方面，本發明包括基本上純化的BFLP0169多肽，例如任何由BFLP0169核酸編碼的BFLP0169多肽，及其片段、同系物、類似物和衍生物。本發明也包括包含BFLP0169多肽和藥物學上可接受的載體或稀釋劑的藥物組合物。
在更進一步的方面，本發明提供特異結合BFLP0169多肽的抗體。該抗體可以是例如，單克隆或多克隆抗體，及其片段、同系物、類似物和衍生物。本發明也包括包含BFLP0169抗體和藥物學上可接受的載體或稀釋劑的藥物組合物。本發明也針對結合由如上所述任何核酸分子編碼的多肽上的表位的分離抗體。
本發明也包括試劑盒，其在一個或多個容器中包括BFLP0169核酸、BFLP0169多肽和/或BFLP0169多肽的抗體的一種或多種化合物。優選該試劑盒配備有使用說明書。如果需要，試劑盒中的化合物與藥物學上可接受的載體一起提供。
本發明進一步通過提供包含BFLP0169核酸，例如包括BFLP0169核酸的載體的細胞，并且在足夠表達由該核酸編碼的BFLP0169多肽的條件下培養細胞，而提供用于生產BFLP0169多肽的方法。然后從該細胞回收表達的BFLP0169多肽。優選地，該細胞產生極少或者幾乎不產生內源的BFLP0169多肽。該細胞可以是例如，原核細胞或真核細胞。
本發明也涉及通過將樣品與特異結合該多肽或核酸的化合物接觸，通過檢測復合物形成而鑒定樣品中的BFLP0169多肽或核酸的方法。
本發明進一步提供通過將BFLP0169多肽與化合物接觸，并且確定BFLP0169多肽活性是否改變而鑒定調節BFLP0169多肽活性的化合物的方法。
本發明還涉及通過將BFLP0169多肽與化合物接觸，并且確定該化合物是否改變BFLP0169多肽的活性、結合BFLP0169多肽、或結合編碼BFLP0169多肽的核酸分子而鑒定的調節BFLP0169多肽活性的化合物。
另一個方面，本發明提供確定受試個體中存在或易患BFLP0169相關病癥的方法。本方法包括提供來自受試個體的樣品并且測量受試個體樣品中BFLP0169多肽的量。然后將受試個體中BFLP0169多肽的量與對照樣品中BFLP0169多肽的量相比。受試個體蛋白質樣品中BFLP0169多肽量相對于對照蛋白質樣品中BFLP0169多肽量的變化，表明受試個體具有組織增殖相關的狀況。優選從相配的個體，即相似年齡、性別、或其它一般條件，但不被懷疑具有組織增殖相關狀況的個體取對照樣品。備選地，對照樣品可取自當受試個體不被懷疑具有組織增殖相關病癥的時候的受試個體。在一些實施方案中，利用BFLP0169抗體檢測BFLP0169。
在另一個方面，本發明提供確定受試個體中存在或易患BFLP0169相關病癥的方法。該方法包括提供來自受試個體的核酸樣品，例如RNA或DNA或兩者，并且測量受試個體核酸樣品中BFLP0169核酸的量。然后將受試個體核酸樣品中BFLP0169核酸樣品的量與對照樣品中BFLP0169核酸的量相比。樣品中BFLP0169核酸量相對于對照樣品中BFLP0169量的變化，表明該受試個體具有組織增殖相關的病癥。
在更進一步的方面，本發明提供治療或預防或延遲BFLP0169相關病癥的方法。該方法包括對需要此種治療或預防或延遲的受試個體施用足以治療、預防或延遲受試個體中組織增殖相關病癥的量的BFLP0169核酸、BFLP0169多肽、或BFLP0169抗體。這種病癥的實例包括風濕性關節炎和多發性硬化。
除非另外限定，否則在此所使用的所有技術和科學術語具有如本發明所屬領域的普通技術人員通常所認為的相同意義。盡管與在此所描述的相似或等效的方法和物質可用于本發明的實施或測試，適當的方法和物質描述如下。
在此提及的所有出版物、專利申請、專利，以及其他參考文獻全部引入作為參考。在出現分岐時，以本說明書的定義為準。此外，材料、方法和實施例只是說明性的而不是限制性的。
本發明的其他特性和優勢可從下列的詳細描述和權利要求中明顯體現出來。
附圖簡述

圖1是顯示在雷帕霉素治療前、治療期間和治療后，在NZB×NZWF1的腎臟以及在不同的對照小鼠株和條件下，人BFLP0169基因的小鼠直向同源物中基因表達相對水平的直方圖。
發明詳述在此公開的BFLP0169核酸序列是根據與來自非患病小鼠腎臟中該基因表達相比，狼瘡腎炎模型小鼠腎臟中該基因表達的變化而鑒定的。更特別地，該基因在幼仔小鼠和不顯示狼瘡腎炎癥狀的小鼠中以相對低的水平表達。在患有狼瘡腎炎的小鼠中基因表達升高，而在已經用雷帕霉素或抗-B7抗體成功處理的小鼠中是較低的。當腎臟功能正常而觀察到表達水平恢復正常，表明升高的水平與疾病進展相關和并可診斷疾病的進展。阻斷這些基因的功能可以抑制或延遲疾病進展。表達水平也可用于評估和比較不同治療介入的有效性。
因此，BFLP0169核酸序列對于檢測受試個體中狼瘡腎炎的存在是有用的。相對于對照樣品中的水平，BFLP0169轉錄本或多肽的水平升高表明在受試個體中存在狼瘡腎炎。BFLP0169核酸序列也可用來監測治療狼瘡腎炎的有效性相對于患病治療水平，BFLP0169基因表達的減少表明該治療是有效的。
另外BFLP0169序列可用來鑒定在受試個體中用于治療或預防狼瘡腎炎的治療劑。例如，可使BFLP0169多肽與測試劑接觸。BFLP0169多肽與測試劑的結合顯示該測試劑調節BFLP0169活性。可進一步測試BFLP0169結合劑，確定它是否在測試生物體(例如，NZB×NZW小鼠)中促進或抑制狼瘡癥狀。狼瘡癥狀的抑制顯示該試劑具有治療或預防狼瘡腎炎、或與狼瘡腎炎相關的癥狀的用途。在此公開其它的用途。
表1顯示了一種包括人BFLP0169核酸在內的5987個核苷酸的序列(SEQ ID NO1)。確定該人序列為鼠基因的人直向同源物，所述鼠基因在患有狼瘡腎炎樣癥狀的NZB×NZW小鼠中其表達增加。
該序列的第1-5259位核苷酸如表1所示，其編碼如表2所示序列的1753個氨基酸的多肽(SEQ ID NO2)。
表1ATGATCAGAAAGAGCAAAATTACCTCTGTTCTCTCATTTTGCAGGAGCAGTAGAGAACTGTGGACTATTCTGCTTGGAAGGTCAGCTCTGAGAGAGCTGAGTCAGATTGAGGCAGAACTGAATAAACATTGGCGGCGATTGTTAGAGGGGCTTTCTTACTACAAACCTCCCAGTCCAAGTTCAGCTGAAAAAGTGAAAGCTAATAAAGATGTAGCTTCACCATTGAAGGAACTGGGTTTAAGAATCAGCAAGTTTTTGGGTCTTGATGAAGAACAGAGTGTGCAGTTACTCCAGTGTTACCTGCAAGAGGACTACAGGGGTACTCGGGACTCAGTAAAGACAGTACTGCAAGATGAGAGGCAGAGCCAGGCCTTAATCCTGAAGATTGCAGATTATTATTATGAAGAAAGAACCTGTATTCTTCGTTGTGTCTTACACCTTCTCACTTACTTCCAAGATGAAAGACACCCCTATAGGGTTGAATATGCAGACTGTGTTGATAAATTGGAGAAGGAACTAGTTTCAAAATACAGACAGCAGTTCGAAGAGCTTTATAAAACTGAAGCACCAACTTGGGAGACACATGGAAATCTCATGACAGAGCGCCAAGTGTCTCGCTGGTTTGTTCAGTGCCTTCGGGAACAGTCCATGCTGCTAGAAATTATTTTCCTTTATTATGCATACTTTGAGATGGCACCCAGTGACTTACTTGTATTAACCAAGATGTTTAAAGAGCAAGGATTTGGTAGTAGGCAGACCAATAGGCACCTGGTGGATGAGACTATGGATCCTTTTGTAGATCGGATTGGCTACTTCAGTGCCCTCATCCTGGTGGAGGGCATGGATATCGAGTCCTTGCATAAGTGTGCTTTGGATGACAGAAGAGAACTGCATCAGTTTGCGCAGGATGGGCTTATTTGTCAGGATATGGACTGTTTAATGTTGACCTTTGGGGACATTCCACATCATGCCCCAGTGCTTTTGGCCTGGGCTCTCCTCCGTCACACTCTGAACCCAGAAGAGACAAGCAGTGTGGTCCGGAAGATAGGTGGCACAGCCATCCAGCTGAATGTGTTTCAGTACTTGACCCGATTGCTCCAGTCCCTTGCCAGTGGGGGAAATGATTGCACCACCAGCACTGCATGCATGTGTGTCTATGGACTGCTCTCTTTCGTTCTGACCTCGTTGGAGCTGCACACCCTGGGCAATCAGCAGGATATAATTGATACAGCATGTGAAGTATTGGCCGACCCTTCTCTTCCGGAACTGTTCTGGGGAACAGAGCCAACTTCTGGCCTTGGGATCATTCTGGACAGTGTGTGTGGAATGTTTCCCCACCTTCTCTCCCCACTCCTGCAACTGCTCCGAGCCCTGGTATCAGGGAAGTCCACAGCCAAAAAGGTGTATAGCTTCTTGGATAAGATGTCTTTCTACAATGAACTTTATAAACACAAGCCTCATGATGTGATCTCCCATGAAGATGGAACTCTTTGGCGGAGACAAACACCCAAACTCCTTTATCCCCTTGGGGGTCAAACCAACCTTCGCATACCTCAAGGCACTGTGGGCCAAGTAATGTTGGATGATAGGGCATACCTGGTACGCTGGGAATACTCCTATAGCAGCTGGACCCTCTTTACCTGCGAGATTGAAATGTTGCTTCATGTTGTTTCAACTGCAGATGTGATTCAGCACTGCCAGCGAGTCAAACCCATCATTGATCTCGTCCATAAGGTCATCAGTACAGACCTGTCGATAGCAGACTGTCTCCTGCCCATCACATCTCGCATCTACATGCTGCTGCAGCGGTTAACGACAGTGATCTCCCCACCTGTGGATGTCATTGCTTCTTGTGTCAACTGCTTAACTGTTTTGGCTGCCCGCAATCCAGCAAAGGTCTGGACTGATCTTCGTCACACAGGTTTTTTACCATTTGTGGCCCATCCTGTCTCCAGCCTGAGTCAGATGATTAGTGCGGAAGGGATGAATGCTGGAGGGTACGGAAACCTCTTGATGAACAGTGAACAGCCTCAGGGCGAGTATGGGGTTACTATTGCCTTTCTGCGCTTGATCACCACCCTTGTCAAGGGGCAACTTGGTAGTACCCAGAGCCAAGGACTTGTACCCTGTGTAATGTTTGTGCTGAAGGAGATGCTTCCCAGCTACCATAAGTGGCGCTACAACTCTCATGGAGTGAGGGAACAGATTGGTTGCCTGATCTTGGAGCTGATTCATGCGATACTGAACCTGTGCCACGAGACAGACCTGCACAGCAGTCATACTCCCAGCCTGCAGTTTCTCTGCATCTGCAGCCTGGCATACACAGAAGCAGGACAGACAGTTATCAATATCATGGGCATTGGCGTGGACACCATTGACATGGTGATGGCTGCTCAGCCTCGAAGTGATGGGGCAGAGGGCCAGGGGCAGGGCCAGCTGCTGATCAAGACAGTGAAACTGGCATTCTCCGTCACCAACAATGTTATTCGGCTGAAACCTCCTTCTAATGTGGTGTCCCCCCTGGAACAGGCTCTCTCACAACATGGTGCTCATGGAAACAACCTCATTGCTGTTCTAGCCAAATACATCTACCACAAACATGACCCTGCTTTGCCACGTCTTGCCATTCAGCTGCTGAAACGTCTGGCCACGGTGGCCCCAATGTCAGTGTATGCTTGTCTGGGCAATGATGCGGCTGCCATTCGTGATGCCTTCCTGACCCGATTGCAGAGCAAAATTGAGGACATGCGCATCAAAGTCATGATTCTAGAGTTCCTCACTGTTGCAGTAGAGACCCAGCCAGGCCTCATCGAACTGTTTCTGAACCTGGAAGTTAAGGATGGCAGTGATGGCTCAAAGGAATTCAGCCTTGGGATGTGGAGCTGTCTCCATGCAGTGCTGGAGCTGATTGATTCCCAACAGCAAGATCGATACTGGTGCCCACCCCTGCTGCATCGTGCCGCCATTGCCTTTTTGCATGCTCTGTGGCAGGATCGGAGGGACAGTGCCATGCTGGTCCTCCGAACCAAACCCAAGTTTTGGGAAAATTTAACCAGTCCGCTGTTTGGAACCCTTTCTCCTCCCTCTGAAACATCAGAGCCCAGCATCCTGGAAACCTGTGCCCTAATCATGAAGATAATTTGCTTGGAGATATACTATGTAGTAAAGGGTTCATTAGACCAGTCATTAAAGGATACACTGAAGAAATTTTCCATCGAGAAACGCTTTGCCTACTGGTCAGGGTATGTCAAGTGATTGGCAGTTCACGTGGCCGAAACAGAAGGCAGCAGCTGCACCTCCTTGTTAGAGTACCAGATGCTGGTGTCCGCCTGGAGGATGCTTCTCATCATTGCCACCACTCATGCAGATATAATGCACCTGACTGACTCTGTGGTGCGTCGCCAGCTCTTTCTTGACGTGCTTGATGGAACCAAAGCATTACTCCTAGTTCCAGCCTCAGTGAACTGCCTTCGCCTTGGCTCCATGAAGTGCACTCTGCTGCTTATCCTCCTCCGGCAGTGGAAGAGAGAGTTAGGTTCTGTGGATGAAATCCTTGGACCCTTGACGGAGATCCTGGAGGGAGTGCTGCAGGCCGACCAGCAACTCATGGAGAAGACCAAGGCCAAGGTGTTCTCAGCATTCATCACAGTGTTGCAAATGAAGGAGATGAAAGTAAGTGACATCCCCCAGTACTCCCAGCTGGTGCTGAATGTCTGTGAGACCCTCCAAGAGGAAGTGATTGCACTCTTCGACCAGACCCGCCACAGTCTGGCATTAGGCAGTGCCACAGAGGACAAGGACAGCATGGAGACTGACGACTGTTCTCGGTCCCGGCACAGGGACCAGCGTGATGGGGTGTGTGTCCTGGGCCTGCACCTGGCCAAGGAGCTGTGTGAGGTAGACGAGGATGGTGACTCCTGGCTGCAGGTAACCCGCAGGCTCCCCATCCTACCCACCCTCCTCACCACTCTAGAGGTGAGCCTTCGCATGAAGCAGAACCTGCATTTCACTGAGGCCACATTGCATCTGCTCCTCACCCTGGCTCGCACTCAGCAGGGAGCCACAGCAGTGGCTGGAGGTGGCATCACCCAGAGCATTTGTTTGCCCCTTCTGAGTGTGTACCAGCTGAGCACCAACGGCACAGCACAGACACCTAGTGCCTCTCGGAAGTCCCTGGATGCCCCCTCTTGGCCAGGAGTCTACCGCCTGTCCATGTCCCTGATGGAGCAGCTGCTCAAAACTCTGCGCTACAACTTCCTGCCTGAGGCCCTGGACTTCGTGGGTGTCCACCAGGAGCGGACCTTACAGTGCCTCAACGCAGTGAGGACAGTGCAGAGTCTGGCCTGCCTGGAGGAGGCGGACCACACCGTGGGTTTTATTCTGCAGCTCTCTAACTTCATGAAGGAGTGGCACTTCCACCTGCCTCAGCTCATGCGTGATATCCAGGTCAACCTGGGTTACTTGTGCCAGGCATGTACCTCTCTCCTGCACAGTCGAAAGATGCTGCAGCATTACTTACAGAACAAAAATGGGGATGGCCTCCCCTCAGCTGTTGCCCAGCGAGTCCAGAGGCCACCGTCTGCTGCTTCTGCTGCCCCCTCCTCCTCAAAGCAGCCCGCTGCTGACACAGAGGCATCAGAGCAGCAGGCCTTGCACACAGTCCAGTATGGCCTTCTCAAGATCCTCAGCAAGACGCTGGCAGCCCTGCGCCACTTCACCCCAGATGTCTGCCAGATTCTGCTGGATCAGTCCCTGGACCTTGCTGAATACAACTTCCTGTTTGCCCTGAGCTTTACCACTCCCACCTTTGACTCCGAAGTGGCCCCCTCCTTCGGGACCCTTCTGGCCACAGTGAATGTGGCCCTCAACATGCTTGGAGAGCTGGACAAGAAAAAGGAGCCCCTCACCCAGGCAGTGGGGCTCAGCACACAGGCAGAAGGGACCAGGACGTTAAAGTCCCTCCTGATGTTTACCATGGAAAACTGCTTCTAC
CTGCTCATCTCTCAGGCGATGCGGTACCTTAGGGACCCGGCTGTGCACCCCCGGGACAAACAGCGGATGAAGCAGGAGCTCAGCTCTGAGTTGAGCACGCTGCTGTCCAGCCTCTCGCGCTACTTCCGCCGGGGAGCCCCCAGCTCCCCTGCCACTGGTGTCCTCCCCTCGCCGCAGGGCAAGTCCACCTCTCTCTCCAAAGCCAGCCCTGAGAGTCAGGAGCCTCTGATCCAGTTGGTGCAGGCGTTTGTCCGGCATATGCAAAGATAGGGCAGTGCTGTTCTGCCCACCTACCCCTCTCCACCAGCCTACACTGCACCCTGGCTGGCAGGGGTGCTGCTGGCTGCTAGGGCCTATACAATGGAGGGCACCTCCTGTCACCCCCCTCCCGGAGTAGCCACGACTCCAGCCACCACCCACTGACGTTATTTTTATACTAGATGAAGAGGTCAACAGCAGGCATGGGGAGCCGAGTCTTCTGTGCTCAGGTCCTCACGCTGCAGACGCCCCCTAGAGGAACTTTCCTTCCTTTCCAGCATTCCCCACAGCACTGCCGGCCAGGGGAGAGGCGGCAGCCCAGCAGAGGGCTCTATGCACGGGTTTCAAACCTGTTTTCCACACTCTGTCTTTGCAGTTTTGGTAATTCTGTGGTCTATTTATACAGATATTAAAATCTTGTTTATAGACAGCTGTGTGATGTTTAACTTCAAAGCCCAGGGATGACAACGTGGCTCTCAGAACCTAGAAAACTCCCCTGGCCAGGCGCCTGGGAGTGGGGCTGCAGCCTCGGGGGAAGGCAGGTACTGATGGATGGCTAGTTCACCAGCATCTCCTCATTCCTGTCCTTGGGCTGAGGGTTTGGCTGGGTGGGCGCTGTCAGATATTCCCTTCCTTGGCCTGCGCTGGTCCTGTCCTTGACCCTGCTTTCATTGGCCCAGTGGGCTGAGCTCATCCCTGGGTGAGCCTTTCTTGAAGCTCTGTGCCTTCCTATTTAT(SEQ ID NO1)表2MIRKSKITSVLSFCRSSRELWTILLGRSALRELSQIEAELNKHWRRLLEGLSYYKPPSPSSAEKVKANKDVASPLKELGLRISKFLGLDEEQSVQLLQCYLQEDYRGTRDSVKTVLQDERQSQALILKIADYYYEERTCILRCVLHLLTYFQDERHPYRVEYADCVDKLEKELVSKYRQQFEELYKTEAPTWETHGNLMTERQVSRWFVQCLREQSMLLEIIFLYYAYFEMAPSDLLVLTKMFKEQGFGSRQTNRHLVDETMDPFVDRIGYFSALILVEGMDIESLHKCALDDRRELHQFAQDGLICQDMDCLMLTFGDIPHHAPVLLAWALLRHTLNPEETSSVVRKIGGTAIQLNVFQYLTRLLQSLASGGNDCTTSTACMCVYGLLSFVLTSLELHTLGNQQDIIDTACEVLADPSLPELFWGTEPTSGLGIILDSVCGMFPHLLSPLLQLLRALVSGKSTAKKVYSFLDKMSFYNELYKHKPHDVISHEDGTLWRRQTPKLLYPLGGQTNLRIPQGTVGQVMLDDRAYLVRWEYSYSSWTLFTCEIEMLLHVVSTADVIQHCQRVKPIIDLVHKVISTDLSIADCLLPITSRIYMLLQRLTTVISPPVDVIASCVNCLTVLAARNPAKVWTDLRHTGFLPFVAHPVSSLSQMISAEGMNAGGYGNLLMNSEQPQGEYGVTIAFLRLITTLVKGQLGSTQSQGLVPCVMFVLKEMLPSYHKWRYNSHGVREQIGCLILELIHAILNLCHETDLHSSHTPSLQFLCICSLAYTEAGQTVINIMGIGVDTIDMVMAAQPRSDGAEGQGQGQLLIKTVKLAFSVTNNVIRLKPPSNVVSPLEQALSQHGAHGNNLIAVLAKYIYHKHDPALPRLAIQLLKRLATVAPMSVYACLGNDAAAIRDAFLTRLQSKIEDMRIKVMILEFLTVAVETQPGLIELFLNLEVKDGSDGSKEFSLGMWSCLHAVLELIDSQQQDRYWCPPLLHRAAIAFLHALWQDRRDSAMLVLRTKPKFWENLTSPLFGTLSPPSETSEPSILETCALIMKIICLEIYYVVKGSLDQSLKDTLKKFSIEKRFAYWSGYVKSLAVHVAETEGSSCTSLLEYQMLVSAWRMLLIIATTHADIMHLTDSVVRRQLFLDVLDGTKALLLVPASVNCLRLGSMKCTLLLILLRQWKRELGSVDEILGPLTEILEGVLQADQQLMEKTKAKVFSAFITVLQMKEMKVSDIPQYSQLVLNVCETLQEEVIALFDQTRHSLALGSATEDKDSMETDDCSRSRHRDQRDGVCVLGLHLAKELCEVDEDGDSWLQVTRRLPILPTLLTTLEVSLRMKQNLHFTEATLHLLLTLARTQQGATAVAGAGITQSICLPLLSVYQLSTNGTAQTPSASRKSLDAPSWPGVYRLSMSLMEQLLKTLRYNFLPEALDFVGVHQERTLQCLNAVRTVQSLACLEEADHTVGFILQLSNFMKEWHFHLPQLMRDIQVNLGYLCQACTSLLHSRKMLQHYLQNKNGDGLPSAVAQRVQRPPSAASAAPSSSKQPAADTEASEQQALHTVQYGLLKILSKTLAALRHFTPDVCQILLDQSLDLAEYNFLFALSFTTPTFDSEVAPSFGTLLATVNVALNMLGELDKKKEPLTQAVGLSTQAEGTRTLKSLLMFTMENCFYLLISQAMRYLRDPAVHPRDKQRMKQELSSELSTLLSSLSRYFRRGAPSSPATGVLPSPQGKSTSLSKASPESQEPLIQLVQAFVRHMQR(SEQ ID NO2)本發明的BFLP0169樣核酸和多肽(包括表1中所示的序列)在此稱為″BFLP0169″核酸和多肽。
根據本發明的BFLP0169核酸和編碼的多肽可用于多種應用和范圍中。
如表3中所描述的BLAST結果所示，BFLP0169顯示與其它蛋白質的同源性。KIAA0169，IMAGE3461492，和3598686，以及cDNAFLJ21639是在基因組DNA中發現的由部分閱讀框(表達序列標記(ESTs))編碼的所有蛋白質。因為BFLP0169與這些蛋白質具有同源性，它也是由全部的開放閱讀框或更大開放閱讀框的一部分(EST)編碼的。
表4顯示上述表3中所示蛋白質與BFLP0169(SEQ ID NO2)的ClustalW序列對比。
表4.SEQ ID NO2的ClustalW分析1) SEQ ID NO22) gi|1136397|dbj|D79991.1|(SEQ ID NO21)3) gi|22046118|ref|XP_052725.6|(XM_052725)(SEQ ID NO22)4) gi|23618434|ref|XP_130085.2|(XM_130085)(SEQ ID NO23)5) gi|13529308|gb|AAH05407.1|AAH05407(BC005407)(SEQ ID NO24)6) gi|19343754|gb|AAH25526.1|(BC025526)(SEQ ID NO25)1020304050 60....|....|....|....|....|....|....|....|....|....|....|....|SEQ ID NO2 ----------MIRKSKITSVLSFCRSSRELWTILLGRSALRELSQIEAELNKHWRALLEG 50gi|1136398|dbj| ------------------AGGPCVRSSRELWTILLGRSALRELSQIEAELNKHWRRLLEG 42gi|22046118|ref MASGGGVRASGRAKMAAAAGGPCVRSSRELWTILLGRSALRELSQIEAELNKHWRRLLEG 60gi|23618434|ref ------------------------------------------------------------ 1gi|13529308|gb| ------------------------------------------------------------ 1gi|19343754|gb| ------------------------------------------------------------ 1708090 100 110 120....|....|....|....|....|....|....|....|....|....|....|....|SEQ ID NO2 LSYYKPPSPSSAEKVKANKDVASPLKELGLRISKFLGLDEEQSVQLLQCYLQEDYRGTRD 110gi|1136398|dbj| LSYYKPPSPSSAEKVKANKDVASPLKELGLRISKFLGLDEEQSVQLLQCYLQEDYRGTRD 102gi|22046118|ref LSYYKPPSPSSAEKVKANKDVASPLKELGLRISKFLGLDEEQSVQLLQCYLQEDYRGTRD 120gi|23618434|ref ------------------------------------------------------------ 1gi|13529308|gb| ------------------------------------------------------------ 1gi|19343754|gb| ------------------------------------------------------------ 1130 140 150 160 170 180....|....|....|....|....|....|....|....|....|....|....|....|SEQ ID NO2 SVKTVLQDERQSQALILKIADYYYEERTCILRCVLHLLTYFQDERHPYRVEYADCVDKLE 170gi|1136398|dbj| SVKTVLQDERQSQALILKIADYYYEERTCILRCVLHLLTYFQDERHPYRVEYADCVDKLE 162gi|22046118|ref SVKTVLQDERQSQALILKIADYYYEERTCILRCVLHLLTYFQDERHPYRVEYADCVDKLE 180gi|23618434|ref ------------------------------------------------------------ 1gi|13529308|gb| ------------------------------------------------------------ 1gi|19343754|gb| ------------------------------------------------------------ 1190 200 210 220 230 240....|....|....|....|....|....|....|....|...|....|....|....|SEQ ID NO2 KELVSKYRQQFEELYKTEAPTWETHGNLMTERQVSRWFVQCLREQSMLLEIIFLYYAYFE 230gi|1136398|dbj| KELVSKYRQQFEELYKTEAPTWETBGNLMTERQVSRWFVQCLREQSMLLEIIFLYYAYFE 222gi|22046118|ref KELVSKYRQQFEELYKTEAPTWETHGNLMTERQVSRWFVQCLREQSMLLEIIFLYYAYFE 240gi|23618434|ref ------------------------------------------------------------ 1gi|13529308|gb| ------------------------------------------------------------ 1gi|19343754|gb| ------------------------------------------------------------ 1250 260 270 280 290 300....|....|....|....|...|....|....|....|....|....|....|....|SEQ ID NO2 MAPSDLLVLTKMFKEQGFGSRQTNRHLVDETMDPFVDRIGYFSALILVEGMDIESLHKCA 290gi|1136398|dbj| MAPSDLLVLTKMFKEQGFGSRQTNRHLVDETMDPFVDRIGYFSALILVEGMDIESLHKCA 282gi|22046118|ref MAPSDLLVLTKMFKEQGFGSRQTNRHLVDETMDPFVDRIGYFSALILVEGMDIESLHKCA 300gi|23618434|ref ------------------------------------------------------------ 1gi|13529308|gb| ------------------------------------------------------------ 1gi|19343754|gb| ------------------------------------------------------------ 1310 320 330 340 350 360
....|....|....|....|....|....|....|....|....|....|....|....|SEQ ID NO2 LDDRRELHQFAQDGLICQDMDCLMLTFGDIPHHAPVLLAWALLRHTLNPEETSSVVRKIG 350gi|1136398|dbj| LDDRRELHQFAQDGLICQDMDCLMLTFGDIPHHAPVLLAWALLRHTLNPEETSSVVRKIG 342gi|22046118|ref LDDRRELHQFAQDGLICQDMDCLMLTFGDIPHHAPVLLAWALLRHTLNPEETSSVVRKIG 360gi|23618434|ref ------------------------------------------------------------ 1gi|13529308|gb| ------------------------------------------------------------ 1gi|19343754|gb| ------------------------------------------------------------ 1370 380 390 400 410 420....|....|....|....|....|....|....|....|....|....|....|....|SEQ ID NO2 GTAIQLNVFQYLTRLLQSLASGGNDCTTSTACMCVYGLLSFVLTSLELHTLGNQQDIIDT 410gi|1136398|dbj| GTAIQLNVFQYLTRLLQSLASGGNDCTTSTACMCVYGLLSFVLTSLELHTLGNQQDIIDT 402gi|22046118|ref GTAIQLNVFQYLTRLLQSLASGGNDCTTSTACMCVYGLLSFVLTSLELHTLGNQQDIIDT 420gi|23618434|re ------------------------------------------------------------ 1gi|13529308|gb| ------------------------------------------------------------ 1gi|19343754|gb| ------------------------------------------------------------ 1430 440 450 460 470 480....|....|....|....|....|....|....|....|....|....|....|....|SEQ ID NO2 ACEVLADPSLPELFWGTEPTSGLGIILDSVCGMFPHLLSPLLQLLRALVSGKSTAKKVYS 470gi|1136398|dbj| ACEVLADPSLPELFWGTEPTSGLGIILDSVCGMFPHLLSPLLQLLRALVSGKSTAKKVYS 462gi|22046118|ref ACEVIADPSLPELFWGTEPTSGLGIILDSVCGMFPHLLSPLLQLLRALVSGKSTAKKVYS 480gi|23618434|ref ------------------------------------------------------------ 1gi|13529308|gb| ------------------------------------------------------------ 1gi|19343754|gb| ------------------------------------------------------------ 1490 500 510 520 530 540....|....|....|....|....|....|....|....|....|....|....|....|SEQ ID NO2 ELDKMSFYNELYKHKPHDVISHEDGTLWRRQTPKLLYPLGGQTNLRIPQGTVGQVMLDDR 530gi|1136398|dbj| FLDKMSFYNELYKHKPHDVISHEDGTLWRRQTPKLLYPLGGQTNLRIPQGTVGQVMLDDR 522gi|22046118|ref FLDKMSFYNELYKHKPHDVISHEDGTLWRRQTPKLLYPLGGQTNLRIPQGTVGQVMLDDR 540gi|23618434|ref ------------------------------------------------------------ 1gi|13529308|gb| ------------------------------------------------------------ 1gi|19343754|gb| ------------------------------------------------------------ 1550 560 570 580 590 600....|....|....|....|....|....|....|....|....|....|....|....|SEQ ID NO2 AYLVRWEYSYSSWTLFTCEIEMLLHVVSTADVIQHCQRVKPIIDLVHKVISTDLSIADCL 590gi|1136398|dbj| AYLVRWEYSYSSWTLFTCEIEMLLHVVSTADVIQHCQRVKPIIDLVHKVISTDLSIADCL 582gi|22046118|ref AYLVRWEYSYSSWTLFTCEIEMLLHVVSTADVIQHCQRVKPIIDLVHKVISTDLSIADCL 600gi|23618434|ref ------------------------------------------------------------ 1gi|13529308|gb| ------------------------------------------------------------ 1gi|19343754|gb| ------------------------------------------------------------ 1610 620 630 640 650 660....|....|....|....|....|....|....|....|....|....|....|....|SEQ ID NO2 LPITSRIYMLLQRLTTVISPPVDVIASCVNCLTVLAARNPAKVWTDLRHTGFLPFVAHPV 650gi|1136398|dbj| LPITSRIYMLLQRLTTVISPPVDVIASCVNCLTVLAARNPAKVWTDLRHTGFLPFVAHPV 642gi|22046118|ref LPITSRIYMLLQRLTTVISPPVDVIASCVNCLTVLAARNPAKVWTDLRHTGFLPFVAHPV 660gi|23618434|ref ------------------------------------------------------------ 1gi|13529308|gb| ------------------------------------------------------------ 1gi|19343754|gb| ------------------------------------------------------------ 1

SEQ ID NO2的第1-14位殘基在此稱為SEQ ID NO20。包括第1-6位氨基酸的SEQ ID NO21的片段在此稱為SEQ ID NO26。
BFLP0169核酸本發明的核酸包括編碼BFLP0169多肽或蛋白質的核酸。如在此所使用的，術語多肽和蛋白質是可互換的。
在一些實施方案中，BFLP0169核酸編碼成熟的BFLP0169多肽。如在此所使用的，在此所描述的″成熟″形式的多肽或蛋白質涉及天然存在的多肽或前體形式或原蛋白的產物。作為非限制性的實例，天然存在的多肽、前體或原蛋白包括由相應基因編碼的全長基因產物。備選地，可定義為由在此所描述的開放閱讀框編碼的多肽、前體或原蛋白。再作為非限制性的實例，出現產物″成熟″形式，作為一個或多個天然存在的進行步驟的結果，可能在細胞內發生，并出現基因產物。這種導致″成熟″形式的多肽或蛋白質的進行步驟的實例包括由開放閱讀框的起始密碼子編碼的N-末端甲硫氨酸殘基的切割，或信號肽或前導序列的蛋白水解切割。如此從具有殘基1至N，其中第1位殘基是N-末端甲硫氨酸的前體多肽或蛋白質產生的成熟形式將在除去N-末端甲硫氨酸后保留有殘基2至N。備選地，從具有殘基1至N，其中從殘基1至殘基M的N-末端信號序列被切割的前體多肽或蛋白質產生的成熟形式，將保留有從殘基M+1至殘基N的殘基。進一步的如在此所使用的，″成熟″形式的多肽或蛋白質可能由于除了蛋白水解切割事件的翻譯后修飾的步驟而產生。作為非限制性的實例，這種附加過程包括，糖基化、豆蔻酰化或磷酸化。通常，成熟多肽或蛋白質可能只由這些過程中的一個，或其任意組合而產生。
本發明包括SEQ ID NO1的突變體或變體核酸、或其片段，其任何堿基可從SEQ ID NO1所示的相應堿基進行變化，同時其仍然編碼至少保持其BFLP0169-樣活性和生理功能(即，調節血管生成、神經元發育)中的一個的蛋白質。本發明進一步包括與SEQ ID NO1的核酸序列，包括其片段、衍生物、類似物和同系物互補的序列。另外本發明包括其結構包括化學修飾的核酸或核酸片段、或其互補物。
本發明的方面涉及編碼BFLP0169蛋白質或其生物學活性部分的分離核酸分子。也包括足以用作雜交探針，以鑒定編碼BFLP0169的核酸，以及用作聚合酶鏈式反應(PCR)的引物片段來用于擴增或突變BFLP0169核酸分子的核酸片段。如在此所使用的，術語″核酸分子″意在包括DNA分子(例如，cDNA或基因組DNA)、RNA分子(例如，mRNA)、利用核苷酸類似物產生的DNA或RNA的類似物、及其衍生物、片段和同系物。核酸分子可以是單鏈或雙鏈，但優選是雙鏈DNA。
″探針″是指長度可變的核酸序列，根據用途優選在至少大約10個核苷酸(nt)、100nt、或多至大約例如6,000nt之間。探針用于檢測相同的、相似的、或互補的核酸序列。更長長度的探針通常獲自天然或重組來源，是高度特異的，并且比低聚物雜交更慢。探針可以是單-或雙鏈的，并且設計成在PCR、基于膜的雜交技術、或ELISA類似技術中具有特異性。
″分離的″核酸分子是與存在于核酸天然來源中的其它核酸分子相分離的核酸分子。分離核酸分子的實例包括但不限于，包含于載體中的重組DNA分子、保持在異源宿主細胞中的重組DNA分子、部分或基本上純化的核酸分子、以及合成的DNA或RNA分子。優選地，″分離的″核酸是與在該核酸所衍生的生物體的基因組DNA中該核酸的側翼序列(即，位于核酸的5′和3′末端的序列)分離開來。例如，在不同的實施方案中，分離的BFLP0169核酸分子可包含小于大約50kb、25kb、5kb、4kb、3kb、2kb、1kb、0.5kb或0.1kb的核苷酸序列，所述的核苷酸序列在該核酸衍生的細胞的基因組DNA中天然側接該核酸分子。此外，″分離的″核酸分子，例如cDNA分子，當通過重組技術產生時，可以是基本上從其它細胞物質或培養基分離出來的，或當通過化學合成時，可以是基本上從化合物前體或其它化合物分離出來的。
本發明的核酸分子，例如具有SEQ ID NO1或其互補核苷酸序列的核酸分子可利用標準的分子生物學技術和在此提供的序列信息加以分離。利用SEQ ID NO1的所有或部分的核酸序列作為雜交探針，可利用標準的雜交和克隆技術(例如，如Sambrook等人，編輯，MOLECMLAR CLONINGA LABORATORY MANUAL 2ndEd.，Cold Spring Harbor Laboratory Press，Cold Spring Harbor，NY，1989；和Ausubel等人，編輯，CURRENT PROTOCOLS INMOLECMLAR BIOLOGY，John Wiley & SonS，紐約，NY，1993.)分離BFLP0169核酸序列。
可利用cDNA、mRNA或備選地，基因組DNA作為模板，以及適當的寡核苷酸引物，根據標準的PCR擴增技術擴增本發明的核酸。可將如此擴增的核酸克隆到適當的載體中并且通過DNA序列分析鑒定。此外，可通過標準的合成技術，例如，利用自動化DNA合成儀制備相應于BFLP0169核苷酸序列的寡核苷酸。
如在此所使用的，術語″寡核苷酸″是指一系列連接的核苷酸殘基，該寡核苷酸具有足夠的核苷酸堿基數目來用于PCR反應。短的寡核苷酸序列可能是基于或從基因組或cDNA序列設計的，用來在特定的細胞或組織中擴增、證實、或顯示相同、相似或互補DNA或RNA的存在。寡核苷酸包括具有長度為大約10nt、50nt、或100nt，優選長度為大約15nt至30nt的核酸序列部分。在一個實施方案中，包括長度小于100nt的核酸分子的寡核苷酸將進一步包括SEQ ID NO1或其互補序列的至少6個連續的核苷酸。寡核苷酸可以化學合成并且可用作探針。
在另一個實施方案中，本發明的分離核酸分子包括SEQ ID NO1所示的核苷酸序列或該核苷酸序列部分的互補序列的核酸分子。與SEQ ID NO1所示的核苷酸序列互補的核酸分子是足夠與SEQ ID NO1所示的核苷酸序列互補的核酸分子，其可與SEQ NO1所示的核苷酸序列以氫鍵作用而很少或沒有錯配，由此形成穩定的雙螺旋。
如在此所使用的，術語″互補的″是指核酸分子的核苷酸單元之間的Watson-Crick或Hoogsteen堿基配對，而術語″結合″是指2個多肽或化合物或相關的多肽或化合物或其組合之間的物理或化學相互作用。結合包括離子的、非離子的、Van der Waals、疏水性相互作用等。物理的相互作用可以是直接或間接的。間接的相互作用可以是指通過或由于另一個多肽或化合物的影響。直接結合是指不通過、或由于另一個多肽或化合物的影響，沒有其它實質性的化學中間體而發生的相互作用。
此外，本發明的核酸分子可以只包括SEQ ID NO1的部分核酸序列，例如可用作探針或引物的片段、或編碼BFLP0169的生物活性部分的片段。在此提供的片段定義為至少6個(連續的)核酸或至少4個(連續的)氨基酸的序列，分別就核酸來說其長度足夠容許特異的雜交，或對于氨基酸來說其長度足夠用于特異的表位識別，并且至多一些部分小于全長序列。片段可以來源于任何連續的所選擇的核酸或氨基酸序列部分。衍生物是由天然化合物直接或通過修飾或部分取代而形成的核酸序列或氨基酸序列。類似物是結構與天然化合物相似，然而并非相同，就某些組分或側鏈而論有差異的核酸序列或氨基酸序列。類似物可以是合成的或來自不同的演化起源，并且可能與野生型相比具有相似或相反的代謝活動。
如下所述如果衍生物或類似物包含修飾的核酸或氨基酸，衍生物和類似物可以是全長或不是全長。本發明核酸或蛋白質的衍生物或類似物包括但不限于，包括基本上與本發明核酸或蛋白質同源的區域的分子，在不同的實施方案中，相同大小的核酸或氨基酸序列的同一性為至少大約70％、80％、85％、90％、95％、98％、甚至99％(優選同一性為80-99％)，或當通過本領域已知的計算機同源性程序與排列的序列進行序列對比時，或其編碼的核酸能夠與編碼上述蛋白質的序列的互補序列在嚴謹、中等嚴謹、或低嚴謹條件下雜交。例證性的程序是利用設置缺省值、使用Smith和Waterman算法的Gap程序(Wisconsin Sequence Analysis Package，Version 8 for UNIX，Genetics Computer Group，University Research Park，Madison，WI)。
″同源的核酸序列″或″同源的氨基酸序列″或其變體，是指通過如上所討論的核苷酸水平或氨基酸水平的同源性而表征的序列。同源的核苷酸序列編碼BFLP0169多肽同工型的編碼序列。同工型可作為例如RNA的選擇性拼接的結果而在相同生物體的不同組織中表達。
備選地，同工型可通過不同的基因編碼。在本發明中，同源的核苷酸序列包括編碼除了人之外的種屬BFLP0169多肽的核苷酸序列，包括但不限于哺乳動物，并且因而可包括例如小鼠、大鼠、兔、狗、貓、牛、馬和其他生物體。同源的核苷酸序列也包括但不限于，在此闡明的核苷酸序列的天然存在的等位變體和突變體。然而同源的核苷酸序列不包括編碼人BFLP0169蛋白質的核苷酸序列。同源的核酸序列包括編碼SEQ ID NO2中的保守氨基酸取代(見下文)的核酸序列，以及具有BFLP0169活性的多肽。BFLP0169蛋白質的生物活性描述如下。同源的氨基酸序列不編碼人BFLP0169多肽的氨基酸序列。
從人BFLP0169基因的克隆確定的核苷酸序列可設計并產生用于鑒定和/或克隆其它細胞類型，例如來自其它組織中的BFLP0169同系物，以及來自其它哺乳動物的BFLP0169同系物的探針和引物。探針/引物一般包括基本上純化的寡核苷酸。寡核苷酸一般包括在嚴謹條件下與至少大約12、25、50、100、150、200、250、300、350或400個或更多以上的SEQ ID NO1的連續有義鏈核苷酸序列；或SEQ ID NO1的反義鏈核苷酸序列；或SEQID NO1的天然存在的突變體雜交的核苷酸序列區域。
基于人BFLP0169核苷酸序列的探針可用于檢測編碼相同或同源蛋白質的轉錄本或基因組序列。在不同的實施方案中，探針進一步包括附著到其上的標記基團，例如標記基團可以是放射性同位素、熒光化合物、酶或酶輔助因子。這種探針可用作，例如通過測量來自受試個體的細胞樣品中編碼BFLP0169的核酸的水平，例如檢測BFLP0169mRNA水平或確定基因組BFLP0169基因是否已經突變或缺失，而用于鑒定錯誤表達BFLP0169蛋白質的細胞或組織的診斷測試試劑盒的部分。
″具有BFLP0169的生物活性部分的多肽″是指通過特定的生物分析測量，有或沒有劑量依賴性地顯示出與本發明的多肽，包括成熟形式活性相似、而并非必須相同的活性的多肽。可通過分離編碼具有BFLP0169生物活性(BFLP0169蛋白質的生物活性描述如下)的多肽的SEQ ID NO1的部分，表達BFLP0169蛋白質的編碼部分(例如，通過體外重組表達)以及評估BFLP0169的編碼部分的活性來制備編碼″BFLP0169生物活性部分″的核酸片段。
本發明也提供BFLP0169核酸序列的多態型，以及檢測BFLP0169序列中多態型序列的方法。多態型包括相應于與BFLP0169相關的外顯子和/或內含子的基因組序列。
可在DNA、RNA、或蛋白質水平，利用本領域公知的多種技術檢測攜帶本發明多態型等位基因的個體。本方法通常使用預先表征的多態性。也就是說，已經確定了存在于位點的多態型的基因型位置和性質。這些信息的有效利用容許設計特異鑒定已知多態型的成組探針。
用于診斷的基因組DNA可獲自機體的任何有核細胞，例如存在于外周血、尿、唾液、口腔樣品、外科手術樣本，和尸檢樣本中的有核細胞。可直接使用DNA或在突變分析前通過使用PCR或其它的體外擴增方法，例如連接酶鏈式反應(LCR)、鏈易位擴增(SDA)、自給的序列復制(3SR)而體外酶促擴增DNA。
在特異的DNA序列中檢測多態性可伴隨有多種方法，包括但不限于，基于等位基因特異的限制性核酸內切酶切割的限制性片段長度多態性檢測、與等位基因特異的寡核苷酸探針，包括固定寡核苷酸或寡核苷酸的陣列雜交、等位基因特異的PCR、錯配修復檢測(MRD)、MutS蛋白質的結合、變性梯度凝膠電泳(DGGE)、單鏈構象多態性檢測、RNA酶切割錯配堿基對、異源雙鏈DNA的化學或酶促切割、基于等位基因特異引物延伸的方法、遺傳位分析(GBA)、寡核苷酸連接分析(OLA)、等位基因特異的連接鏈式反應(LCR)、缺口-LCR、利用本領域公知標準方法的放射性和/或熒光DNA測序，以及肽核酸(PNA)分析。
BFLP0169變體本發明進一步包括由于遺傳密碼的簡并性而不同于SEQ ID NO1所示核苷酸序列的核酸分子。這些核酸因此編碼與由SEQ ID NO1所示核苷酸序列編碼的，例如SEQ ID NO2的多肽相同的BFLP01 69蛋白質。
在另一個實施方案中，本發明的分離核酸分子具有編碼SEQID NO2所示氨基酸序列的蛋白質的核苷酸序列。
除SEQ ID NO1所示的人BFLP0169核苷酸序列之外，本領域的技術人員可認識到導致BFLP0169氨基酸序列變化的DNA序列多態性可能存在于群體內(例如人類群體)。BFLP0169基因中的這種遺傳多態性可能由于天然的等位變體而存在于群體內的個體中。如在此所使用的，術語″基因″和″重組基因″是指包括編碼BFLP0169蛋白質，優選哺乳動物BFLP0169蛋白質的開放閱讀框的核酸分子。這種天然的等位變體一般可能導致BFLP0169基因核苷酸序列的1-5％的變化。由天然等位變體產生的、并且不改變BFLP0169功能活性的BFLP0169中，任何和所有的這種核苷酸變體和所得到的氨基酸多態性都在本發明的范圍內。
此外，來自其它種屬的編碼BFLP0169蛋白質的核酸分子，和具有不同于SEQ ID NO1的人序列的核苷酸序列也在本發明的范圍內。可根據其與在此公開的人BFLP0169核酸的同源性，利用人cDNAs或其部分作為雜交探針，根據標準的雜交技術在嚴謹雜交條件下，分離相應于本發明BFLP0169 cDNAs的天然等位變體和同系物的核酸分子。例如，可根據其與人的膜結合BFLP0169的同源性分離可溶的人BFLP0169 cDNA。同樣地，可根據其與可溶的人BFLP0169的同源性分離膜-結合的人BFLP0169 cDNA。
因此，在另一個實施方案中，本發明的分離核酸分子長度是至少6個核苷酸，并且在嚴謹條件下與包括SEQ ID NO1的核苷酸序列的核酸分子雜交。
在另一個實施方案中，該核酸長度是至少10、25、50、100、250、500或750個核苷酸。在另一個實施方案中，本發明的分離核酸分子與編碼區域雜交。如在此所使用的，術語″在嚴謹條件下雜交″是用來描述用于在該條件下彼此至少60％同源的核苷酸序列一般保持相互雜交的雜交和洗滌條件。
可通過以全部或部分的特定人序列作為探針，利用本領域用于核酸雜交和克隆的公知方法進行低的、中等或高嚴謹雜交來獲得同系物(即，編碼來源于除了人外種屬的BFLP0169蛋白質的核酸)或其它相關序列(例如平行同源物)。因此，本發明也包括能夠在降低的嚴謹條件，更優選嚴謹條件，以及最優選高度嚴謹條件下與在此所描述的多核苷酸雜交的多核苷酸。嚴謹條件的實例如下列表格所示高嚴謹條件是至少如例如條件A-F一樣嚴謹的條件；嚴謹條件是至少如例如條件G-L一樣嚴謹的條件；以及較低的嚴謹條件是至少如例如條件M-R一樣嚴謹的條件。
表4.嚴謹條件
1雜合物的長度是預期用于雜交多核苷酸的雜交區域的長度。當使多核苷酸與未知序列的靶多核苷酸雜交時，假定雜合物長度是雜交多核苷酸的長度。當使用已知序列的多核苷酸進行雜交時，可通過排列多核苷酸的序列并且鑒定該區域或最佳序列互補的區域來確定雜合物的長度。
H在雜交和洗滌緩沖液中SSPE(1×SSPE是0.15M NaCl，10mMNaH2PO4，和1.25mM EDTA，pH7.4)可替換為SSC(1×SSC是0.15MNaCl，和15mM檸檬酸鈉)；完成雜交后洗滌15分鐘。
TB*-TR*預期長度小于50個堿基對的雜合物的雜交溫度應低于雜合物的解鏈溫度(Tm)5-10℃，其中根據下列方程式確定Tm。對于長度小于18個堿基對的雜合物，Tm(℃)＝2(A+T堿基#)+4(G+C堿基#)。對于長度在18和49個堿基之間的雜合物，Tm(℃)＝81.5+16.6(log10Na+)+0.41(％G+C)-(600/N)，其中N是雜合物中堿基的數目，而Na+是雜交緩沖液中鈉離子的濃度(1×SSC的Na+＝0.165M)。
優選地，每個這種雜交多核苷酸的長度為其雜交的本發明多核苷酸長度的至少25％(更優選至少50％，以及最優選至少75％)，并且當通過排列使重疊部分和同一性最大化，同時使序列缺口最小化來比較雜交多核苷酸的序列而確定序列同一性時，和與其雜交的本發明多核苷酸具有至少60％的序列同一性(更優選至少75％同一性；最優選至少90％或95％同一性)。
嚴謹雜交條件的非限制性實例是在包含6×SSC，50mM Tris-HCl(pH7.5)，1mM EDTA，0.02％ PVP，0.02％ Ficoll，0.02％ BSA，和500mg/ml變性的鮭魚精DNA高鹽緩沖液中于65℃雜交。雜交后于50℃在0.2×SSC，0.01％BSA中進行一次或多次洗滌。在嚴謹條件下與SEQ ID NO1的序列雜交的本發明的分離核酸分子相應于天然存在的核酸分子。如在此所使用的，″天然存在的核酸分子″是指具有天然存在的核苷酸序列(例如，編碼天然的蛋白質)的RNA或DNA分子。
在第二個實施方案中，提供可與包括SEQ ID NO1的核苷酸序列、或其片段、類似物或衍生物的核酸分子在中等嚴謹條件下雜交的核酸序列。中等嚴謹雜交條件的非限制性實例是在6×SSC、5×Denhardt′s溶液、0.5％ SDS和100mg/ml變性鮭魚精DNA中于55℃雜交，然后于37℃在1×SSC，0.1％SDS中進行一次或多次洗滌。
在第三個實施方案中，提供可與包括SEQ ID NO1的核苷酸序列、或其片段、類似物或衍生物的核酸分子在低嚴謹條件下雜交的核酸。低嚴謹雜交條件的非限制性實例是在35％甲酰胺，5×SSC，50mMTris-HCl(pH7.5)，5mM EDTA，0.02％ PVP，0.02％ Ficoll，0.2％BSA，100mg/ml變性鮭魚精DNA，10％(wt/vol)硫酸葡聚糖中于40℃雜交，然后于50℃在2×SSC，25 Mm Tris-HCl(pH7.4)，5mM EDTA，和0.1％ SDS中進行一次或多次洗滌。
保守突變除可能存在于人群中的BFLP0169序列的天然等位變體外，熟練技術人員將進一步認識到可通過突變SEQ ID NO1的核苷酸序列而導入變化，由此導致改變編碼的BFLP0169蛋白質的氨基酸序列，而不改變BFLP0169蛋白質的功能性能力。例如，可在SEQ ID NO1的序列中產生導致在″非必需的″氨基酸殘基的氨基酸取代的核苷酸取代。″非必需的″氨基酸殘基是可從BFLP0169的野生型序列改變而不改變其生物活性的殘基，同時″必需的″氨基酸殘基是為生物活性所需要的。
例如，改變在本發明的BFLP0169蛋白質中保守的氨基酸殘基很可能導致喪失BFLP0169蛋白質活性。
本發明的另一個方面涉及編碼包含活性非必需的氨基酸殘基發生變化的BFLP0169蛋白質的核酸分子。這種BFLP0169蛋白質與SEQ IDNO2有氨基酸序列的差異，然而保留生物活性。在一個實施方案中，分離的核酸分子包括編碼蛋白質的核苷酸序列，其中該蛋白質包括與SEQ ID NO2的氨基酸序列至少大約75％同源的氨基酸序列。優選地，由核酸編碼的蛋白質與SEQ ID NO2至少大約80％同源，更優選與SEQ ID NO2至少大約90％、95％、98％，以及最優選至少大約99％同源。
可通過將一個或多個核苷酸取代、添加或缺失導入到SEQ ID NO1的核苷酸序列中，以將一個或多個氨基酸的取代、添加或缺失導入到編碼的蛋白質中，而產生編碼與SEQ ID NO2的蛋白質同源的BFLP0169蛋白質的分離核酸分子。
可通過常規技術，例如定點誘變和PCR-介導的誘變將突變導入SEQ ID NO1的核苷酸序列。優選地，在一個或多個預期的非必需氨基酸殘基產生保守的氨基酸取代。″保守的氨基酸取代″是其中氨基酸殘基用具有相似側鏈的氨基酸殘基替換的取代。具有相似側鏈的氨基酸殘基家族已經是本領域中確定的。這些家族包括具有堿性側鏈(例如，賴氨酸、精氨酸、組氨酸)、酸性側鏈(例如，天冬氨酸、谷氨酸)、不帶電的極性側鏈(例如甘氨酸、天門冬酰胺、谷氨酰胺、絲氨酸、蘇氨酸、酪氨酸、半胱氨酸)、非極性的側鏈(例如，丙氨酸、纈氨酸、亮氨酸、異亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸、色氨酸)、β-分支側鏈(例如，蘇氨酸、纈氨酸、異亮氨酸)和芳族側鏈(例如，酪氨酸、苯丙氨酸、色氨酸、組氨酸)的氨基酸。因此，BFLP0169中預期的非必需氨基酸殘基用來自相同側鏈家族的另一個氨基酸殘基替換。備選地，在另一個實施方案中，例如通過飽和誘變，可向全部或部分的BFLP0169編碼序列隨機導入突變，并且可篩選所得到的突變體的BFLP0169生物活性以鑒定保留活性的突變體。SEQ ID NO1的誘變后可通過本領域已知的任何重組技術表達編碼的蛋白質并且確定蛋白質的活性。
在一個實施方案中，可分析突變BFLP0169蛋白質的(1)與其它BFLP0169蛋白質、其它細胞表面蛋白質、或其生物活性部分形成蛋白質蛋白質相互作用的能力，(2)突變BFLP0169蛋白質和BFLP0169受體之間的復合物形成；(3)突變BFLP0169蛋白質結合胞內靶蛋白質或其生物活性部分的能力；(例如，抗生物素蛋白的蛋白質)；(4)結合BFLP0169蛋白質的能力；或(5)特異結合抗-蛋白質抗體的能力。
反義BFLP0169核酸本發明的另一個方面涉及分離的反義核酸分子，其與包括SEQ IDNO1的核苷酸序列、或其片段、類似物或衍生物的核酸分子雜交或互補。″反義″核酸包括與編碼蛋白質的″有義″核酸互補的核苷酸序列，例如與雙鏈cDNA分子的編碼鏈互補或互補于mRNA序列。在特定的方面，反義核酸分子包括與BFLP0169編碼鏈有至少大約10、25、50、100、250或500個核苷酸或全部的BFLP0169編碼鏈，或只有其部分互補的序列。另外也提供編碼SEQ ID NO2的BFLP0169蛋白質的片段、同系物、衍生物和類似物的核酸分子，或與SEQ ID NO1的BFLP0169核酸序列互補的反義核酸。
在一個實施方案中，反義核酸分子是編碼BFLP0169的核苷酸序列編碼鏈的″編碼區″的反義。術語″編碼區″是指包括翻譯成為氨基酸殘基的密碼子的核苷酸序列區域(例如，相應于SEQ ID NO2的人BFLP0169蛋白質編碼區)。
在另一個實施方案中，反義核酸分子反義于編碼BFLP0169的核苷酸序列編碼鏈的″非編碼區域″。術語″非編碼區″是指編碼區兩側不被翻譯成氨基酸的5′和3′序列(即，也稱為5′和3′非翻譯區)。
考慮到在此公開的編碼BFLP0169的編碼鏈序列(例如，SEQ IDNO1)，可根據Watson和Crick或Hoogsteen堿基配對規律設計本發明的反義核酸。反義核酸分子可以是與BFLP0169 mRNA的全部編碼區互補的，但更優選地是只與BFLP0169 mRNA的編碼或非編碼區部分反義的寡核苷酸。例如，反義寡核苷酸可與BFLP0169 mRNA翻譯起始位點周圍的區域互補。反義寡核苷酸的長度可以是例如大約5、10、15、20、25、30、35、40、45或50個核苷酸。可利用本領域已知的方法利用化學合成或酶促連接反應構建本發明的反義核酸。例如，可利用天然存在的核苷酸或設計成能增加分子的生物穩定性或增加在反義和有義核酸之間形成雙螺旋的物理穩定性而不同修飾的核苷酸化學合成反義核酸(例如，反義寡核苷酸)，例如可使用硫代磷酸衍生物和吖啶取代的核苷酸。
可用于產生反義核酸的修飾核苷酸的實例包括5-氟尿嘧啶、5-溴尿嘧啶、5-氯尿嘧啶、5-碘尿嘧啶、次黃嘌呤、黃嘌呤、4-乙酰胞密啶、5-(羧羥甲基)尿嘧啶、5-羧甲基氨甲基-2-硫尿核苷、5-羧甲基氨甲基尿嘧啶、二氫尿嘧啶、β-D-半乳糖基辮苷、次黃嘌呤核苷、N6-異戊烯基腺嘌呤、1-甲基鳥嘌呤、1-甲基次黃嘌呤苷、2，2-二甲基鳥嘌呤、2-甲基腺嘌呤、2-甲基鳥嘌呤、3-甲胞嘧啶、5-甲胞嘧啶、N6-腺嘌呤、7-甲基鳥嘌呤、5-甲基氨甲尿嘧啶、5-甲氧基氨甲基-2-硫尿嘧啶、β-D-甘露糖基辮苷、5′-甲氧基羧甲尿嘧啶、5-甲氧基尿嘧啶、2-甲硫基-N6-異戊烯基腺嘌呤、尿嘧啶-5-羥丙酸(v)、wybutoxosine、假尿嘧啶、辮苷、2-巰基胞嘧啶、5-甲基-2-硫尿嘧啶、2-硫尿嘧啶、4-硫尿嘧啶、5-甲基尿嘧啶、尿嘧啶-5-羥丙酸甲酯、尿嘧啶-5-羥丙酸(v)、5-甲基-2-硫尿嘧啶、3-(3-氨基-3-N-2-羧丙基)尿嘧啶、((acp3)w，和2，6-二氨基嘌呤。備選地，可利用已經被以反義方向亞克隆入核酸的表達載體以生物的方式產生反義核酸(即，從插入的核酸轉錄的RNA可以是令人感興趣的靶核酸的反義方向，其將在下文的小節中進一步描述)。
一般將本發明的反義核酸分子施用于受試個體或原位產生，以使得它們與編碼BFLP0169蛋白質的細胞mRNA和/或基因組DNA雜交或結合，由此通過抑制轉錄和/或翻譯而抑制該蛋白質的表達。可通過傳統的核苷酸互補性雜交而形成穩定的雙螺旋或例如，就結合DNA雙螺旋的反義核酸分子來說，通過雙螺旋寬溝中特異的相互作用而形成穩定的雙螺旋。本發明的反義核酸分子的給藥途徑實例包括在組織位點直接注入。備選地，可修飾反義核酸分子以靶向所選擇的細胞然后全身性施用。例如，對于全身性給藥，可改進反義分子以使得它們特異結合受體或在所選擇細胞表面上表達的抗原，例如使反義核酸分子與結合細胞表面受體或抗原的肽或抗體連接。也可利用在此所描述的載體將反義核酸分子遞送至細胞。為了獲得足夠胞內濃度的反義分子，其中將反義核酸分子放置在強pol II或pol III啟動子調控下的載體構建體是優選的。
在另一個實施方案中，本發明的反義核酸分子是α-端基異構核酸分子。α-端基異構核酸分子與互補RNA形成特異的雙鏈雜合物，其中與通常的β-單元相反，該鏈是相互平行的。反義核酸分子也可包括2′-o-甲基核糖核苷酸。
這種修飾包括，作為非限制性的實施例，修飾的堿基，以及修飾或衍生糖磷酸骨架的核酸。至少部分地進行這些修飾以增強修飾核酸的化學穩定性，以使得例如可使用它們作為受試個體的治療應用中的反義結合核酸。
BFLP0169核酶和PNA部分在另一個實施方案中，本發明的反義核酸是核酶。核酶是具有核糖核酸酶活性的催化RNA分子，其能夠切割對其具有互補區域的單鏈核酸，例如mRNA。因此，核酶(例如錘狀核酶)可用于催化切割BFLP0169 mRNA轉錄本而由此抑制BFLP0169 mRNA的翻譯。可根據在此公開的BFLP0169 DNA的核苷酸序列設計特異于編碼BFLP0169的核酸的核酶(即，SEQ ID NO1)。例如，可構建四膜蟲的L-19 IVS RNA的衍生物，其中活性位點的核苷酸序列與在編碼BFLP0169的mRNA中待切割的核苷酸序列是互補的。備選地，BFLP0169 mRNA可用于從RNA分子庫選擇具有特異核糖核酸酶活性的催化RNA。
備選地，可通過指導核苷酸序列互補于BFLP0169的調節區(例如BFLP0169啟動子和/或增強子)以形成三螺旋結構，防止BFLP0169基因在靶細胞中轉錄而抑制BFLP0169基因表達。
在不同的實施方案中，可在堿基部分、糖部分或磷酸酯骨架上對BFLP0169的核酸進行修飾以改善例如分子的穩定性、雜交作用或溶解度。例如，可改變核酸的脫氧核糖核苷磷酸酯骨架以產生縮氨酸核酸。如在此所使用的，術語″肽核酸″或″PNAs″是指核酸模擬物，例如DNA模擬物，其中脫氧核糖核苷磷酸酯骨架由假縮氨酸骨架替代而只保留4個天然的核堿基。已經顯示PNAs的中性骨架容許在低離子強度的條件下與DNA和RNA特異雜交。可利用標準的固相肽合成方法進行PNA低聚物的合成。
BFLP0169的PNAs可用于治療和診斷應用。例如，可使用PNAs作為通過例如誘導轉錄或翻譯停滯或抑制復制而序列特異地調節基因表達的反義或抗基因劑。BFLP0169的PNAs也可用于，例如，通過例如PNA指導的PCR定位而分析基因中單個堿基對的突變；當與其它酶，例如S1核酸酶組合時，作為人工的限制性內切酶；或作為用于DNA測序和雜交的探針或引物。
在另一個實施方案中，可修飾BFLP0169的PNAs，例如通過使親脂性或其它輔助基團附著于PNA、通過形成PNA-DNA嵌合體，或通過利用本領域已知的藥物遞送的脂質體或其它技術而增強其穩定性或細胞的攝取。例如，可產生可能組合PNA和DNA的有利特性的BFLP0169的PNA-DNA嵌合體。
寡核苷酸可包括其它的附加基團，例如肽(例如，用于體內導向宿主細胞受體)，或幫助轉運跨越細胞膜或血腦屏障的試劑。此外，可用雜交觸發裂解劑或插入劑對寡核苷酸進行修飾。所以，可以使寡核苷酸結合另一個分子，例如肽、雜交觸發交聯劑、轉運試劑、雜交觸發裂解劑等。
BFLP0169干擾核酸本發明也提供能夠介導BFLP0169基因表達的特異性抑制的分離雙鏈核酸(DNA或RNA)。在優選的實施方案中，雙鏈分子的一條或兩條鏈是RNA分子。優選地，每個RNA鏈長度為19-25個，特別是19-23個核苷酸，更特別的是20-22個核苷酸，并且能夠介導BFLP0169的靶特異性核酸修飾，特別是RNA干擾和/或DNA甲基化。雙鏈BFLP0169分子可以是雙鏈的或在5′和/或3′末端具有突出的末端。例如，該分子可具有3′突出。3-突出的長度可以是例如1-6個核苷酸、2-5個核苷酸、3-4個核苷酸或2個核苷酸。對于每個鏈該突出的長度可以是相同或不同的。在一個實施方案中，dsRNAs由2個成對的21個核苷酸鏈組成，以使得雙鏈RNA的兩個末端突出1、2、或3個核苷酸。
優選該RNA鏈具有3′-羥基。5′-末端優選包括磷酸酯、二磷酸、三磷酸或羥基。如果需要，可針對降解作用穩定化3′-突出。例如，可進行選擇以使得它們由嘌呤核苷酸，特別是腺苷酸或鳥嘌呤核苷核苷酸組成。備選地，可用修飾的類似物替換嘧啶核苷酸，例如容許由2-脫氧胸腺嘧啶核苷取代尿嘧啶核苷-2核苷酸3′突出，并且不影響RNA干擾的效能。RNA分子可包含至少一個修飾的核苷酸類似物。核苷酸類似物可位于基本上不影響靶特異活性，例如RNAi調節活性的位置。修飾的核苷酸優選存在于雙鏈RNA分子的5′-末端和/或3′-末端區域。在一些實施方案中，通過摻入修飾的核苷酸類似物穩定化突出。
核苷酸類似物可包括修飾糖-或骨架的核糖核苷酸。其它合適的核苷酸包括非天然存在的核酶而不是天然存在的核酶。例如，類似物可包括在5-位置修飾的尿嘧啶核苷或胞嘧啶，例如5-(2-氨基)丙基尿嘧啶核苷、5-溴基尿嘧啶核苷；在8-位置修飾的腺苷酸和鳥嘌呤核苷，例如8-溴基鳥嘌呤核苷；脫氮核苷酸，例如7-脫氮-腺苷酸；O-和N-烷基化的核苷酸，例如N6-甲基腺苷酸是合適的。在優選的糖修飾的核糖核苷酸中，以選自H、OR、R、鹵素、SH、SR、NH2、NHR、NR2或CN的基團替代2′OH-基團，其中R是C1-C6烷基、烯基或炔基，而鹵素是F、Cl、Br或I。在優選的實施方案中，使用修飾骨架的核糖核苷酸作為與鄰近的核糖核苷酸連接的磷酸酯基團，其以修飾的基團替代，例如硫代磷酸基團。應注意到可以組合上述修飾。
BFLP0169干擾RNA分子可以是天然的分離RNA分子或可以是合成的RNA分子。優選地，BFLP0169干擾RNA分子基本上不含存在于細胞抽提物中，例如來自果蠅胚胎的雜質。進一步的，BFLP0169干擾RNA分子優選基本上不含任何非靶特異性的雜質，特別是非靶特異的RNA分子，例如來自存在于細胞抽提物的雜質。
分離的雙鏈BFLP0169干擾分子可用于在哺乳動物細胞，特別是人細胞中介導BFLP0169靶特異的核酸修飾，特別是RNAi。
本發明的雙鏈BFLP0169干擾分子的序列具有與核酸BFLP0169靶分子足夠的同一性以便增強BFLP0169基因表達和/或DNA甲基化的靶特異性干擾。優選地，該序列與RNA分子雙鏈部分中所需要的靶分子具有至少50％，特別是至少70％的同一性。更優選地，在RNA分子的雙鏈部分中同一性是至少85％，以及最優選是100％。BFLP0169雙鏈干擾RNA分子與預定的核酸靶分子，例如具有SEQ ID NO1所示序列的BFLP0169mRNA靶分子的同一性可利用等式確定I＝(n/L)×100，其中I是同一性百分數，n是ds RNA和靶的雙鏈部分中相同核苷酸的數目，以及L是dsRNA和靶的雙鏈部分中序列重疊的長度。
備選地，也可限定雙鏈RNA分子相對于靶序列的同一性包括3′突出，特別是長度為1-3個核苷酸的突出。在這種情況下該序列與靶序列的同一性優選是至少50％，更優選至少70％，以及最優選至少85％。例如，可修飾從3′突出的核苷酸和直到雙鏈5′和/或3′末端的2個核苷酸而不使活性有顯著損失。
可通過包括合成每個長度為19-25，例如19-23個核苷酸的2條RNA鏈的方法制備雙鏈BFLP0169 RNA分子，其中所述的RNA鏈能夠形成雙鏈RNA分子，其中優選地至少一條鏈具有1-5個核苷酸的3′-突出，以及(b)在形成雙鏈RNA分子的條件下組合合成的RNA鏈。雙鏈RNA分子能夠介導靶特異性的核酸修飾，特別是RNA干擾和/或DNA甲基化。
合成RNA分子的方法是本領域已知的。也可通過從合成的DNA模板或從分離自重組細菌的DNA質粒進行酶促轉錄來制備單鏈RNAs。一般使用噬菌體RNA聚合酶，例如T7、T3或SP6 RNA聚合酶。
本發明進一步的方面涉及在細胞或生物體中通過將細胞或生物體與本發明的雙鏈RNA分子在可能發生靶特異性的核酸修飾的條件下接觸介導BFLP0169-特異的核酸修飾，特別是RNA干擾和/或DNA甲基化的方法，以及介導受到雙鏈RNA對BFLP0169靶核酸影響的靶特異性核酸修飾的方法。
BFLP0169多肽本發明的BFLP0169多肽包括SEQ ID NO2所提供的BFLP0169樣蛋白質。本發明也包括公開的BFLP0169多肽的突變體或變體形式，或在此公開的BFLP0169多肽序列的任何片段。
因此，BFLP0169多肽包括其中可從相應于SEQ ID NO2所示的殘基而變化任何殘基，同時仍然編碼保持其BFLP0169樣活性和生理功能的蛋白質，或其功能性片段的BFLP0169多肽。在一些實施方案中，在突變體或變體蛋白質中達到20％或更多的殘基的變化。在一些實施方案中，根據本發明的BFLP0169多肽是成熟多肽。
雷帕霉素結合結構域為了鑒定包含雷帕霉素結合結構域的BFLP0169多肽序列的區域(例如，包括所有或部分的SEQ ID NO2的多肽)，測試BFLP0169多肽序列的全部編碼序列或片段的結合雷帕霉素的能力。可使用本領域已知的用于確定多肽結合小分子的任何技術。例如，可標記雷帕霉素(即，用非放射性的標記或放射性標記(例如，14C、32P、3H或125I標記)，并且與包含一些或全部的BFLP0169多肽序列的多肽混合。任選地多肽包括便于檢測的部分，例如該多肽可以是包括BFLP0169序列和非BFLP0169多肽序列的融合多肽。
向混合物加入特異于包含BFLP0169多肽序列的多肽的試劑(例如就融合多肽來說，特異于BFLP0169的抗體或特異于非BFLP0169多肽的探針)。分離結合試劑的復合物，確定標記的存在，從而顯示存在雷帕霉素。
通常，保持BFLP0169樣功能的BFLP0169樣變體包括其中序列特定位置的殘基已經由其他氨基酸取代的任何變體，并且進一步包括插入附加殘基或親本蛋白質的2個殘基之間的殘基的可能性，從親本序列缺失一個或多個殘基的可能性。本發明包括任何氨基酸取代、插入或缺失。
在有利的情況中，取代是如上所限定的保守取代。
本發明的一個方面涉及分離的BFLP0169蛋白質，以及其生物活性部分，或其衍生物、片段、類似物或同系物。片段可包括SEQ ID NO2的連續的一段序列，或SEQ ID NO2的散在節段。也提供適合用作產生抗BFLP0169抗體的免疫原的多肽片段。在一個實施方案中，可通過適當的純化方案利用標準的蛋白質純化技術從細胞或組織來源分離天然的BFLP0169蛋白質。在另一個實施方案中，通過重組DNA技術產生BFLP0169蛋白質。對于重組表達的備選，可利用標準的肽合成技術化學合成BFLP0169蛋白質或多肽。
″純化的″蛋白質或其生物活性部分基本上不含細胞物質或來自從中衍生出BFLP0169蛋白質的細胞或組織來源的其它雜質蛋白質，或當化學合成時，基本上不含化學前體或其它化學品。術語″基本上不含細胞物質″包括BFLP0169蛋白質的制品，其中從分離或重組產生該蛋白質的細胞的細胞組分分離所述的蛋白質。在一個實施方案中，術語″基本上不含細胞物質″包括制備具有小于大約30％(以干重計)的非BFLP0169蛋白質(在此也稱為″污染蛋白質″)的BFLP0169蛋白質，更優選小于大約20％的非BFLP0169蛋白質，更優選地小于大約10％的非BFLP0169蛋白質，以及最優選地小于大約5％的非BFLP0169蛋白質。當BFLP0169蛋白質或其生物活性部分是重組產生的時，也優選基本上不含培養基，即，存在的培養基小于蛋白質制品體積的大約20％，更優選小于大約10％，以及最優選小于大約5％。
術語″基本上不含化學品前體或其它化學品″包括BFLP0169蛋白質的制品，其中該蛋白質是從涉及該蛋白質合成的化學品前體或其它化學品分離的。
在一個實施方案中，術語″基本上不含化學品前體或其它化學品″包括制備的BFLP0169蛋白質具有小于大約30％(以干重計)的化學品前體或非BFLP0169化學品，更優選地小于大約20％的化學品前體或非BFLP0169化學品，更優選地小于大約1 0％的化學品前體或非BFLP0169化學品，以及最優選地小于大約5％的化學品前體或非BFLP0169化學品。
BFLP0169蛋白質的生物活性部分包括包含與BFLP0169蛋白質的氨基酸序列，例如SEQ ID NO2所示的氨基酸序列足夠同源或來源于該BFLP0169蛋白質氨基酸序列的肽，其包括少于全長的BFLP0169蛋白質的氨基酸，并且顯示出BFLP0169蛋白質的至少一種活性。一般生物活性部分包括具有BFLP0169蛋白質的至少一種活性的結構域或基序。BFLP0169蛋白質的生物活性部分可以是長度為例如10、25、50、100或更多個氨基酸的多肽。
本發明的BFLP0169蛋白質的生物活性部分可包含BFLP0169蛋白質中間的至少一個上述鑒定的保守結構域。此外，可通過重組技術以及評估天然BFLP0169蛋白質的一種或多種功能活性來制備刪除蛋白質其它區域的其它生物活性部分。
在一個實施方案中，BFLP0169蛋白質具有SEQ ID NO2所示的氨基酸序列。在其他的實施方案中，BFLP0169蛋白質是與SEQ ID NO2基本上同源的，并且保持SEQ ID NO2的蛋白質的功能活性，然而由于天然的等位變體或誘變而在氨基酸序列上有差異，如下進行詳細描述。因此，在另一個實施方案中，BFLP0169蛋白質是包含與SEQ IDNO2的氨基酸序列至少大約45％同源的氨基酸序列，并且保持SEQID NO2的BFLP0169蛋白質功能活性的蛋白質。
確定兩個或多個序列之間的同源性為了確定2個氨基酸序列或2個核酸序列的同源性百分數，將序列排序以進行最佳比較(例如，可在待進行序列間的最佳序列對比的任何一個序列中導入缺口)。然后比較相應氨基酸位置或核苷酸位置的氨基酸殘基或核苷酸。當第一個序列的一個位置被與第二個序列中相應位置的相同氨基酸殘基或核苷酸占據時，則在該位置分子是同源的(即，如在此所使用的，氨基酸或核酸″同源性″相當于氨基酸或核酸的″同一性″)。
可確定核酸序列的同源性作為2個序列之間同一性的程度。可利用該領域已知的計算機程序確定同源性，例如GCG程序包中提供的GAP軟件。利用GCG缺口軟件，其用于核酸序列比較的設置如下缺口產生罰分為5.0，缺口延伸罰分為0.3，參考上述的類似核酸序列的編碼區與SEQ ID NO1所示的DNA序列CDS(編碼)部分顯示的同一性程度優選為至少70％、75％、80％、85％、90％、95％、98％、或99％。
術語″序列同一性″是指在特定區域比較的逐個殘基的堿基上2個多核苷酸或多肽序列相同的程度。術語″序列同一性的百分比″是如下計算的比較在比較區域進行最佳排列的2個序列，確定在兩個序列中存在相同核酸堿基的位置的數目(例如，就核酸來說為A、T、C、G、U、I)，以產生相配位置的數目，將相配位置的數目除以比較區域中位置的總數(即讀框的大小)，并且將結果乘以100以產生序列同一性的百分比。如在此所使用的術語″基本上的同一性″表示多核苷酸序列的特征，其中該多核苷酸包含與對照序列就比較區域相比，具有至少80％序列同一性，優選至少85％同一性，以及經常為90％至95％序列同一性，更通常為至少99％序列同一性的序列。術語″陽性殘基的百分比″是如下計算的比較在比較區域進行最佳排列的2個序列，確定在兩個序列中存在相同的和如上所限定的保守氨基酸取代的位置的數目以產生相配位置的數目，將相配位置的數目除以比較區域中位置的總數(即，讀框大小)，并且將結果乘以100以產生陽性殘基的百分比。
嵌合和融合的蛋白質本發明也提供BFLP0169嵌合或融合的蛋白質。如在此所使用的，BFLP0169″嵌合蛋白質″或″融合蛋白質″包括與非BFLP0169多肽可操作連接的BFLP0169多肽。″BFLP0169多肽″是指具有相應于BFLP0169的氨基酸序列的多肽，而″非BFLP0169多肽″是指具有相應于基本上不與BFLP0169蛋白質同源的蛋白質，例如不同于BFLP0169蛋白質以及來源于相同或不同生物體的蛋白質的氨基酸序列的多肽。在BFLP0169融合蛋白內，BFLP0169多肽可相應于BFLP0169蛋白質的全部或部分。BFLP0169融合蛋白多肽的實例是該多肽包括SEQ IDNO2的第21-230位氨基酸(例如，包括SEQ ID NO2的第1-246位氨基酸或第21-246位氨基酸的多肽)。在一個實施方案中，BFLP0169融合蛋白包括BFLP0169蛋白質的至少一個生物活性部分。在另一個實施方案中，BFLP0169融合蛋白包括BFLP0169蛋白質的至少2個生物活性部分。在融合蛋白內，術語″可操作地連接″是用來表明BFLP0169多肽和非BFLP0169多肽是在讀框中相互融合的。非BFLP0169多肽可融合到BFLP0169多肽的N-末端或C-末端。
例如，在一個實施方案中，BFLP0169融合蛋白包括與第二蛋白質，即非BFLP0169蛋白質的胞外結構域，或第二蛋白質，即非BFLP0169蛋白質的跨膜和胞內結構域可操作連接的BFLP0169多肽。這種融合蛋白可進一步用于篩選調節BFLP0169活性的化合物的分析(下文中將詳細描述這種分析)。
在另一個實施方案中，融合蛋白是GST-BFLP0169融合蛋白，其中BFLP0169序列融合到GST序列(即，谷胱甘肽S-轉移酶)的C末端。這種融合蛋白可有助于純化重組的BFLP0169。
在另一個實施方案中，融合蛋白是BFLP0169-免疫球蛋白融合蛋白，其中包括一個或多個結構域的BFLP0169序列與來源于免疫球蛋白家族成員的序列融合。
BFLP0169配體/BFLP0169相互作用的抑制可治療性地用于增殖和分化紊亂，例如癌癥的治療，通過改變細胞因子和趨化因子級聯機理調節(例如促進或抑制)細胞存活以及治療免疫調節紊亂，自身免疫、移植和炎癥。此外，本發明的BFLP0169-免疫球蛋白的融合蛋白可用作免疫原以在受試個體中產生抗-BFLP0169的抗體，來純化BFLP0169配體，并用于篩選分析來鑒定抑制BFLP0169與BFLP0169配體相互作用的分子。
可通過標準的重組DNA技術產生本發明的BFLP0169嵌合或融合蛋白。例如，根據常規方法，例如使用鈍末端或交錯末端連接，進行限制性內切酶消化以提供適當的末端，酌情補平粘末端，堿性磷酸酶處理以避免不合需要的連接，并進行酶促連接而將編碼不同多肽序列的DNA片段在讀框內連接在一起。在另一個實施方案中，可通過常規方法，包括自動化的DNA合成儀合成融合基因。備選地，可利用在2個連續的基因片段之間產生互補突出的錨定引物進行基因片段的PCR擴增，隨后可進行退火和再擴增以產生嵌合的基因序列。
此外，已經編碼融合蛋白的許多表達載體是可商購的(例如，GST多肽)。可將編碼BFLP0169的核酸克隆到這種表達載體中，以使得融合部分在讀框內與BFLP0169蛋白質連接。
如果需要，可使用BFLP0169蛋白質編碼序列片段的文庫來產生BFLP0169片段的多樣化群體而用于篩選和后繼的選擇BFLP0169蛋白質的變體。
BFLP0169抗體本發明也包括針對BFLP0169蛋白質或BFLP0169蛋白質片段的抗體。如在此所使用的術語″抗體″是指免疫球蛋白分子和免疫球蛋白(Ig)分子的免疫活性部分，即包含特異結合(免疫反應)抗原的抗原結合位點的分子。這種抗體包括但不限于，多克隆、單克隆、嵌合、單鏈、Fab、Fab′和F(ab′)2片段、以及Fab表達文庫。通常，獲得自人的抗體分子涉及任何種類的IgG、IgM、IgA、IgE和IgD，其相互之間由于存在于分子中的重鏈的特性而不同。某些種類也具有亞類，例如，IgG1、IgG2等。此外在人中，輕鏈可以是κ鏈或λ鏈。在此參考的抗體包括參考所有這些種類、亞類和類型的人抗體種類。
本發明的分離BFLP0169相關蛋白質可用作抗原或其部分或片段，并且另外可利用多克隆和單克隆抗體制備的常規技術，用作免疫原以產生特異地免疫結合該抗原的抗體。可使用全長的蛋白質，或備選地，本發明提供用作免疫原的抗原的抗原性肽片段。抗原性的肽片段包括全長蛋白質氨基酸序列，例如SEQ ID NO2所示的氨基酸序列的至少6個氨基酸殘基，并且包括其表位，以使得產生的針對肽的抗體與全長蛋白質或與包含表位的任何片段形成特異的免疫復合物。優選地，抗原性的肽包括至少10個氨基酸殘基，或至少15個氨基酸殘基，或至少20個氨基酸殘基，或至少30個氨基酸殘基。抗原性肽包括的優選表位是位于其表面的蛋白質的區域；通常是親水的區域。
在本發明的某些實施方案中，抗原性肽包括至少一個表位是BFLP0169相關蛋白質的位于蛋白質表面的區域，例如親水的區域。人BFLP0169相關蛋白質序列的疏水性分析將表明BFLP0169相關蛋白質的哪些區域是特別親水的，并且因此很可能編碼可用于靶抗體生產的表面殘基。作為靶抗體生產的方式，親水性曲線圖顯示可通過本領域公知的任何方法產生親水性和疏水性的區域，包括例如伴隨有或沒有Fourier變換法的Kyte Doolittle或Hopp Woods方法。產生關于BFLP0169蛋白質的Kylte和Doolitle曲線圖，并如下列表5所示。
表5.BFLP0169的Kyte和Doolittle曲線圖 本發明的編碼BFLP0169蛋白質的新核酸或其片段可進一步用于評估核酸或蛋白質的存在或數量的診斷應用。這些材料進一步可用于產生特異地免疫結合本發明的新物質的抗體而用于治療或診斷方法。公開的BFLP0169蛋白質具有多個親水區域，每個都可用作免疫原。在一個實施方案中，預期BFLP0169表位是大約第20至90位氨基酸。在另一個實施方案中，預期BFLP0169表位是大約第100至130位氨基酸。在另外的實施方案中，BFLP0169表位是大約第140至220位氨基酸、大約第240至250位氨基酸、大約第280至290位氨基酸、大約第330至340位氨基酸、大約第370至380位氨基酸、大約第400至410位氨基酸、大約第450至520位氨基酸、大約第530至540位氨基酸、大約第640至650位氨基酸、大約第720至730位氨基酸、大約第800至820位氨基酸、大約第850至855位氨基酸、大約第900至910位氨基酸、大約第920至930位氨基酸、大約第940至950位氨基酸、大約第970至990位氨基酸、大約第1000至1030位氨基酸、大約第1060至1080位氨基酸、大約第1100至1110位氨基酸、大約第1170至1180位氨基酸、大約第1190至1210位氨基酸、大約第1250至1280位氨基酸、大約第1310至1320位氨基酸、大約第1350至1370位氨基酸、大約第1400至1420位氨基酸、大約第1430至1440位氨基酸、大約第1500至1560位氨基酸、大約第1600至1610位氨基酸、大約第1650至1690位氨基酸、大約第1700至1710位氨基酸、以及大約第1720至1730位氨基酸。
在此也提供特異于抗原性蛋白質、或其衍生物、片段、類似物或同系物內的一個或多個結構域的抗體。
本發明的蛋白質，或其衍生物、片段、類似物、同系物或直向同源物可用作產生特異地免疫結合這些蛋白質成分的抗體中的免疫原。
本領域內已知的多種方法可用于生產直接針對本發明蛋白質、或針對其衍生物、片段、類似物、同系物或直向同源物的多克隆或單克隆抗體。術語″單克隆抗體″(MAb)或″單克隆抗體組合物″，如在此所使用的，是指只包含由唯一的輕鏈基因產物和唯一的重鏈基因產物組成的抗體分子的一個分子種類的抗體分子群。
直接針對本發明的蛋白質抗原的抗體可進一步包括人化的抗體或人抗體。人化形式的抗體包括嵌合的免疫球蛋白、免疫球蛋白鏈或其片段(例如Fv、Fab、Fab′、F(ab′)2或抗體的其它抗原結合亞序列)，其主要由人免疫球蛋白的序列組成，并且包含來源于非人免疫球蛋白的最小序列。
抗體也可以是人抗體，例如其中輕鏈和重鏈，包括CDRs的基本上全部序列都由人基因產生。
可通過三源雜交瘤技術、人B細胞雜交瘤技術和EBV雜交瘤技術制備人單克隆抗體。
也可利用噬菌體展示文庫，或通過將人免疫球蛋白基因座導入轉基因動物，例如內源免疫球蛋白基因已經部分或完全失活的小鼠中而產生人抗體。另外可利用修飾的轉基因非人類的動物產生人抗體，以便產生完全地人抗體而不是通過抗原激發而應答產生的動物內源抗體。
本發明也提供特異于本發明的抗原性蛋白質的單鏈抗體。此外，可改進方法使其適合于構建Fab表達文庫以容許快速和有效的鑒定具有針對蛋白質或其衍生物、片段、類似物或同系物的所需要特異性的單克隆Fab片段。可通過本領域已知的技術產生包含針對蛋白質抗原的個體基因型的抗體片段，包括但不限于(i)通過胃蛋白酶消化抗體分子而產生的F(ab′)2片段；(ii)通過還原F(ab′)2片段的二硫橋產生的Fab片段；(iii)通過用木瓜蛋白酶和還原劑處理抗體分子產生的Fab片段以及(iv)Fv片段。
本發明也提供雙特異性的抗體。雙特異性抗體是單克隆的，優選人或人化的抗體，其具有針對至少2種不同抗原的結合特異性。一個結合特異性是針對本發明的抗原性蛋白質。第二結合靶任何其它抗原，以及有益地是細胞表面蛋白質或受體或受體亞基。
如果需要，具有所需要的結合特異性(抗體-抗原結合部位)的抗體可變域可與免疫球蛋白的恒定結構域序列融合。優選與至少包括部分的鉸鏈、CH2、和CH3區域的免疫球蛋白的重鏈恒定結構域融合。優選具有包含存在于至少一個融合體中為輕鏈結合所必需的位點的第一重鏈恒定區(CH1)。
可提供作為全長抗體或抗體片段的雙特異性抗體(例如F(ab′)2雙特異性抗體)。
本發明也包括具有多于2價的抗體(例如三特異性抗體)。
例證性的雙特異性抗體結合2個不同的表位，其中至少一個起源于本發明的蛋白質抗原。
本發明也包括異共軛配合物抗體，其包括2個共價連接的抗體。
可修飾本發明的抗體以改變(例如，增強或減弱)其功能。例如，可將半胱氨酸殘基導入Fc區域，由此容許在這個區域中形成鏈間二硫鍵。本發明也包括包含與細胞毒素試劑，例如化療劑、毒素(例如，細菌、真菌、植物、或動物來源的酶促活性毒素，或其片段)、或放射性同位素(即，放射性共軛物)共軛的抗體的免疫共軛物。
可使用的酶促活性的毒素及其片段包括白喉A鏈、白喉毒素的非結合活性片段、外毒素A鏈(來自綠膿假單胞菌)、蓖麻毒A鏈、相思豆毒素A鏈、蒴蓮根毒素A鏈、α-八疊球菌素、油桐蛋白質、石竹素蛋白質、美國商陸蛋白質(PAPI、PAPII、和PAP-S)、苦瓜抑制劑、麻風樹毒蛋白、巴豆毒素、sapaonaria officinalis抑制劑、白樹毒素、米托潔林、局限曲菌素、酚霉素、伊諾霉素、和tricothecenes。對于生產放射性共軛物的抗體多種放射性核素是有效的。實例包括212Bi、131I、131In、90Y、和186Re。
抗體可與″受體″共軛(例如鏈霉抗生物素)而用于腫瘤的預導向，其中將抗體受體共軛物施用于患者，然后利用清除劑從循環除去未結合的共軛物，然后施用隨后結合細胞毒素試劑的″配體″(例如，抗生物素蛋白)。
BFLP0169重組表達載體和宿主細胞本發明的另一個方面涉及載體，優選包含編碼BFLP0169蛋白質，或其衍生物、片段、類似物或同系物的核酸的表達載體。如在此所使用的，術語″載體″是指能夠轉運已經連接的另一個核酸的核酸分子。一個類型的載體是″質粒″，其是指其中可連接附加的DNA節段的環狀雙鏈DNA環。另一類型的載體是病毒載體，其中附加的DNA節段可連接到病毒基因組中。某些載體能夠在其被導入的宿主細胞中自發復制(例如，具有細菌復制原點的細菌載體和游離基因的哺乳動物載體)。將其它載體(例如，非游離基因哺乳動物載體)在導入到宿主細胞中時整合到宿主細胞的基因組中，并由此與其整合的宿主基因組序列一起復制。此外，某些載體能夠指導與其進行可操作地連接的基因進行表達。這種載體在此稱為″表達載體″。″質粒″和″載體″可互換使用，因為質粒是載體最通常使用的形式。然而，本發明旨在包括這種其它形式的表達載體，例如病毒載體(例如，復制缺陷型反向病毒、腺病毒和腺伴隨病毒)，其發揮相等的功能。
在重組表達載體內，″可操作地連接″是指將令人感興趣的核苷酸序列與調節序列連接，其連接方式允許核苷酸序列的表達(例如，在體外轉錄/翻譯系統或當將載體導入宿主細胞時，在宿主細胞中表達)。術語″調節序列″旨在包括啟動子、增強子和其他表達控制元件(例如，多聚腺苷酸信號)。調節序列包括在許多類型的宿主細胞中指導核苷酸序列組成性表達，以及只在某些宿主細胞中指導核苷酸序列表達的調節序列(例如，組織特異性調節序列)。可將本發明的表達載體導入宿主細胞，由此產生蛋白質或肽，包括由如在此所描述的核酸編碼的融合蛋白或肽(例如，BFLP0169蛋白質、BFLP0169蛋白質的突變體形式、融合蛋白等)。
本發明的重組表達載體可設計成在原核或真核細胞中表達BFLP0169蛋白質。例如，BFLP0169蛋白質可以在細菌細胞，例如大腸桿菌，昆蟲細胞(利用桿狀病毒表達載體)、酵母細胞或哺乳動物細胞中表達。備選地，可例如利用T7啟動子調節序列和T7聚合酶體外轉錄和翻譯重組表達載體。
在另一實施方案中，利用哺乳動物表達載體在哺乳動物中表達本發明的核酸。哺乳動物表達載體的實例包括pCDM8和pMT2PC。當用于哺乳動物細胞時，經常由病毒調控元件提供表達載體的控制功能。例如，通常所使用的啟動子來源于多形瘤、腺病毒2、巨細胞病毒、和猿猴病毒40。對于其它合適的表達系統適于原核和真核細胞。
在另一個實施方案中，重組的哺乳動物表達載體能夠優選在特定的細胞類型中指導核酸的表達(例如，使用組織特異性調控元件表達核酸)。組織特異性調控元件是本領域已知的。合適的組織特異性啟動子的非限制性實例包括白蛋白啟動子(肝特異性)、淋巴特異性啟動子、特別是T細胞受體和免疫球蛋白的啟動子、神經元特異性啟動子(例如，神經絲啟動子)、胰腺特異性啟動子，和乳腺特異性啟動子(例如，牛奶乳清啟動子)。也包括發育性調控啟動子，例如鼠的hox啟動子和α-甲胎蛋白啟動子。
本發明進一步提供包括以反義方向克隆到表達載體中的本發明DNA分子的重組表達載體。也就是說，使DNA分子以容許表達與BFLP0169 mRNA反義的RNA分子的方式(通過DNA分子的轉錄)可操作地連接調控序列。可選擇可操作地與以反義方向克隆的核酸連接的調控序列來指導反義RNA分子在多種細胞類型中連續表達，例如病毒啟動子和/或增強子，或可選擇調控序列來指反義RNA的組成性、組織特異的或細胞類型特異性表達。反義表達載體可以是重組質粒、噬菌粒或減毒病毒的形式，其中在高效調控區域的控制下產生反義核酸，可通過導入載體的細胞類型來確定其活性。
本發明的另一個方面涉及已經導入本發明的重組表達載體的宿主細胞。術語″宿主細胞″和″重組宿主細胞″在此是可互換使用的。可以理解這個術語不僅是指特定的受試個體細胞而且是指這種細胞的后代或潛在后代。因為由于突變或環境影響在后繼的世代中可能存在某些改變，實際上這種后代可能與親本細胞未必相同，但是仍然包括在在此所使用的術語的范圍內。
宿主細胞可以是任何的原核或真核細胞。例如，可在細菌細胞中表達BFLP0169蛋白質，例如大腸桿菌、昆蟲細胞酵母或哺乳動物細胞(例如人，中國倉鼠卵巢細胞(CHO)或COS細胞)。其他合適的宿主細胞是本領域技術人員公知的。
一般將編碼可選擇的標記(例如抗生素的抗藥性)的基因與令人感興趣的基因一起導入宿主細胞。多種可選擇的標記包括賦予抗藥性，例如G418、潮霉素和氨甲蝶呤抗性的標記。可在與編碼BFLP0169的載體相同的載體上，將編碼可選擇標記的核酸導入宿主細胞，或可在分開的載體上導入。可通過藥物選擇鑒定用導入的核酸穩定轉染的細胞(例如，具有整合的可選擇標記基因的細胞將存活，而其它的細胞將死亡)。
本發明的宿主細胞，例如培養中的原核或真核宿主細胞，可用于生產(即表達)BFLP0169蛋白質。因此，本發明進一步提供利用本發明的宿主細胞生產BFLP0169蛋白質的方法。在一個實施方案中，該方法包括在合適的培養基中培養本發明的宿主細胞(其中已經導入了編碼BFLP0169蛋白質的重組表達載體)，以生產BFLP0169蛋白質。在另一個實施方案中，該方法進一步包括從培養基或宿主細胞分離BFLP0169蛋白質。
轉基因的BFLP0169動物本發明的宿主細胞也可用來生產非人的轉基因動物。例如，在一個實施方案中，本發明的宿主細胞是已經導入編碼BFLP0169蛋白質的序列的受精卵母細胞或胚胎干細胞。然后這種宿主細胞可用于產生其中已經在其基因組中導入外源BFLP0169序列的非人轉基因動物或其中已經改變了內源BFLP0169序列的同源重組動物。這種動物可用于研究BFLP0169蛋白質的功能和/或活性，并用于鑒定和/或評估BFLP0169蛋白質活性的調節劑。如在此所使用的，″轉基因的動物″是非人的動物，優選哺乳動物，更優選嚙齒類，例如大鼠或小鼠，其中該動物的一種或多種細胞包括轉基因。轉基因動物的其它實例包括非人的靈長類、綿羊、狗、牛、山羊、雞、兩棲類等。轉基因是整合到來自發育的轉基因動物的細胞基因組中，并且保持在成熟動物的基因組中的外源性DNA，由此在轉基因動物的一個或多個細胞類型或組織中指導編碼基因產物的表達。如在此所使用的，″同源的重組動物″是非人的動物，優選哺乳動物，更優選小鼠，其中已經通過在內源基因和在動物發育前導入動物細胞，例如動物的胚細胞的外源性DNA分子之間的同源重組而改變了內源的BFLP0169基因。
可通過將編碼BFLP0169的核酸導入到受精卵母細胞的精原核中(例如，通過微注射、反向病毒感染)，并容許卵母細胞在假孕的雌性哺育動物中發育產生本發明的轉基因動物。可將包括SEQ ID NO1的序列作為轉基因導入非人動物的基因組中。備選地，可根據與人BFLP0169cDNA(上文所述)的雜交作用分離人BFLP0169基因的非人同系物，例如小鼠BFLP0169基因，并用作轉基因。內含子序列和多聚腺苷酸信號也可包括在轉基因內以增加轉基因表達的效力。可將組織特異性調控序列可操作地與BFLP0169轉基因連接以指導BFLP0169蛋白質至特定的細胞表達。借助于胚胎操作和微注射產生轉基因動物，特別是例如小鼠的動物的方法已經成為本領域的常規方法。類似的方法可用于產生其它的轉基因動物。可根據其基因組中BFLP0169轉基因的存在和/或該動物的組織或細胞中BFLP0169mRNA的表達鑒定轉基因的建立動物。然后轉基因的建立動物可用來繁殖攜帶該轉基因的附加動物。此外，可進一步使攜帶編碼BFLP0169蛋白質的轉基因的轉基因動物與攜帶其他轉基因的其它轉基因動物進行繁殖。
為了產生同源的重組動物，所制備的載體包含至少部分的BFLP0169基因，而該基因中已經導入了缺失、添加或取代，由此改變，例如功能性破壞BFLP0169基因。BFLP0169基因可以是人基因(例如，SEQ ID NO1的DNA)，但更優選地是人BFLP0169基因的非人同系物。
例如，SEQ ID NO1的人BFLP0169基因的小鼠同系物可用于構建適于改變小鼠基因組中的內源BFLP0169基因的同源重組載體。在一個實施方案中，設計該載體以使得在同源重組時，內源的BFLP0169基因功能性斷裂(即，不再編碼功能蛋白；也稱為″敲除″載體)。
備選地，可設計該載體以使得在同源重組時，內源的BFLP0169基因突變或其它改變，但仍編碼功能蛋白(例如，可改變上游調控區由此改變內源BFLP0169蛋白質的表達)。在同源的重組載體中，BFLP0169基因的改變部分是BFLP0169基因附加核酸5′-和3′-末端側翼的部分，以容許同源重組發生在由載體攜帶的外源BFLP0169基因和胚胎干細胞的內源BFLP0169基因之間。BFLP0169核酸的附加側翼對于與內源基因的成功同源重組具有足夠的長度。一般DNA側翼的幾千個堿基(在5′和3′-末端)包括在載體中。然后將載體導入胚胎干細胞系(例如，通過電穿孔)，并且選擇導入的BFLP0169基因已經與內源的BFLP0169基因同源重組的細胞。
然后將所選擇的細胞注射到動物(例如小鼠)的胚囊中以形成聚集的嵌合體。然后可將嵌合的胚胎移植到合適的假孕雌性哺育動物中，并且使胚胎生長至妊娠期滿。使同源重組的DNA停泊在其生殖細胞中的后代可用于繁殖其中該動物的所有細胞通過生殖系傳輸該轉基因而都包含同源重組的DNA的動物。
在另一個實施方案中，可產生轉基因的非人動物，其包含容許轉基因的調控表達的選擇系統。這種系統的一個實例是細菌噬菌體P1的cre/loxP重組酶系統。關于cre/loxP重組酶系統的說明。重組酶系統的另一個實例是釀酒酵母的FLP重組酶系統。如果使用cre/loxP重組酶系統調節轉基因的表達，需要包含編碼Cre重組酶和選擇蛋白質的轉基因的動物。可通過構建″雙″轉基因的動物，例如通過使2種轉基因動物交配來提供這種動物，其中一種包含編碼選擇蛋白質的轉基因，而另一種包含編碼重組酶的轉基因。
也可根據本領域所描述的方法生產在此所描述的非人轉基因動物的克隆。
簡言之，可從轉基因的動物分離細胞(例如體細胞)，并誘導至離開生長周期而進入Go期。然后例如通過使用電脈沖使休眠細胞與來自分離休眠細胞的相同種類動物的卵母細胞融合。然后培養重構的卵母細胞，以使得其發育至桑椹胚或胚細胞，然后轉入假孕的雌性哺育動物。這雌性哺育動物生產的后代將成為分離該細胞(例如體細胞)的動物的克隆。
檢測BFLP0169核酸和診斷狼瘡腎炎的方法檢測BFLP0169核酸和/或多肽的試劑可用于檢測樣品中BFLP0169RNA和/或蛋白質序列的水平。因為在患有狼瘡腎炎的動物中發現BFLP0169 RNA水平升高，檢測到BFLP0169 RNA和/或BFLP0169多肽水平增強表明受試個體中存在狼瘡或易患狼瘡的體質。此外，與未經治療狼瘡的相比，治療狼瘡的受試個體中BFLP0169 RNA的水平降低表明恢復到非狼瘡狀態。因此，可通過與患病但未經治療的樣品(或來自已經短期治療過的個體的樣品)比較，來自治療群體的樣品中BFLP0169 RNA或蛋白質的水平監測狼瘡治療的效果。
可通過與已知狼瘡狀態的參考細胞群的水平比較來自未知狼瘡狀態的受試個體的測試細胞群中的水平來評估BFLP0169 RNA的水平。因此，一般測試細胞群將包括能夠表達BFLP0169基因的至少一個細胞。″能夠表達″是指該基因以完整的形式存在于細胞中，并且可以表達。然后檢測BFLP0169序列的表達，如果存在，優選地利用本領域已知的方法測量。例如，在此公開的BFLP0169序列可用于構建在例如northern印跡雜交分析或特異地并且優選地定量擴增BFLP0169特異性核酸序列的方法中檢測BFLP0169 RNA序列的探針。備選地，該序列可用于構建在例如，基于擴增的檢測方法，例如基于逆轉錄的聚合酶鏈式反應中用于特異擴增BFLP0169序列的引物。
也可在蛋白質水平，即通過測量BFLP0169多肽的水平來測量BFLP0169表達。這種方法是本領域已知的，包括例如基于針對由該基因編碼的蛋白質的抗體的免疫測定。
可利用任何本領域公認用于比較核酸序列表達的方法來比較測試和對照細胞群體中序列的表達。在測試細胞群對參照細胞群的基因表達圖譜的比較中是否顯示測量參數的存在或程度取決于參照細胞群的組成。例如，如果參照細胞群由來自沒有狼瘡的受試個體的細胞組成，測試細胞群和參照細胞群中類似的基因表達水平表明測來自于沒有狼瘡的受試個體。相反地，如果參照細胞群由來自患病的受試個體的細胞組成，測試細胞群和參照細胞群之間類似的基因表達圖譜表明測試細胞群來自于患有狼瘡的受試個體。
在多種實施方案中，如果測試細胞群的表達水平比參照細胞群中BFLP0169轉錄本的水平變化在2.0、1.5、或1.0倍的系數內，則認為測試細胞群中BFLP0169序列與參照細胞群中ADIPO序列的表達水平相當。在多種實施方案中，如果測試細胞群的表達水平比參照細胞群體中相應的BFLP0169序列表達水平變化大于1.0、1.5、2.0以上的倍數，則認為測試細胞群體中BFLP0169序列在表達水平發生改變。
如果需要，相對于其表達與測量的參數或條件無關的對照核酸，可比較測試細胞群和參照細胞群之間差異表達的序列。測試和參照核酸中對照核酸的表達水平可用于校正所比較的群體中的信號水平。本領域的普通技術人員可容易地確定合適的對照核酸。
在一些實施方案中，測試細胞群與多個參照細胞群進行比較。每一多重的參照群體可能在已知的參數中有差異。因此，測試細胞群可與來自已知患有狼瘡的受試個體的第一參照細胞群，以及已知不患有狼瘡的第二參照群進行比較。
所暴露的測試細胞群可以是任何數目的細胞，即一個或多個細胞，并且可以是體外、體內或自體內提供的。
優選地，參照細胞群中的細胞來源于與測試細胞盡可能類似的組織類型，例如腎組織。在一些實施方案中，對照細胞來源于與測試細胞相同的受試個體。在其他的實施方案中，參照細胞群來源于來自多個受試個體的細胞多元群。例如，參照細胞群可以是來自先前測試細胞的表達模式的數據庫。
受試個體優選是哺乳動物。哺乳動物可以是例如人、非人靈長類、小鼠、大鼠、狗、貓、馬或牛。
藥物組合物本發明的BFLP0169核酸分子、BFLP0169蛋白質、和抗BFLP0169(在此也稱為″活性化合物″)，以及其衍生物、片段、類似物和同系物，可摻入到適于給藥的藥物組合物中。這種組合物一般包括核酸分子、蛋白質、或抗體和藥物學上可接受的載體。如在此所使用的，″藥物學上可接受的載體″旨在包括與藥物給藥相適應的任何和所有的溶劑，分散介質、包衣、抗細菌劑和抗真菌劑、等滲劑和吸收延遲劑等。在最近出版的Remington′s Pharmaceutical Sciences，本領域的標準參考教科書中描述了合適的載體，其在此引入作為參考。這種載體或稀釋劑的優選實例包括但不限于水、鹽水、Ringer′s溶液、葡萄糖溶液、和5％的人血清白蛋白。也可使用脂質體和無水的溶劑，例如固定油類。這種介質和試劑用作藥物學上的活性物質是本領域公知的。
除非任何常規的介質或試劑與該活性化合物不相容，否則將其使用在組合物中是可以預料得到的。也可將輔助的活性化合物摻入到組合物中。
配制本發明的藥物組合物以與其預定的給藥途徑相適應。給藥途徑的實例包括非胃腸道的，例如靜脈內的、皮內的、皮下的、口服的(例如吸入)、透過皮膚的(即局部的)、轉化粘液質的和直腸給藥。
適合注射用途的藥物組合物包括無菌的水溶液(水溶性的)或分散劑和用于臨時制備無菌的可注射溶液或分散劑的無菌粉劑。
如在此所使用的劑量單位形式是指對待治療的受試者適合作為單一劑量的物理上非連續的單位；每種單位包含經計算的預先確定量的活性化合物以產生與要求的藥物載體相應的所需治療效果。本發明劑量單位形式的規格決定于和直接依賴于活性化合物的獨特特性和所需獲得的特定治療效果，以及在化合物領域中這種活性化合物對于個體治療所固有的局限性。
可制備持續釋放的制劑。持續釋放制劑的合適實例包括包含抗體的固體疏水性聚合物的半透性基質，其中基質是加工成形的物品形式，例如薄膜或微膠囊。持續釋放基質的實例包括聚酯、水凝膠(例如，聚(2-羥乙基-異丁烯酸)、或聚(乙烯醇))、聚交酯、L-谷氨酸和γ乙基-L-谷氨酸的共聚物、不可降解的乙烯-醋酸乙烯酯、可降解的乳酸-羥基乙酸共聚物，例如LUPRON DEPOTTM(由乳酸-羥基乙酸共聚物和醋酸亮丙瑞林乙酸酯組成的可注射的微球體)、和聚-D-(-)-3-羥丁酸。當聚合物，例如乙烯-醋酸乙烯酯和乳酸-羥基乙酸能夠釋放分子100天時，某些水凝膠釋放蛋白質較短的時間段。
該藥物組合物可被包括在與給藥說明一起的容器、包裝或分散劑中。
篩選和檢測方法本發明的分離核酸分子可用于表達BFLP0169蛋白質(例如借助于基因治療應用的宿主細胞中的重組表達載體)，以檢測BFLP0169mRNA(例如，在生物樣品中)或BFLP0169基因中的遺傳學病變，以及調節BFLP0169活性，如下進行進一步的描述。此外，BFLP0169蛋白質可用于篩選調節BFLP0169蛋白質活性或表達，以及治療病癥的藥物或化合物，其中該病癥的特征是產生的BFLP0169蛋白質不足或過量、或與BFLP0169野生型蛋白質相比，產生活性降低或異常的BFLP0169蛋白質形式。此外，本發明的抗BFLP0169抗體可用于檢測和分離BFLP0169蛋白質以及調節BFLP0169活性。例如，BFLP0169活性包括T細胞或NK細胞的生長和分化、抗體產生和腫瘤生長。
本發明進一步涉及通過在此所描述的篩選分析鑒定的新試劑及其用于如上所述的治療的用途。
篩選分析本發明提供用于鑒定結合BFLP0169蛋白質或對例如BFLP0169蛋白質表達或BFLP0169蛋白質活性具有刺激或抑制效果的調節劑，即候選或測試化合物或試劑(例如、肽、肽模擬物、小分子或其它藥物)的方法(在此也稱為″篩選分析″)。本發明也包括在在此所描述的篩選分析中鑒定的化合物。
在一個實施方案中，使用篩選分析來鑒定用于治療自身免疫疾病的治療劑。該自身免疫性疾病可以是例如狼瘡，包括狼瘡腎炎。
在一個實施方案中，本發明提供用于篩選結合或調節膜結合形式的BFLP0169蛋白質或多肽的活性或其生物活性部分的候選或測試化合物的分析。可利用本領域已知的任何多種途徑組合的文庫方法來獲得本發明的測試化合物，包括生物學文庫；空間可選址的并聯的固相或液相文庫；需要反演的合成文庫方法；″一珠子-一化合物″的文庫方法；以及利用親和色譜法選擇的合成文庫方法。生物學文庫方法限于肽文庫，而另4個方法適用于肽、非肽低聚物或化合物的小分子文庫。
如在此使用的″小分子″，是指分子量小于大約5kD以及最優選小于大約4kD的組合物。小分子可以是例如，雷帕霉素、核酸、肽、多肽、肽模擬物、碳水化合物、脂類或其它有機或無機分子。
化學品和/或生物學混合物，例如真菌、細菌、或海藻提取物的文庫，是本領域已知的，并且可用本發明的任何分析篩選。化合物的文庫可存在于溶液中、或珠子上、芯片上、細菌、孢子、質粒或噬菌體上。
在一個實施方案中，分析是基于細胞的分析，其中將在細胞表面上表達膜結合形式的BFLP0169蛋白質、或其生物活性部分的細胞與測試化合物接觸，并且確定測試化合物結合BFLP0169蛋白質的能力。細胞例如可以是哺乳動物起源或酵母細胞。可例如通過使測試化合物與放射性同位素或酶促標記偶聯，以使得可通過檢測復合物中的標記化合物來測試化合物與BFLP0169蛋白質或其生物活性部分的結合而實現對測試化合物結合BFLP0169蛋白質的能力的確定。例如，可用125I、35S、14C、或3H直接或間接地標記測試化合物，并通過放射性發射的直接計數或通過閃爍計數檢測放射性同位素。備選地，可用例如辣根過氧化物酶、堿性磷酸酶、或熒光素酶來酶促標記測試化合物，并通過確定適當底物向產物的轉化而檢測酶促標記。在一個實施方案中，該分析包括將在細胞表面上表達膜結合形式的BFLP0169蛋白質、或其生物活性部分的細胞與結合BFLP0169形成分析混合物的已知化合物接觸，將分析混合物與測試化合物接觸，并且確定測試化合物與BFLP0169蛋白質相互作用的能力，其中對測試化合物與BFLP0169蛋白質相互作用的能力的確定包括確定測試化合物與已知化合物相比，優先結合BFLP0169蛋白質或其生物活性部分的能力。
在另一個實施方案中，分析是基于細胞的分析，包括將在細胞表面上表達膜結合形式的BFLP0169蛋白質、或其生物活性部分的細胞與測試化合物接觸，并且確定測試化合物調節(例如刺激或抑制)BFLP0169蛋白質的活性或其生物活性部分的能力。可通過例如確定BFLP0169蛋白質結合或與BFLP0169靶分子相互作用的能力來實現對測試化合物調節BFLP0169的活性或其生物活性部分的能力的確定。如在此使用的，″靶分子″是BFLP0169蛋白質天然結合或相互作用的分子，例如在表達BFLP0169相互作用蛋白質的細胞表面上的分子、在第二細胞表面上的分子、在胞外環境中的分子、與細胞膜內表面相關的分子或細胞質分子。BFLP0169靶分子可以是非BFLP0169分子或本發明的BFLP0169蛋白質或多肽。在一個實施方案中，BFLP0169靶分子是幫助轉導胞外信號(例如通過化合物結合膜結合得BFLP0169分子而產生的信號)通過細胞膜并進入細胞內的信號轉導途徑的成分。該靶，例如可以是具有催化活性的第二胞間蛋白質或幫助下游信號分子與BFLP0169締合的蛋白質。
可通過如上所述用于確定直接結合的方法中的一個來完成對BFLP0169蛋白質結合或與BFLP0169靶分子相互作用的能力的確定。在一個實施方案中，可通過確定靶分子的活性來完成對BFLP0169蛋白質結合或與BFLP0169靶分子相互作用的能力的確定。例如，可通過檢測靶的細胞第二信使的誘導(即胞內Ca2+、二酰甘油、IP3等)，檢測靶對適當底物的催化/酶促活性，檢測報告基因(包括可操作地與編碼可檢測標記，例如熒光素酶的核酸連接的BFLP0169應答性調控元件)的誘導，或檢測細胞反應，例如細胞存活、細胞分化，或細胞增殖來確定靶分子的活性。
在另一實施方案中，本發明的分析是基于無細胞的分析，包括將BFLP0169蛋白質、或其生物活性部分與測試化合物接觸，并且確定測試化合物結合BFLP0169蛋白質或其生物活性部分的能力。可如上所述直接或間接地確定測試化合物與BFLP0169蛋白質的結合。在一個這種實施方案中，該分析包括將BFLP0169蛋白質或其生物活性部分與結合BFLP0169形成分析混合物的已知化合物接觸，將分析混合物與測試化合物接觸，并且確定測試化合物與BFLP0169蛋白質相互作用的能力，其中對測試化合物與BFLP0169蛋白質相互作用的能力的確定包括確定測試化合物與已知化合物相比，優先結合BFLP0169蛋白質或其生物活性部分的能力。
在另一個實施方案中，分析是無細胞的分析，包括將BFLP0169蛋白質或其生物活性部分與測試化合物接觸，并且確定測試化合物調節(例如刺激或抑制)BFLP0169蛋白質或其生物活性部分的活性的能力。可通過例如通過如上所述用于確定直接結合的方法中的一個來確定BFLP0169蛋白質結合BFLP0169靶分子的能力而完成對測試化合物調節BFLP0169活性的能力的確定。在備選的實施方案中，可通過確定BFLP0169蛋白質進一步調節BFLP0169靶分子的能力來完成對測試化合物調節BFLP0169蛋白質活性的能力的確定。例如，可如上所述確定靶分子對適當底物的催化/酶促活性。
在另一實施方案中，無細胞分析包括將BFLP0169蛋白質或其生物活性部分與結合BFLP0169蛋白質形成分析混合物的已知化合物接觸，將分析混合物與測試化合物接觸，并且確定測試化合物與BFLP0169蛋白質相互作用的能力，其中對測試化合物與BFLP0169蛋白質相互作用的能力的確定包括確定BFLP0169蛋白質優先結合或調節BFLP0169靶分子活性的能力。
本發明的無細胞分析可順應地用作BFLP0169蛋白質的可溶形式或膜結合形式。就包括膜結合形式的BFLP0169蛋白質的無細胞分析來說，可能需要利用增溶劑以使得膜結合形式的BFLP0169蛋白質保持在溶液中。這種增溶劑的實例包括非離子洗滌劑，例如n-辛基葡糖苷、n-十二烷基葡糖苷、n-十二烷基麥芽糖苷、辛酰基-N-甲基葡糖胺、癸酰基-N-甲基葡糖胺、Triton_X-100、Triton_X-114、Thesit_、Isotridecypoly(乙烯基乙二醇醚)n、N-十二烷基-N，N-二甲基-3-胺基-1-丙烷磺酸鹽、3-(3-膽胺丙基)二甲基氨合-1-丙烷磺酸鹽(CHAPS)、或3-(3-膽胺丙基)二甲基氨合-2-羥基-1-丙烷磺酸鹽(CHAPSO)。
在本發明上述測定法的一個以上的實施方案中，可能需要固定BFLP0169蛋白質或其靶分子以便于從未復合形式的一個或兩個蛋白質分離復合物，以及提供自動操作的分析。在存在和缺少候選化合物時，可在任何適于容納反應物的容器中完成測試化合物與BFLP0169蛋白質的結合，或BFLP0169蛋白質與靶分子的相互作用。這種容器的實例包括微量滴定板、試管、和微離心管。在一個實施方案中，提供的融合蛋白可加入了容許一個或兩個蛋白質結合基質的結構域。例如，可使GST-BFLP0169融合蛋白或GST-靶融合蛋白吸附到谷胱甘肽瓊脂糖凝膠珠子(Sigma Chemical，St.Louis，MO)或谷胱甘肽衍生的微量滴定板上，然后與測試化合物或測試化合物與非吸附的靶蛋白質或BFLP0169蛋白質結合，并且在有助于復合物形成的條件(例如，在鹽和pH的生理條件)下孵育混合物。孵育后，洗滌珠子或微量滴定板的孔以除去任何未結合的成分，就固定基質為珠子的情形來說，例如如上文所描述的直接或間接地確定復合物。備選地，可從基質分離復合物，并利用常規技術確定BFLP0169蛋白結合或活性的水平。
用于使蛋白質固定在基質上的其它技術也可用于本發明的篩選分析。例如，可利用生物素和鏈霉抗生物素的接合作用固定BFLP0169蛋白質或其靶分子。可利用本領域眾所周知的技術從生物素-NHS(N-羥基-琥珀酰亞胺)制備生物素酰化的BFLP0169蛋白質或靶分子(例如，生物素酰化試劑盒，Pierce Chemicals，Rockford，Ill.)，并且固定在涂有鏈霉抗生物素的96孔平板的孔中(Pierce Chemical)。備選地，與BFLP0169蛋白質或靶分子反應、但不防礙BFLP0169蛋白質結合其靶分子的抗體可以是平板的孔衍生的，并且不結合通過抗體接合作用截留在孔中的靶或BFLP0169蛋白質。用于檢測這種復合物的檢測方法，除如上所述用于GST固定復合物的方法之外，包括利用與BFLP0169蛋白質或靶分子反應的抗體免疫檢測復合物以及依賴于檢測與BFLP0169蛋白質或靶分子相關的酶活性的酶聯測定。
在另一個實施方案中，在將細胞接觸候選化合物并且確定細胞中BFLP0169 mRNA或蛋白質表達的方法中鑒定BFLP0169蛋白質表達的調節劑。將在存在候選化合物時，BFLP0169 mRNA或蛋白質表達的水平與缺乏候選化合物時BFLP0169 mRNA或蛋白質表達的水平相比。然后根據這個比較可確定候選化合物是BFLP0169 mRNA或蛋白質表達的調節劑。例如，當存在候選化合物時BFLP0169 mRNA或蛋白質的表達大于缺乏該候選化合物時，(即，統計學上顯著大于)，則確定該候選化合物為BFLP0169 mRNA或蛋白質表達的刺激劑。備選地，當存在候選化合物時BFLP0169 mRNA或蛋白質的表達低于缺乏該候選化合物時，(即，統計學上顯著地小于)，則確定該候選化合物為BFLP0169 mRNA或蛋白質表達的抑制劑。可通過在此所描述的用于檢測BFLP0169 mRNA或蛋白質的方法確定細胞中BFLP0169mRNA或蛋白質表達的水平。
在本發明的另一方面，可使用BFLP0169蛋白質作為雙-雜合測定或3雜合測定中的″餌蛋白質″，以鑒定結合或與BFLP0169(″BFLP0169-結合蛋白″或″BFLP0169-bp″)相互作用，以及調節BFLP0169活性的其它蛋白質。這種BFLP0169-結合蛋白也可能通過BFLP0169蛋白質，例如BFLP0169途徑的上游或下游元件而涉及信號的增殖。
雙雜合系統是基于大多數轉錄因子的調節特性，該轉錄因子由可分離的DNA-結合和活化結構域組成。簡而言之，本測定利用2個不同的DNA構建體。在一個構建體中，編碼BFLP0169的基因與編碼已知轉錄因子(例如GAL-4)的DNA結合結構域的基因融合。在另一個構建體中，來自DNA序列文庫、編碼未鑒別的蛋白質(″捕獲″或″樣品″)的DNA序列與編碼已知轉錄因子的活化結構域的基因融合。如果″餌″和″捕獲″蛋白質能夠相互作用，體內形成BFLP0169-依賴的復合物，則使轉錄因子的DNA-結合和活化結構域更為緊密相鄰。這種接近度容許轉錄與應答轉錄因子的轉錄調節位點可操作地連接的報告基因(例如LacZ)。可檢測報告基因的表達，可分離包含功能性轉錄因子的細胞集落并用于獲得編碼與BFLP0169相互作用的蛋白質的克隆基因。
本發明進一步涉及通過上述的篩選分析鑒定的新試劑及其用于在此所述的治療的用途。
在下列的非限制性實施例中說明本發明。
實施例1.無病的、狼瘡腎炎模擬疾病、和雷帕霉素治療的患病小鼠中鼠BFLP0169序列的表達模式在本領域公認的NZB×NZW鼠模型的發展狼瘡腎炎樣癥狀的小鼠中檢驗鼠BFLP0169序列的表達(參見例如，Drake等人，Geneticanalysis the NZB contribution to lupus-like autoimmune disease in(NZB xNZI FI mice，.Proc Natl Acad Sci U S A 914062-66，1994；Finck等人，Interleukin 6 promotes murine lupus in NZB/NZWF1 mice，J.Clin.Invest 94585-91，1994；Gμglielmotti等人，Bindarit prlongssurvival and reduces renal damage ofNSB/W lupus mice.Clin.Exp.RheμMatol.16149，1998；Yang等人，Dietary conjugated linoleicacidprotects against end stage disease of systemic lupus erythematosus inthe NZB/WF1 mouse，Immunopharmacol.Immunotoxicol.22433-49,2000。將患病小鼠中的表達與年齡不同的非患病小鼠、和用雷帕霉素或抗-B7的抗體治療后其狼瘡腎炎樣癥狀減弱的小鼠中序列的表達進行比較。
從Jackson實驗室獲得6至8周齡的小鼠并且在原地老化。從小鼠的腎臟獲得數據并且在標明的時間點收獲數據C57BL/6雌性小鼠為8和32周齡；F1(NZB×NZW)雌性小鼠為12、25和42周齡；用雷帕霉素處理的小鼠為42和55周齡；用B7.1和B7.2的抗體處理的小鼠為52周齡。每組包含3個小鼠。
雷帕霉素處理的小鼠每周接受3次5mg/kg雷帕霉素的皮下注射，在29周齡開始，持續8周。對照小鼠按照相同的時間表接受溶劑(甲基纖維素)的注射。通過蛋白尿和腎組織結構(數據未顯示)的標準化確定治療的有效性。在治療過程結束(36周齡，數據未顯示)，和42周齡(處理后6周)和55周齡(處理后20周)時，對殺死的小鼠預先形成基因表達分析。
用抗-B7處理的小鼠通過腹膜內注射接受每周3次200μg的抗-B7.1(1G10F9單克隆)和200μg的抗-B7.2(GL1單克隆)，在29周齡開始，持續2周。處理后21周進行基因表達分析。
RNA分離和與寡聚核苷酸陣列雜交從雄性和雌性小鼠收集腎臟并迅速冷凍用于RNA分離。使用每個腎臟的一半。對于每個個體動物使用左腎的縱切面和右腎的橫切面。
利用勻漿器使迅速冷凍的小鼠腎臟組織懸浮在加2ME的RLT緩沖液中勻漿30至45秒。利用Qiagen Midi試劑盒按照制造商的方案制備總RNA。使RNA懸浮在用DEPC處理的H2O中，并且通過OD2180定量。
利用Superscript試劑盒(BRL)從5μg的總RNA合成cDNA。利用Phage lock gel管用酚∶氯仿∶異戊醇(25∶24∶1)按照Phage lock方案純化cDNA。收集上清液并利用乙醇澄清。使樣品重懸浮在DEPC處理的H2O中。
體外T7聚合酶驅動合成的轉錄反應和反義cRNA的生物素標記。使用Qiagen RNeasy離心柱的純化作用來純化cRNA。按照每個制造商的用法說明，基因芯片雜交混合物包含在1×MES緩沖液中的15μgcRNA片段、0.5mg/ml乙酰化BSA、0.1mg/ml鯡魚精DNA，總體積為200μl。將反應混合物與Affymetrix Mul 1KsubA和Mul 1KsubB寡聚核苷酸陣列在45℃雜交16小時。除去雜交混合物，洗滌陣列，利用GeneChip Fluidics Station 400用抗生蛋白鏈菌素R-藻紅蛋白(Molecular Probes)染色，并用Hewlett Packard GeneArray掃描儀按照制造商的指導掃描。收集熒光數據，并利用MicroArray Suite軟件轉換為基因特異性差異的平均數。
寡聚核苷酸陣列數據的分析使由來源于克隆細菌和噬菌體序列的基因片段組成的11個元素的標準曲線對于每個雜交混合物在表示RNA頻率為大約百萬分之3.3至1000(ppm)的0.5pm至150pM的濃度范圍成峰波狀。通過T7聚合酶從基于質粒的模板驅動IVT反應來合成生物素酰化的標準曲線片段。峰狀的生物素酰化RNA片段不僅作為評估芯片靈敏性的內標準而且作為如由Hill等人所描述的將測量的熒光差異平均數從個別基因轉換成為ppm的RNA頻率的標準曲線。
測量來自每個個體小鼠腎臟的基因表達頻率，并對表達數據進行統計分析。對于給定的小鼠組取根據個體測量所確定的頻率值的平均值。將在12和32周齡的C57B16腎臟之間其頻率有顯著差異的基因分類為由于自然老化過程，而不是由于疾病過程而產生的變化。
顯示了通過限定標準aaO02653_s_at，在Affymetrix Murine 11K芯片上鑒定的寡聚核苷酸序列在年輕的(無病的)、年老的(患病的)、和有效治療的年老的(無病的)F1(NZB×NZW)小鼠和C57BL6對照小鼠中的表達頻率。這些序列表示未知的小鼠基因。
結果如圖1所示。所顯示的是表示來自標明小鼠的腎臟中基因表達水平的直方圖。在12周齡的C57BL/6腎臟和32周齡的腎臟之間，BFLP0169的表達水平沒有顯著差異，表明在不患病的小鼠腎臟中該表達水平不隨年齡而增加。在(NXB×NZW)F1腎臟中，在疾病發作前(12周齡)基因以正常的水平表達。隨著小鼠年齡和疾病的發展，在25周、36周(36周的數據未顯示)，和42周觀察到表達水平增加。到55周齡，小鼠由于腎衰竭而死亡。在29周齡開始用雷帕霉素處理小鼠8周，保持健康狀態度過55周齡。已經接受有效治療(雷帕霉素治療或抗-B7治療)的小鼠腎臟表達正常水平的BFLP0169，并且在停止雷帕霉素治療20周后和停止抗-B7治療15周后在無癥狀的腎臟中保持該正常水平。當腎臟功能是正常的時，觀察到表達水平恢復正常，表明升高的水平與疾病進展相關，并且可診斷疾病的進展。阻斷這些基因的功能可能抑制或延遲疾病進展。表達水平也可用于評估和比較各種治療介入的有效性。
實施例2.表2中所示的人BFLP0169多肽序列的變體從存在于表2中的BFLP0169氨基酸序列變化一個氨基酸的多肽序列顯示如下。對于顯示的序列，表2中所示的BFLP0169序列的第78位的L已經替換為V，其以粗體顯示。
MIRKSKITSVLSFCRSSRELWTILLGRSALRELSQIEAELNKHWRRLLEGLSYYKPPSPSSAEKVKANKDVASPLKEVGLRISKFLGLDEEQSVQLLQCYLQEDYRGTRDSVKTVLQDERQSQALILKIADYYYEERTCILRCVLHLLTYFQDERHPYRVEYADCVDKLEKELVSKYRQQFEELYKTEAPTWETHGNLMTERQVSRWFVQCLREQSMLLEIIFLYYAYFEMAPSDLLVLTKMFKEQGFGSRQTNRHLVDETMDPFVDRIGYFSALILVEGMDIESLHKCALDDRRELHQFAQDGLICQDMDCLMLTFGDIPHHAPVLLAWALLRHTLNPEETSSVVRKIGGTAIQLNVFQYLTRLLQSLASGGNDCTTSTACMCVYGLLSFVLTSLELHTLGNQQDIIDTACEVLADPSLPELFWGTEPTSGLGIILDSVCGMFPHLLSPLLQLLRALVSGKSTAKKVYSFLDKMSFYNELYKHKPHDVISHEDGTLWRRQTPKLLYPLGGQTNLRIPQGTVGQVMLDDRAYLVRWEYSYSSWTLFTCEIEMLLHVVSTADVIQHCQRVKPIIDLVHKVISTDLSIADCLLPITSRIYMLLQRLTTVISPPVDVIASCVNCLTVLAARNPAKVWTDLRHTGFLPFVAHPVSSLSQMISAEGMNAGGYGNLLMNSEQPQGEYGVTIAFLRLITTLVKGQLGSTQSQGLVPCVMFVLKEMLPSYHKWRYNSHGVREQIGCLILELIHAILNLCHETDLHSSHTPSLQFLCICSLAYTEAGQTVINIMGIGVDTIDMVMAAQPRSDGAEGQGQGQLLIKTVKLAFSVTNNVIRLKPPSNVVSPLEQALSQHGAHGNNLIAVLAKYIYHKHDPALPRLAIQLLKRLATVAPMSVYACLGNDAAAIRDAFLTRLQSKIEDMRIKVMILEFLTVAVETQPGLIELFLNLEVKDGSDGSKEFSLGMWSCLHAVLELIDSQQQDRYWCPPLLHRAAIAFLHALWQDRRDSAMLVLRTKPKFWENLTSPLFGTLSPPSETSEPSILETCALIMKIICLEIYYVVKGSLDQSLKDTLKKFSIEKRFAYWSGYVKSLAVHVAETEGSSCTSLLEYQMLVSAWRMLLIIATTHADIMHLTDSVVRRQLFLDVLDGTKALLLVPASVNCLRLGSMKCTLLLILLRQWKRELGSVDEILGPLTEILEGVLQADQQLMEKTKAKVFSAFITVLQMKEMKVSDIPQYSQLVLNVCETLQEEVIALFDQTRHSLALGSATEDKDSMETDDCSRSRHRDQRDGVCVLGLHLAKELCEVDEDGDSWLQVTRRLPILPTLLTTLEVSLRMKQNLHFTEATLHLLLTLARTQQGATAVAGAGITQSICLPLLSVYQLSTNGTAQTPSASRKSLDAPSWPGVYRLSMSLMEQLLKTLRYNFLPEALDFVGVHQERTLQCLNAVRTVQSLACLEEADHTVGFILQLSNFMKEWHFHLPQLMRDIQVNLGYLCQACTSLLHSRKMLQHYLQNKNGDGLPSAVAQRVQRPPSAASAAPSSSKQPAADTEASEQQALHTVQYGLLKILSKTLAALRHFTPDVCQILLDQSLDLAEYNFLFALSFTTPTFDSEVAPSFGTLLATVNVALNMLGELDKKKEPLTQAVGLSTQAEGTRTLKSLLMFTMENCFYLLISQAMRYLRDPAVHPRDKQRMKQELSSELSTLLSSLSRYFRRGAPSSPATGVLPSPQGKSTSLSKASPESQEPLIQLVQAFVRHMQR(SEQ ID NO3)實施例3.表2中所示的人BFLP0169多肽序列的變體從存在于表2中的BFLP0169氨基酸序列變化一個氨基酸的多肽序列顯示如下。對于顯示的序列，表2中所示的BFLP0169序列的第198位的L已經替換為I，其以粗體顯示。
MIRKSKITSVLSFCRSSRELWTILLGRSALRELSQIEAELNKHWRRLLEGLSYYKPPSPSSAEKVKANKDVASPLKELGLRISKFLGLDEEQSVQLLQCYLQEDYRGTRDSVKTVLQDERQSQALILKIADYYYEERTCILRCVLHLLTYFQDERHPYRVEYADCVDKLEKELVSKYRQQFEELYKTEAPTWETHGNTMTERQVSRWFVQCLREQSMLLEIIFLYYAYFEMAPSDLLVLTKMFKEQGFGSRQTNRHLVDETMDPFVDRIGYFSALILVEGMDIESLHKCALDDRRELHQFAQDGLICQDMDCLMLTFGDIPHHAPVLLAWALLRHTLNPEETSSVVRKIGGTAIQLNVFQYLTRLLQSLASGGNDCTTSTACMCVYGLLSFVLTSLELHTLGNQQDIIDTACEVLADPSLPELFWGTEPTSGLGIILDSVCGMFPHLLSPLLQLLRALVSGKSTAKKVYSFLDKMSFYNELYKHKPHDVISHEDGTLWRRQTPKLLYPLGGQTNLRIPQGTVGQVMLDDRAYLVRWEYSYSSWTLFTCEIEMLLHVVSTADVIQHCQRVKPIIDLVHKVISTDLSIADCLLPITSRIYMLLQRLTTVISPPVDVIASCVNCLTV
LAARNPAKVWTDLRHTGFLPFVAHPVSSLSQMISAEGMNAGGYGNLLMNSEQPQGEYGVTIAFLRLITTLVKGQLGSTQSQGLVPCVMFVLKEMLPSYHKWRYNSHGVREQIGCLILELIHAILNLCHETDLHSSHTPSLQFLCICSLAYTEAGQTVINIMGIGVDTIDMVMAAQPRSDGAEGQGQGQLLIKTVKLAFSVTNNVIRLKPPSNVVSPLEQALSQHGAHGNNLIAVLAKYIYHKHDPALPRLAIQLLKRLATVAPMSVYACLGNDAAAIRDAFLTRLQSKIEDMRIKVMILEFLTVAVETQPGLIELFLNLEVKDGSDGSKEFSLGMWSCLHAVLELIDSQQQDRYWCPPLLHRAAIAFLHALWQDRRDSAMLVLRTKPKFWENLTSPLFGTLSPPSETSEPSILETCALIMKIICLEIYYVVKGSLDQSLKDTLKKFSIEKRFAYWSGYVKSLAVHVAETEGSSCTSLLEYQMLVSAWRMLLIIATTHADIMHLTDSVVRRQLFLDVLDGTKALLLVPASVNCLRLGSMKCTLLLILLRQWKPELGSVDEILGPLTEILEGVLQADQQLMEKTKAKVFSAFITVLQMKEMKVSDIPQYSQLVLNVCETLQEEVIALFDQTRHSLALGSATEDKDSMETDDCSRSRHRDQRDGVCVLGLHLAKELCEVDEDGDSWLQVTRRLPILPTLLTTLEVSLRMKQNLHFTEATLHLLLTLARTQQGATAVAGAGITQSICLPLLSVYQLSTNGTAQTPSASRKSLDAPSWPGVYRLSMSLMEQLLKTLRYNFLPEALDFVGVHQERTLQCLNAVRTVQSLACLEEADHTVGFILQLSNFMKEWHFHLPQLMRDIQVNLGYLCQACTSLLHSRKMLQHYLQNKNGDGLPSAVAQRVQRPPSAASAAPSSSKQPAADTEASEQQALHTVQYGLLKILSKTIAALRHFTPDVCQILLDQSLDLAEYNFLFALSFTTPTFDSEVAPSFGTLLATVNVALNMLGELDKKKEPLTQAVGLSTQAEGTRTLKSLLMFTMENCFYLLISQAMRYLRDPAVHPRDKQRMKQELSSELSTLLSSLSRYFRRGAPSSPATGVLPSPQGKSTSLSKASPESQEPLIQLVQAFVRHMQR(SEQ ID NO4)實施例4.表2中所示的人BFLP0169多肽序列的變體從存在于表2中的BFLP0169氨基酸序列變化一個氨基酸的多肽序列顯示如下。對于顯示的序列，表2中所示的BFLP0169序列的第267位的R已經替換為K，其以粗體顯示。
MIRKSKITSVLSFCRSSRELWTILLGRSALRELSQIEAELNKHWRRLLEGLSYYKPPSPSSAEKVKANKDVASPLKELGLRISKFLGLDEEQSVQLLQCYLQEDYRGTRDSVKTVLQDERQSQALILKIADYYYEERTCILRCVLHLLTYFQDERPYRVEYADCVDKLEKELVSKYRQQFEELYKTEAPTWETHGNLMTERQVSRWFVQCLREQSMLLEIIFLYYAYFEMAPSDLLVLTKMFKEQGFGSRQTNRHLVDETMDPFVDKIGYFSALILVEGMDIESLHKCALDDRRELHQFAQDGLICQDMDCLMLTFGDIPHHAPVLLAWALLRHTLNPEETSSVVRKIGGTAIQLNVFQYLTRLLQSLASGGNDCTTSTACMCVYGLLSFVLTSLELHTLGNQQDIIDTACEVLADPSLPELFWGTEPTSGLGIILDSVCGMFPHLLSPLLQLLRALVSGKSTAKKVYSFLDKMSFYNELYKHKPHDVISHEDGTLWRRQTPKLLYPLGGQTNLRIPQGTVGQVMLDDRAYLVRWEYSYSSWTLFTCEIEMLLHVVSTADVIQHCQRVKPIIDLVHKVISTDLSIADCLLPITSRIYMLLQRLTTVISPPVDVIASCVNCLTVLAARNPAKVWTDLRHTGFLPFVAHPVSSLSQMISAEGMNAGGYGNLLMNSEQPQGEYGVTIAFLRLITTLVKGQLGSTQSQGLVPCVMFVLKEMLPSYHKWRYNSHGVREQIGCLILELIHAILNLCHETDLHSSHTPSLQFLCICSLAYTEAGQTVINIMGIGVDTIDMVMAAQPRSDGAEGQGQGQLLIKTVKLAFSVTNNVIRLKPPSNVVSPLEQALSQHGAHGNNLIAVLAKYIYHKHDPALPRLAIQLLKRLATVAPMSVYACLGNDAAAIRDAFLTRLQSKIEDMRIKVMILEFLTVAVETQPGLIELFLNLEVKDGSDGSKEFSLGMWSCLHAVLELIDSQQQDRYWCPPLLHRAAIAFLHALWQDRRDSAMLVLRTKPKFWENLTSPLFGTLSPPSETSEPSILETCALIMKIICLEIYYVVKGSLDQSLKDTLKKFSIEKRFAYWSGYVKSLAVHVAETEGSSCTSLLEYQMLVSAWRMLLIIATTHADIMHLTDSVVRRQLFLDVLDGTKALLLVPASVNCLRLGSMKCTLLLILLRQWKRELGSVDEILGPLTEILEGVLQADQQLMEKTKAKVFSAFITVLQMKEMKVSDIPQYSQLVLNVCETLQEEVIALFDQTRHSLALGSATEDKDSMETDDCSRSRHRDQRDGVCVLGLHLAKELCEVDEDGDSWLQVTRRLPILPTLLTTLEVSLRMKQNLHFTEATLHLLLTLARTQQGATAVAGAGITQSICLPLLSVYQLSTNGTAQTPSASRKSLDAPSWPGVYRLSMSLMEQLLKTLRYNFLPEALDFVGVHQERTLQCLNAVRTVQSLACLEEADHTVGFILQLSNFMKEWHFHLPQLMRDIQVNLGYLCQACTSLLHSRKMLQHYLQNKNGDGLPSAVAQRVQRPPSAASAAPSSSKQPAADTEASEQQALHTVQYGLLKILSKTLAALRHFTPDVCQILLDQSLDLAEYNFLFALSFTTPTFDSEVAPSFGTLLATVNVALNMLGELDKKKEPLTQAVGLSTQAEGTRTLKSLLMFTMENCFYLLISQAMRYLRDPAVHPRDKQRMKQELSSELSTLLSSLSRYFRRGAPSSPATGVLPSPQGKSTSLSKASPESQEPLIQLVQAFVRHMQR(SEQ ID NO5)實施例5.表2中所示的人BFLP0169多肽序列的變體從存在于表2中的BFLP0169氨基酸序列變化一個氨基酸的多肽序列顯示如下。對于顯示的序列，表2中所示的BFLP0169序列的第355位的Q已經替換為N，其以粗體顯示。
MIRKSKITSVLSFCRSSRELWTILLGRSALRELSQIEAELNKHWRRLLEGLSYYKPPSPSSAEKVKANKDVASPLKELGLRISKFLGLDEEQSVQLLQCYLQEDYRGTRDSVKTVLQDERQSQALILKIADYYYEERTCILRCVLHLLTYFQDERHPYRVEYADCVDKLEKELVSKYRQQFEELYKTEAPTWETHGNLMTERQVSRWFVQCLREQSMLLEIIFLYYAYFEMAPSDLLVLTKMFKEQGFGSRQTNRHLVDETMDPFVDRIGYFSALILVEGMDIESLHKCALDDRRELHQFAQDGLICQDMDCLMLTFGDIPHHAPVLLAWALLRHTLNPEETSSVVRKIGGTAINLNVFQYLTRLLQSLASGGNDCTTSTACMCVYGLLSFVLTSLELHTLGNQQDIIDTACEVLADPSLPELFWGTEPTSGLGIILDSVCGMFPHLLSPLLQLLRALVSGKSTAKKV
YSFLDKMSFYNELYKHKPHDVISHEDGTLWRRQTPKLLYPLGGQTNLRIPQGTVGQVMLDDRAYLVRWEYSYSSWTLFTCEIEMLLHVVSTADVIQHCQRVKPIIDLVHKVISTDLSIADCLLPITSRIYMLLQPLTTVISPPVDVIASCVNCLTVLAARNPAKVWTDLRHTGFLPFVAHPVSSLSQMISAEGMNAGGYGNLLMNSEQPQGEYGVTIAFLRLITTLVKGQLGSTQSQGLVPCVMFVLKEMLPSYHKWRYNSHGVREQIGCLILELIHAILNLCHETDLHSSHTPSLQFLCICSLAYTEAGQTVINIMGIGVDTIDMVMAAQPRSDGAEGQGQGQLLIKTVKLAFSVTNNVIRLKPPSNVVSPLEQALSQHGAHGNNLIAVLAKYIYHKHDPALPRLAIQLLKRLATVAPMSVYACLGNDAAAIRDAFLTRLQSKIEDMRIKVMILEFLTVAVETQPGLIELFLNLEVKDGSDGSKEFSLGMWSCLHAVLELIDSQQQDRYWCPPLLHRAAIAFLHALWQDRRDSAMLVLRTKPKFWENLTSPLFGTLSPPSETSEPSILETCALIMKIICLEIYYVVKGSLDQSLKDTLKKFSIEKRFAYWSGYVKSLAVHVAETEGSSCTSLLEYQMLVSAWRMLLIIATTHADIMHLTDSVVRRQLFLDVLDGTKALLLVPASVNCLRLGSMKCTLLLILLRQWKRELGSVDEILGPLTEILEGVLQADQQLMEKTKAKVFSAFITVLQMKEMKVSDIPQYSQLVLNVCETLQEEVIALFDQTRHSLALGSATEDKDSMETDDCSRSRHRDQRDGVCVLGLHLAKELCEVDEDGDSWLQVTRRLPILPTLLTTLEVSLRMKQNLHFTEATLHLLLTLARTQQGATAVAGAGITQSICLPLLSVYQLSTNGTAQTPSASRKSLDAPSWPGVYRLSMSLMEQLLKTLRYNFLPEALDFVGVHQERTLQCLNAVRTVQSLACLEEADHTVGFILQLSNFMKEWHFHLPQLMRDIQVNLGYLCQACTSLLHSRKMLQHYLQNKNGDGLPSAVAQRVQRPPSAASAAPSSSKQPAADTEASEQQALHTVQYGLLKILSKTLAALRHFTPDVCQILLDQSLDLAEYNFLFALSFTTPTFDSEVAPSFGTLLATVNVALNMLGELDKKKEPLTQAVGLSTQAEGTRTLKSLLMFTMENCFYLLISQAMRYLRDPAVHPRDKQRMKQELSSELSTLLSSLSRYFRRGAPSSPATGVLPSPQGKSTSLSKASPESQEPLIQLVQAFVRHMQR(SEQ ID NO6)實施例6.表2中所示的人BFLP0169多肽序列的變體從存在于表2中的BFLP0169氨基酸序列變化一個氨基酸的多肽序列顯示如下。對于顯示的序列，表2中所示的BFLP0169序列的第446位的H已經替換為R，其以粗體顯示。
MIRKSKITSVLSFCRSSRELWTILLGRSALRELSQIEAELNKHWRRLLFGLSYYKPPSPSSAEKVKANKDVASPLKELGLRISKFLGLDEEQSVQLLQCYLQEDYRGTRDSVKTVLQDERQSQALILKIADYYYEERTCILRCVLHLLTYFQDERHPYRVEYADCVDKLEKELVSKYRQQFEELYKTEAPTWETHGNLMTERQVSRWFVQCLREQSMLLEIIFLYYAYFEMAPSDLLVLTKMFKEQGFGSRQTNRHLVDETMDPFVDRIGYFSALILVEGMDIESLHKCALDDRRELHQFAQDGLICQDMDCLMLTFGDIPHHAPVLLAWALLRHTLNPEETSSVVRKIGGTAIQLNVFQYLTRLLQSLASGGNDCTTSTACMCVYGLLSFVLTSLELHTLGNQQDIIDTACEVLADPSLPELFWGTEPTSGLGIILDSVCGMFPRLLSPLLQLLRALVSGKSTAKKVYSFLDKMSFYNELYKHKPHDVISHEDGTLWRRQTPKLLYPLGGQTNLRIPQGTVGQVMLDDRAYLVRWEYSYSSWTLFTCEIEMLLHVVSTADVIQHCQRVKPIIDLVHKVISTDLSIADCLLPITSRIYMLLQRLTTVISPPVDVIASCVNCLTVLAARNPAKVWTDLRHTGFLPFVAHPVSSLSQMISAEGMNAGGYGNLLMNSEQPQGEYGVTIAFLRLITTLVKGQLGSTQSQGLVPCVMFVLKEMLPSYHKWRYNSHGVREQIGCLILELIHAILNLCHETDLHSSHTPSLQFLCICSLAYTEAGQTVINIMGIGVDTIDMVMAAQPRSDGAEGQGQGQLLIKTVKLAFSVTNNVIRLKPPSNVVSPLEQALSQHGAHGNNLIAVLAKYIYHKHDPALPRLAIQLLKRLATVAPMSVYACLGNDAAAIRDAFLTRLQSKIEDMRIKVMILEFLTVAVETQPGLIELFLNLEVKDGSDGSKEFSLGMWSCLHAVLELIDSQQQDRYWCPPLLHRAAIAFLHALWQDRRDSAMLVLRTKPKFWENLTSPLFGTLSPPSETSEPSILETCALIMKIICLEIYYVVKGSLDQSLKDTLKKFSIEKRFAYWSGYVKSLAVHVAETEGSSCTSLLEYQMLVSAWRMLLIIATTHADIMHLTDSVVRRQLFLDVLDGTKALLLVPASVNCLRLGSMKCTLLLILLRQWKRELGSVDEILGPLTEILEGVLQADQQLMEKTKAKVFSAFITVLQMKEMKVSDIPQYSQLVLNVCETLQEEVIALFDQTRHSLALGSATEDKDSMETDDCSRSRHRDQRDGVCVLGLHLAKELCEVDEDGDSWLQVTRRLPILPTLLTTLEVSLRMKQNLHFTEATLHLLLTLARTQQGATAVAGAGITQSICLPLLSVYQLSTNGTAQTPSASRKSLDAPSWPGVYRLSMSLMEQLLKTLRYNFLPEALDFVGVHQERTLQCLNAVRTVQSLACLEEADHTVGFILQLSNFMKEWHFHLPQLMRDIQVNLGYLCQACTSLLHSRKMLQHYLQNKNGDGLPSAVAQRVQRPPSAASAAPSSSKQPAADTEASEQQALHTVQYGLLKILSKTLAALRHFTPDVCQILLDQSLDLAEYNFLFALSFTTPTFDSEVAPSFGTLLATVNVALNMLGELDKKKEPLTQAVGLSTQAEGTRTLKSLLMFTMENCFYLLISQAMRYLRDPAVHPRDKQRMKQELSSELSTLLSSLSRYFRRGAPSSPATGVLPSPQGKSTSLSKASPESQEPLIQLVQAFVRHMQR(SEQ ID NO7)實施例7.表2中所示的人BFLP0169多肽序列的變體從存在于表2中的BFLP0169氨基酸序列變化一個氨基酸的多肽序列顯示如下。對于顯示的序列，表2中所示的BFLP01 69序列的第553位的L已經替換為I，其以粗體顯示。
MIRKSKITSVLSFCRSSRELWTILLGRSALRELSQIEAELNKHWRRLLEGLSYYKPPSPSSAEKVKANKDVASPLKELGLRISKFLGLDEEQSVQLLQCYLQEDYRGTRDSVKTVLQDERQSQALILKIADYYYEERTCILRCVLHLLTYFQDERHPYRVEYADCVDKLEKELVSKYRQQFEELYKTEAPTWETHGNLMTERQVSRWFVQCLREQSMLLEIIFLYYAYFEMAPSDLLVLTKMFKEQGFGSRQTNRHLVDETMDPFVDRIGYFSALILVEGMDIESLHKCALDDRRELHQFAQDGLICQDMDCLMLTFGDIPHHAPVLLAWALLRHTLNPEETSSVVRKIGGTAIQLNVFQYLTRLLQSLASGGNDCTTSTACMCVYGLLSFVLTSLELHTLGNQQDIIDTACEVLADPSLPELFWGTEPTSGLGIILDSVCGMFPHLLSPLLQLLRALVSGKSTAKKV
YSFLDKMSFYNELYKHKPHDVISHEDGTLWRRQTPKLLYPLGGQTNLRIPQGTVGQVMLDDRAYLVRWEYSYSSWTLFTCEIEMILHVVSTADVIQHCQRVKPIIDLVHKVISTDLSIADCLLPITSRIYMLLQRLTTVISPPVDVIASCVNCLTVLAARNPAKVWTDLRHTGFLPFVAHPVSSLSQMISAEGMNAGGYGNLLMNSEQPQGEYGVTIAFLRLITTLVKGQLGSTQSQGLVPCVMFVLKEMLPSYHKWRYNSHGVREQIGCLILELIHAILNLCHETDLHSSHTPSLQFLCICSLAYTEAGQTVINIMGIGVDTIDMVMAAQPRSDGAEGQGQGQLLIKTVKLAFSVTNNVIRLKPPSNVVSPLEQALSQHGAHGNNLIAVLAKYIYHKHDPALPRLAIQLLKRLATVAPMSVYACLGNDAAAIRDAFLTRLQSKIEDMRIKVMILEFLTVAVETQPGLIELFLNLEVKDGSDGSKEFSLGMWSCLHAVLELIDSQQQDRYWCPPLLHRAAIAFLHALWQDRRDSAMLVLRTKPKFWENLTSPLFGTLSPPSETSEPSILETCALIMKIICLEIYYVVKGSLDQSLKDTLKKFSIEKRFAYWSGYVKSLAVHVAETEGSSCTSLLEYQMLVSAWRMLLIIATTHADIMHLTDSVVRRQLFLDVLDGTKALLLVPASVNCLRLGSMKCTLLLILLRQWKRELGSVDEILGPLTEILEGVLQADQQLMEKTKAKVFSAFITVLQMKEMKVSDIPQYSQLVLNVCETLQEEVIALFDQTRHSLALGSATEDKDSMETDDCSRSRHRDQRDGVCVLGLHLAKELCEVDEDGDSWLQVTRRLPILPTLLTTLEVSLRMKQNLHFTEATLHLLLTLARTQQGATAVAGAGITQSICLPLLSVYQLSTNGTAQTPSASRKSLDAPSWPGVYRLSMSLMEQLLKTLRYNFLPEALDFVGVHQERTLQCLNAVRTVQSLACLEEADHTVGFILQLSNFMKEWHFHLPQLMRDIQVNLGYLCQACTSLLHSRKMLQHYLQNKNGDGLPSAVAQRVQRPPSAASAAPSSSKQPAADTEASEQQALHTVQYGLLKILSKTLAALRHFTPDVCQILLDQSLDLAEYNFLFALSFTTPTFDSEVAPSFGTLLATVNVALNMLGELDKKKEPLTQAVGLSTQAEGTRTLKSLLMFTMENCFYLLISQAMRYLRDPAVHPRDKQRMKQELSSELSTLLSSLSRYFRRGAPSSPATGVLPSPQGKSTSLSKASPESQEPLIQLVQAFVRHMQR(SEQ ID NO8)實施例8.表2中所示的人BFLP0169多肽序列的變體從存在于表2中的BFLP0169氨基酸序列變化一個氨基酸的多肽序列顯示如下。對于顯示的序列，表2中所示的BFLP0169序列的第634位的W已經替換為F，其以粗體顯示。
MIRKSKITSVLSFCRSSRELWTILLGRSALRELSQIEAELNKHWRRLLEGLSYYKPPSPSSAEKVKANKDVASPLKELGLRISKFLGLDEEQSVQLLQCYLQEDYRGTRDSVKTVLQDERQSQALILKIADYYYEERTCILRCVLHLLTYFQDERHPYRVEYADCVDKLEKELVSKYRQQFEELYKTEAPTWETHGNLMTERQVSRWFVQCLREQSMLLEIIFLYYAYFEMAPSDLLVLTKMFKEQGFGSRQTNRHLVDETMDPFVDRIGYFSALILVEGMDIESLHKCALDDRRELHQFAQDGLICQDMDCLMLTFGDIPHHAPVLLAWALLRHTLNPEETSSVVRKIGGTAIQLNVFQYLTRLLQSLASGGNDCTTSTACMCVYGLLSFVLTSLELHTLGNQQDIIDTACEVLADPSLPELFWGTEPTSGLGIILDSVCGMFPHLLSPLLQLLRALVSGKSTAKKVYSFLDKMSFYNELYKHKPHDVISHEDGTLWRRQTPKLLYPLGGQTNLRIPQGTVGQVMLDDRAYLVRWEYSYSSWTLFTCEIEMLLHVVSTADVIQHCQRVKPIIDLVHKVISTDLSIADCLLPITSRIYMLLQRLTTVISPPVDVIASCVNCLTVLAARNPAKVFTDLRHTGFLPFVAHPVSSLSQMISAEGMNAGGYGNLLMNSEQPQGEYGVTIAFLRLITTLVKGQLGSTQSQGLVPCVMFVLKEMLPSYHKWRYNSHGVREQIGCLILELIHAILNLCHETDLHSSHTPSLQFLCICSLAYTEAGQTVINIMGIGVDTIDMVMAAQPRSDGAEGQGQGQLLIKTVKLAFSVTNNVIRLKPPSNVVSPLEQALSQHGAHGNNLIAVLAKYIYHKHDPALPRLAIQLLKRLATVAPMSVYACLGNDAAAIRDAFLTRLQSKIEDMRIKVMILEFLTVAVETQPGLIELFLNLEVKDGSDGSKEFSLGMWSCLHAVLELIDSQQQDRYWCPPLLHRAAIAFLHALWQDRRDSAMLVLRTKPKEWENLTSPLFGTLSPPSETSEPSILETCALIMKIICLEIYYVVKGSLDQSLKDTLKKFSIEKRFAYWSGYVKSLAVHVAETEGSSCTSLLEYQMLVSAWRMLLIIATTHADIMHLTDSVVRRQLFLDVLDGTKALLLVPASVNCLRLGSMKCTLLLILLRQWKRELGSVDEILGPLTEILEGVLQADQQLMEKTKAKVFSAFITVLQMKEMKVSDIPQYSQLVLNVCETLQEEVIALFDQTRHSLALGSATEDKDSMETDDCSRSRHRDQRDGVCVLGLHLAKELCEVDEDGDSWLQVTRRLPILPTLLTTLEVSLRMKQNLHFTEATLHLLLTLARTQQGATAVAGAGITQSICLPLLSVYQLSTNGTAQTPSASRKSLDAPSWPGVYRLSMSLMEQLLKTLRYNFLPEALDFVGVHQERTLQCLNAVRTVQSLACLEEADHTVGFILQLSNFMKEWHFHLPQLMRDIQVNLGYLCQACTSLLHSRKMLQHYLQNKNGDGLPSAVAQRVQRPPSAASAAPSSSKQPAADTEASEQQALHTVQYGLLKILSKTLAALRHFTPDVCQILLDQSLDLAEYNFLFALSFTTPTFDSEVAPSFGTLLATVNVALNMLGELDKKKEPLTQAVGLSTQAEGTRTLKSLLMFTMENCFYLLISQAMRYLRDPAVHPRDKQRMKQELSSELSTLLSSLSRYFRRGAPSSPATGVLPSPQGKSTSLSKASPESQEPLIQLVQAFVRHMQR(SEQ ID NO9)實施例9.表2中所示的人BFLP0169多肽序列的變體從存在于表2中的BFLP0169氨基酸序列變化一個氨基酸的多肽序列顯示如下。對于顯示的序列，表2中所示的BFLP0169序列的第749位的N已經替換為D，其以粗體顯示。
MIRKSKITSVLSFCRSSRELWTILLGRSALRELSQIEAELNKHWRRLLEGLSYYKPPSPSSAEKVKANKDVASPLKELGLRISKFLGLDEEQSVQLLQCYLQEDYRGTRDSVKTVLQDERQSQALILKIADYYYEERTCILRCVLHLLTYFQDERHPYRVEYADCVDKLEKELVSKYRQQFEELYKTEAPTWETHGNLMTERQVSRWFVQCLREQSMLLEIIFLYYAYFEMAPSDLLVLTKMFKEQGFGSRQTNRHLVDETMDPFVDRIGYFSALILVEGMDIESLHKCALDDRRELHQFAQDGLICQDMDCLMLTFGDIPHHAPVLLAWALLRHTLNPEETSSVVRKIGGTAIQLNVFQYLTRLLQSLASGGNDCTTSTACMCVYGLLSFVLTSLELHTLGNQQDIIDTACEVLADPSLPELFWGTEPTSGLGIILDSVCGMFPHLLSPLLQLLRALVSGKSTAKKVYSFLDKMSFYNELYKHKPHDVISHEDGTLWRRQTPKLLYPLGGQTNLRIPQGTVGQVMLDDRAYLVRWEYSYSSWTLFTCEIEMLLHVVSTADVIQHCQRVKPIIDLVHKVISTDLSIADCLLPITSRIYMLLQRLTTVISPPVDVIASCVNCLTV
LAARNPAKVWTDLRHTGFLPFVAHPVSSLSQMISAEGMNAGGYGNLLMNSEQPQGEYGVTIAFLRLITTLVKGQLGSTQSQGLVPCVMFVLKEMLPSYHKWRYNSHGVREQIGCLILELIHAILDLCHETDLHSSHTPSLQFLCICSLAYTEAGQTVINIMGIGVDTIDMVMAAQPRSDGAEGQGQGQLLIKTVKLAFSVTNNVIRLKPPSNVVSPLEQALSQHGAHGNNLIAVLAKYIYHKHDPALPRLAIQLLKRLATVAPMSVYACLGNDAAAIRDAFLTRLQSKIEDMRIKVMILEFLTVAVETQPGLIELFLNLEVKDGSDGSKEFSLGMWSCLHAVLELIDSQQQDRYWCPPLLHRAAIAFLHALWQDRRDSAMLVLRTKPKFWENLTSELFGTLSPPSETSEPSILETCALIMKIICLEIYYVVKGSLDQSLKDTLKKFSIEKRFAYWSGYVKSLAVHVAETEGSSCTSLLEYQMLVSAWRMLLIIATTHADIMHLTDSVVRRQLFLDVLDGTKALLLVPASVNCLRLGSMKCTLLLILLRQWKRELGSVDEILGPLTEILEGVLQADQQLMEKTKAKVFSAFITVLQMKEMKVSDIPQYSQLVLNVCETLQEEVIALFDQTRHSLALGSATEDKDSMETDDCSRSRHRDQRDGVCVLGLHLAKELCEVDEDGDSWLQVTRRLPILPTLLTTLEVSLRMKQNLHFTEATLHLLLTLARTQQGATAVAGAGITQSICLPLLSVYQLSTNGTAQTPSASRKSLDAPSWPGVYRLSMSLMEQLLKTLRYNFLPEALDFVGVHQERTLQCLNAVRTVQSLACLEEADHTVGFILQLSNFMKEWHFHLPQLMRDIQVNLGYLCQACTSLLHSRKMLQHYLQNKNGDGLPSAVAQRVQRPPSAASAAPSSSKQPAADTEASEQQALHTVQYGLLKILSKTLAALRHFTPDVCQILLDQSLDLAEYNFLFALSFTTPTFDSEVAPSFGTLLATVNVALNMLGELDKKKEPLTQAVGLSTQAEGTRTLKSLLMFTMENCFYLLISQAMRYLRDPAVHPRDKQRMKQELSSELSTLLSSLSRYFRRGAPSSPATGVLPSPQGKSTSLSKASPESQEPLIQLVQAFVRHMQR(SEQ ID NO10)實施例10.表2中所示的人BFLP0169多肽序列的變體從存在于表2中的BFLP0169氨基酸序列變化一個氨基酸的多肽序列顯示如下。對于顯示的序列，表2中所示的BFLP0169序列的第838位的V已經替換為M，其以粗體顯示。
MIRKSKITSVLSFCRSSRELWTILLGRSALRELSQIEAELNKHWRRLLEGLSYYKPPSPSSAEKVKANKDVASPLKELGLRISKFLGLDEEQSVQLLQCYLQEDYRGTRDSVKTVLQDERQSQALILKIADYYYEERTCILRCVLHLLTYFQDERHPYRVEYADCVDKLEKELVSKYRQQFEELYKTEAPTWETHGNLMTERQVSRWFVQCLREQSMLLEIIFLYYAYFEMAPSDLLVLTKMFKEQGFGSRQTNRHLVDETMDPFVDRIGYFSALILVEGMDIESLHKCALDDRRELHQFAQDGLICQDMDCLMLTFGDIPHHAPVLLAWALLRHTLNPEETSSVVRKIGGTAIQLNVFQYLTRLLQSLASGGNDCTTSTACMCVYGLLSFVLTSLELHTLGNQQDIIDTACEVLADPSLPELFWGTEPTSGLGIILDSVCGMFPHLLSPLLQLLRALVSGKSTAKKVYSFLDKMSFYNELYKHKPHDVISHEDGTLWRRQTPKLLYPLGGQTNLRIPQGTVGQVMLDDRAYLVRWEYSYSSWTLFTCEIEMLLHVVSTADVIQHCQRVKPIIDLVRKVISTDLSIADGLLPITSRIYMLLQRLTTVISPPVDVIASCVNCLTVLAARNPAKVWTDLRHTGFLPFVAHPVSSLSQMISAEGMNAGGYGNLLMNSEQPQGEYGVTIAFLRLITTLVKGQLGSTQSQGLVPCVMFVLKEMLPSYHKWRYNSHGVREQIGCLILELIHAILNLCHETDLHSSHTPSLQFLCICSLAYTEAGQTVINIMGIGVDTIDMVMAAQPRSDGAEGQGQGQLLIKTVKLAFSVTNNVIRLKPPSNVMSPLEQALSQHGAHGNNLIAVLAKYIYHKHDPALPRLAIQLLKRLATVAPMSVYACLGNDAAAIRDAFLTRLQSKIEDMRIKVMILEFLTVAVETQPGLIELFLNLEVKDGSDGSKEFSLGMWSCLHAVLELIDSQQQDRYWCPPLLHRAAIAFLHALWQDRRDSAMLVLRTKPKFWENLTSPLFGTLSPPSETSEPSILETCALIMKIICLEIYYVVKGSLDQSLKDTLKKFSIEKRFAYWSGYVKSLAVHVAETEGSSCTSLLEYQMLVSAWRMLLIIATTHADIMHLTDSVVRRQLFLDVLDGTKALLLVPASVNCLRLGSMKCTLLLILLRQWKRELGSVDEILGPLTEILEGVLQADQQLMEKTKAKVFSAFITVLQMKEMKVSDIPQYSQLVLNVCETLQEEVIALFDQTRHSLALGSATEDKDSMETDDCSRSRHRDQRDGVCVLGLHLAKELCEVDEDGDSWLQVTRRLPILPTLLTTLEVSLRMKQNLHFTEATLHLLLTLARTQQGATAVAGAGITQSICLPLLSVYQLSTNGTAQTPSASRKSLDAPSWPGVYRLSMSLMEQLLKTLRYNFLPEALDFVGVHQERTLQCLNAVRTVQSLACLEEADHTVGFILQLSNFMKEWHFHLPQLMRDIQVNLGYLCQACTSLLHSRKMLQHYLQNKNGDGLPSAVAQRVQRPPSAASAAPSSSKQPAADTEASEQQALHTVQYGLLKILSKTLAALRHFTPDVCQILLDQSLDLAEYNFLFALSFTTPTFDSEVAPSFGTLLATVNVALNMLGELDKKKEPLTQAVGLSTQAEGTRTLKSLLMFTMENCFYLLISQAMRYLRDPAVHPRDKQRMKQELSSELSTLLSSLSRYERRGAPSSPATGVLPSPQGKSTSLSKASPESQEPLIQLVQAFVRHMQR(SEQ ID NO11)實施例11.表2中所示的人BFLP01 69多肽序列的變體從存在于表2中的BFLP0169氨基酸序列變化一個氨基酸的多肽序列顯示如下。對于顯示的序列，表2中所示的BFLP0169序列的第958位的G已經替換為T，其以粗體顯示。
MIRKSKITSVLSFCRSSRELWTILLGRSALRELSQIEAELNKHWRRLLEGLSYYKPPSPSSAEKVKANKDVASPLKELGLRISKFLGLDEEQSVQLLQCYLQEDYRGTRDSVKTVLQDERQSQALILKIADYYYEERTCILRCVLHLLTYFQDERHPYRVEYADCVDKLEKELVSKYRQQFEELYKTEAPTWETHGNLMTERQVSRWFVQCLREQSMLLEIIFLYYAYFEMAPSDLLVLTKMFKEQGFGSRQTNRHLVDETMDPFVDRIGYFSALILVEGMDIESLHKCALDDRRELHQFAQDGLICQDMDCLMLTFGDIPHHAPVLLAWALLRHTLNPEETSSVVRKIGGTAIQLNVFQYLTRLLQSLASGGNDCTTSTACMCVYGLLSFVLTSLELHTLGNQQDIIDTACEVLADPSLPELFWGTEPTSGLGIILDSVCGMFPHLLSPLLQLLRALVSGKSTAKKVYSFLDKMSFYNELYKHKPHDVISHEDGTLWRRQTPKLLYPLGGQTNLRIPQGTVGQVMLDDRAYLVRWEYSYSSWTLF
TCEIEMLLHVVSTADVIQHCQRVKPIIDLVHKVISTDLSIADCLLPITSRIYMLLQRLTTVISPPVDVIASCVNCLTVLAARNPAKVWTDLRHTGFLPFVAHPVSSLSQMISAEGMNAGGYGNLLMNSEQPQGEYGVTIAFLRLITTLVKGQLGSTQSQGLVPCVMFVLKEMLPSYHKWRYNSHGVREQIGCLILELIHAILNLCHETDLHSSHTPSLQFLCICSLAYTEAGQTVINIMGIGVDTIDMVMAAQPRSDGAEGQGQGQLLIKTVKLAFSVTNNVIRLKPPSNVVSPLEQALSQHGAHGNNLIAVLAKYIYHKHDPALPRLAIQLLKRLATVAPMSVYACLGNDAAAIRDAFLTRLQSKIEDMRIKVMILEFLTVAVETQPGLIELFLNLEVKDGSDGSKEFSLTMWSCLHAVLELIDSQQQDRYWCPPLLHRAAIAFLHALWQDRRDSAMLVLRTKPKFWENLTSPLFGTLSPPSETSEPSILETCALIMKIICLEIYYVVKGSLDQSLKDTLKKFSIEKRFAYWSGYVKSLAVHVAETEGSSCTSLLEYQMLVSAWRMLLIIATTHADIMHLTDSVVRRQLFLDVLDGTKALLLVPASVNCLRLGSMKCTLLLILLRQWKRELGSVDEILGPLTEILEGVLQADQQLMEKTKAKVFSAFITVLQMKEMKVSDIPQYSQLVLNVCETLQEEVIALFDQTRHSLALGSATEDKDSMETDDCSRSRHRDQRDGVCVLGLHLAKELCEVDEDGDSWLQVTRRLPILPTLLTTLEVSLRMKQNLHFTEATLHLLLTLARTQQGATAVAGAGITQSICLPLLSVYQLSTNGTAQTPSASRKSLDAPSWPGVYRLSMSLMEQLLKTLRYNFLPEALDFVGVHQERTLQCLNAVRTVQSLACLEEADHTVGFILQLSNFMKEWHFHLPQLMRDIQVNLGYLCQACTSLLHSRKMLQHYLQNKNGDGLPSAVAQRVQRPPSAASAAPSSSKQPAADTEASEQQALHTVQYGLLKILSKTLAALRHFTPDVCQILLDQSLDLAEYNFLFALSFTTPTFDSEVAPSFGTLLATVNVALNMLGELDKKKEPLTQAVGLSTQAEGTRTLKSLLMFTMENCFYLLISQAMRYLRDPAVHPRDKQRMKQELSSELSTLLSSLSRYFRRGAPSSPATGVLPSPQGKSTSLSKASPESQEPLIQLVQAFVRHMQR(SEQ ID NO12)實施例12.表2中所示的人BFLP0169多肽序列的變體從存在于表2中的BFLP0169氨基酸序列變化一個氨基酸的多肽序列顯示如下。對于顯示的序列，表2中所示的BFLP0169序列的第1084位的K已經替換為R，其以粗體顯示。
MIRKSKITSVLSFCRSSRELWTILLGRSALRELSQIEAELNKHWRRLLEGLSYYKPPSPSSAEKVKANKDVASPLKELGLRISKFLGLDEEQSVQLLQCYLQEDYRGTRDSVKTVLQDERQSQALILKIADYYYEERTCILRCVLHLLTYFQDERHPYRVEYADCVDKLEKELVSKYRQQFEELYKTEAPTWETHGNLMTERQVSRWFVQCLREQSMLLEIIFLYYAYFEMAPSDLLVLTKMFKEQGFGSRQTNRHLVDETMDPFVDRIGYFSALILVEGMDIESLHKCALDDRRELHQFAQDGLICQDMDCLMLTFGDIPHHAPVLLAWALLRHTLNPEETSSVVRKIGGTAIQLNVFQYLTRLLQSLASGGNDCTTSTACMCVYGLLSFVLTSLELHTLGNQQDIIDTACEVLADPSLPELFWGTEPTSGLGIILDSVCGMFPHLLSPLLQLLRALVSGKSTAKKVYSFLDKMSFYNELYKHKPHDVISHEDGTLWRRQTPKLLYPLGGQTNLRIPQGTVGQVMLDDRAYLVRWEYSYSSWTLFTCEIEMLLHVVSTADVIQHCQRVKPIIDLVHKVISTDLSIADCLLPITSRIYMLLQRLTTVISPPVDVIASCVNCLTVLAARNPAKVWTDLRHTGFLPFVAHPVSSLSQMISAEGMNAGGYGNLLMNSEQPQGEYGVTIAFLRLITTLVKGQLGSTQSQGLVPCVMFVLKEMLPSYHKWRYNSHGVREQIGCLILELIHAILNLCHETDLHSSHTPSLQFLCICSLAYTEAGQTVINIMGIGVDTIDMVMAAQPRSDGAEGQGQGQLLIKTVKLAFSVTNNVIRLKPPSNVVSPLEQALSQHGAHGNNLIAVLAKYIYHKHDPALPRLAIQLLKRLATVAPMSVYACLGNDAAAIRDAFLTRLQSKIEDMRIKVMILEFLTVAVETQPGLIELFLNLEVKDGSDGSKEFSLGMWSCLHAVLELIDSQQQDRYWCPPLLHRAAIAFLHALWQDRRDSAMLVLRTKPKFWENLTSPLFGTLSPPSETSEPSILETCALIMKIICLEIYYVVKGSLDQSLKDTLKKFSIEKRFAYWSGYVRSLAVHVAETEGSSCTSLLEYQMLVSAWRMLLIIATTHADIMHLTDSVVRRQLFLDVLDGTKALLLVPASVNCLRLGSMKCTLLLILLRQWKRELGSVDEILGPLTEILEGVLQADQQLMEKTKAKVFSAFITVLQMKEMKVSDIPQYSQLVLNVCETLQEEVIALFDQTRHSLALGSATEDKDSMETDDCSRSRHRDQRDGVCVLGLHLAKELCEVDEDGDSWLQVTRRLPILPTLLTTLEVSLRMKQNLHFTEATLHLLLTLARTQQGATAVAGAGITQSICLPLLSVYQLSTNGTAQTPSASRKSLDAPSWPGVYRLSMSLMEQLLKTLRYNFLPEALDFVGVHQERTLQCLNAVRTVQSLACLEEADHTVGFILQLSNFMKEWHFHLPQLMRDIQVNLGYLCQACTSLLHSRKMLQHYLQNKNGDGLPSAVAQRVQRPPSAASAAPSSSKQPAADTEASEQQALHTVQYGLLKILSKTLAALRHFTPDVCQILLDQSLDLAEYNFLFALSFTTPTFDSEVAPSFGTLLATVNVALNMLGELDKKKEPLTQAVGLSTQAEGTRTLKSLLMFTMENCFYLLISQAMRYLRDPAVHPRDKQRMKQELSSELSTLLSSLSRYFRRGAPSSPATGVLPSPQGKSTSLSKASPESQEPLIQLVQAFVRHMQR(SEQ ID NO13)實施例13.表2中所示的人BFLP0169多肽序列的變體從存在于表2中的BFLP0169氨基酸序列變化一個氨基酸的多肽序列顯示如下。對于顯示的序列，表2中所示的BFLP0169序列的第1152位的A已經替換為S，其以粗體顯示。
MIRKSKITSVLSFCRSSRELWTILLGRSALRELSQIEAELNKHWRRLLEGLSYYKPPSPSSAEKVKANKDVASPLKELGLRISKFLGLDEEQSVQLLQCYLQEDYRGTRDSVKTVLQDERQSQALILKIADYYYEERTCILRCVLHLLTYFQDERHPYRVEYADCVDKLEKELVSKYRQQFEELYKTEAPTWETHGNLMTERQVSRWFVQCLREQSMLLEIIFLYYAYFEMAPSDLLVLTKMFKEQGFGSRQTNRHLVDETMDPFVDRIGYFSALILVEGMDIESLHKCALDDRRELHQFAQDGLICQDMDCLMLTFGDIPHHAPVLLAWALLRHTLNPEETSSVVRKIGGTAIQLNVFQYLTRLLQSLASGGNDCTTSTACMCVYGLLSFVLTSLELHTLGNQQDIIDTACEVLADPSLPELFWGTEPTSGLGIILDSVCGMFPHLLSPLLQLLRALVSGKSTAKKVYSFLDKMSFYNELYKHKPHDVISHEDGTLWRRQTPKLLYPLGGQTNLRIPQGTVGQVMLDDRAYLVRWEYSYSSWTLFTCEIEMLLHVVSTADVIQHCQRVKPIIDLVHKVISTDLSIADCLLPITSRIYMLLQRLTTVISPPVDVIASCVNCLTVLAARNPAKVWTDLRHTGFLPFVAHPVSSLSQMISAEGMNAGGYGNLLMNSEQPQGEYGVTIAFLRLITTLVKGQLGSTQSQGLVPCVMFVLKEMLPSYHKWRYNSHGVPEQIGCLILELIHAILNLCHETDLHSSHTPSLQFLCICSLAYTEAGQTVINIMGIGVDTIDMVMAAQPRSDGAEGQGQGQLLIKTVKLAFSVTNNVIRLKPPSNVVSPLEQALSQHGAHGNNLIAVLAKYIYHKHDPALPRLAIQLLKRLATVAPMSVYACLGNDAAAIRDAFLTRLQSKIEDMRIKVMILEFLTVAVETQPGLIELFLNLEVKDGSDGSKEFSLGMWSCLHAVLELIDSQQQDRYWCPPLLHRAAIAFLHALWQDRRDSAMLVLRTKPKFWENLTSPLFGTLSPPSETSEPSILETCALIMKIICLEIYYVVKGSLDQSLKDTLKKFSIEKRFAYWSGYVKSLAVHVAETEGSSCTSLLEYQMLVSAWRMLLIIATTHADIMHLTDSVVRRQLFLDVLDGTKALLLVPSSVNCLRLGSMKCTLLLILLRQWKRELGSVDEILGPLTEILEGVLQADQQLMEKTKAKVFSAFITVLQMKEMKVSDIPQYSQLVLNVCETLQEEVIALFDQTRHSLALGSATEDKDSMETDDCSRSRHRDQRDGVCVLGLHLAKELCEVDEDGDSWLQVTRRLPILPTLLTTLEVSLRMKQNLHFTEATLHLLLTLARTQQGATAVAGAGITQSICLPLLSVYQLSTNGTAQTPSASRKSLDAPSWPGVYRLSMSLMEQLLKTLRYNFLPEALDFVGVHQERTLQCLNAVRTVQSLACLEEADHTVGFILQLSNFMKEWHFHLPQLMRDIQVNLGYLCQACTSLLHSRKMLQHYLQNKNGDGLPSAVAQRVQRPPSAASAAPSSSKQPAADTEASEQQALHTVQYGLLKILSKTLAALRHFTPDVCQILLDQSLDLAEYNFLFALSFTTPTFDSEVAPSFGTLLATVNVALNMLGELDKKKEPLTQAVGLSTQAEGTRTLKSLLMFTMENCFYLLISQAMRYLRDPAVHPRDKQRMKQELSSELSTLLSSLSRYFRRGAPSSPATGVLPSPQGKSTSLSKASPESQEPLIQLVQAFVRHMQR(SEQ ID NO14)實施例14.表2中所示的人BFLP0169多肽序列的變體從存在于表2中的BFLP0169氨基酸序列變化一個氨基酸的多肽序列顯示如下。對于顯示的序列，表2中所示的BFLP01 69序列的第1247位的I已經替換為V，其以粗體顯示。
MIRKSKITSVLSFCRSSRELWTILLGRSALRELSQIEAELNKHWRRLLEGLSYYKPPSPSSAEKVKANKDVASPLKELGLRISKFLGLDEEQSVQLLQCYLQEDYRGTRDSVKTVLQDERQSQALILKIADYYYEERTCILRCVLHLLTYFQDERHPYRVEYADCVDKLEKELVSKYRQQFEELYKTEAPTWETHGNLMTERQVSRWFVQCLREQSMLLEIIFLYYAYFEMAPSDLLVLTKMFKEQGFGSRQTNRHLVDETMDPFVDRIGYFSALILVEGMDIESLHKCALDDRRELHQFAQDGLICQDMDCLMLTFGDIPHHAPVLLAWALLRHTLNPEETSSVVRKIGGTAIQLNVFQYLTRLLQSLASGGNDCTTSTACMCVYGLLSFVLTSLELHTLGNQQDIIDTACEVLADPSLPELFWGTEPTSGLGIILDSVCGMFPHLLSPLLQLLRALVSGKSTAKKVYSFLDKMSFYNELYKHKPHDVISHEDGTLWRRQTPKLLYPLGGQTNLRIPQGTVGQVMLDDRAYLVRWEYSYSSWTLFTCEIEMLLHVVSTADVIQHCQRVKPIIDLVHKVISTDLSIADCLLPITSRIYMLLQRLTTVISPPVDVIASCVNCLTVLAARNPAKVWTDLRHTGFLPFVAHPVSSLSQMISAEGMNAGGYGNLLMNSEQPQGEYGVTIAFLRLITTLVKGQLGSTQSQGLVPCVMFVLKEMLPSYHKWRYNSHGVREQIGCLILELIHAILNLCHETDLHSSHTPSLQFLCICSLAYTEAGQTVINIMGIGVDTIDMVMAAQPRSDGAEGQGQGQLLIKTVKLAFSVTNNVIRLKPPSNVVSPLEQALSQHGAHGNNLIAVLAKYIYHKHDPALPRLAIQLLKRLATVAPMSVYACLGNDAAAIRDAFLTRLQSKIEDMRIKVMILEFLTVAVETQPGLIELFLNLEVKDGSDGSKEFSLGMWSCLHAVLELIDSQQQDRYWCPPLLHRAAIAFLHALWQDRRDSAMLVLRTKPKFWENLTSPLFGTLSPPSETSEPSILETCALIMKIICLEIYYVVKGSLDQSLKDTLKKFSIEKRFAYWSGYVKSLAVHVAETEGSSCTSLLEYQMLVSAWRMLLIIATTHADIMHLTDSVVRRQLFLDVLDGTKALLLVPSSVNCLRLGSMKCTLLLILLRQWKRELGSVDEILGPLTEILEGVLQADQQLMEKTKAKVFSAFITVLQMKEMKVSDIPQYSQLVLNVCETLQEEVVALFDQTRHSLALGSATEDKDSMETDDCSRSRHRDQRDGVCVLGLHLAKELCEVDEDGDSWLQVTRRLPILPTLLTTLEVSLRMKQNLHFTEATLHLLLTLARTQQGATAVAGAGITQSICLPLLSVYQLSTNGTAQTPSASRKSLDAPSWPGVYRLSMSLMEQLLKTLRYNFLPFALDFVGVHQERTLQCLNAVRTVQSLACLEEADHTVGFILQLSNFMKEWHFHLPQLMRDIQVNLGYLCQACTSLLHSRKMLQHYLQNKNGDGLPSAVAQRVQRPPSAASAAPSSSKQPAADTEASEQQALHTVQYGLLKILSKTLAALRHFTPDVCQILLDQSLDLAEYNFLFALSFTTPTFDSEVAPSFGTLLATVNVALNMLGELDKKKEPLTQAVGLSTQAEGTRTLKSLLMFTMENCFYLLISQAMRYLRDRAVHPRDKQRMKQELSSELSTLLSSLSRYFRRGAPSSPATGVLPSPQGKSTSLSKASPESQEPLIQLVQAFVRHMQR(SEQ ID NO15)實施例15.表2中所示的人BFLP0169多肽序列的變體從存在于表2中的BFLP0169氨基酸序列變化一個氨基酸的多肽序列顯示如下。對于顯示的序列，表2中所示的BFLP0169序列的第1331位的K已經替換為R，其以粗體顯示。
MIRKSKITSVLSFCRSSRELWTILLGRSALRELSQIEAELNKHWRRLLEGLSYYKPPSPSSAEKVKANKDVASPLKELGLRISKFLGLDEEQSVQLLQCYLQEDYRGTRDSVKTVLQDERQSQALILKIADYYYEERTCILRCVLHLLTYFQDERHPYRVEYADCVDKLEKELVSKYRQQFEELYKTEAPTWETHGNLMTERQVSRWFVQCLREQSMLLEIIFLYYAYFEMAPSDLLVLTKMFKEQGFGSRQTNRHLVDETMDPFVDRIGYFSALILVEGMDIESLHKCALDDRRELHQFAQDGLICQDMDCLMLTFGDIPHHAPVLLAWALLRHTLNPEETSSVVRKIGGTAIQLNVFQYLTRLLQSLASGGNDCTTSTACMCVYGLLSFVLTSLELHTLGNQQDIIDTACEVLADPSLPELFWGTEPTSGLGIILDSVCGMFPHLLSPLLQLLRALVSGKSTAKKVYSFLDKMSFYNELYKHKPHDVISHEDGTLWRRQTPKLLYPLGGQTNLRIPQGTVGQVMLDDRAYLVRWEYSYSSWTLFTCEIEMLLHVVSTADVIQHCQRVKPIIDLVHKVISTDLSIADCLLPITSRIYMLLQRLTTVISPPVDVIASCVNCLTVLAARNPAKVWTDLRHTGFLPFVAHPVSSLSQMISAEGMNAGGYGNLLMNSEQPQGEYGVTIAFLRLITTLVKGQLGSTQSQGLVPCVMFVLKEMLPSYHKWRYNSHGVREQIGCLILELIHAILNLCHETDLHSSHTPSLQFLCICSLAYTEAGQTVINIMGIGVDTIDMVMAAQPRSDGAEGQGQGQLLIKTVKLAFSVTNNVIRLKPPSNVVSPLEQALSQHGAHGNNLIAVLAKYIYHKHDPALPRLAIQLLKRLATVAPMSVYACLGNDAAAIRDAFLTRLQSKIEDMRIKVMILEFLTVAVETQPGLIELFLNLEVKDGSDGSKEFSLGMWSCLHAVLELIDSQQQDRYWCPPLLHRAAIAFLHALWQDRRDSAMLVLRTKPKFWENLTSPLFGTLSPPSETSEPSILETCALIMKIICLEIYYVVKGSLDQSLKDTLKKFSIEKRFAYWSGYVKSLAVHVAETEGSSCTSLLEYQMLVSAWRMLLIIATTHADIMHLTDSVVRRQLFLDVLDGTKALLLVPSSVNCLRLGSMKCTLLLILLRQWKRELGSVDEILGPLTEILEGVLQADQQLMEKTKAKVFSAFITVLQMKEMKVSDIPQYSQLVLNVCETLQEEVIALFDQTRHSLALGSATEDKDSMETDDCSRSRHRDQRDGVCVLGLHLAKELCEVDEDGDSWLQVTRRLPILPTLLTTLEVSLRMRQNLHFTEATLHLLLTLARTQQGATAVAGAGITQSICLPLLSVYQLSTNGTAQTPSASRKSLDAPSWPGVYRLSMSLMEQLLKTLRYNFLPEALDFVGVHQERTLQCLNAVRTVQSLACLEEADHTVGFILQLSNFMKEWHFHLPQLMRDIQVNLGYLCQACTSLLHSRKMLQHYLQNKNGDGLPSAVAQRVQRPPSAASAAPSSSKQPAADTEASEQQALHTVQYGLLKILSKTLAALRHFTPDVCQILLDQSLDLAEYNFLFALSFTTPTFDSEVAPSFGTLLATVNVALNMLGELDKKKEPLTQAVGLSTQAEGTRTLKSLLMFTMENCFYLLISQAMRYLRDPAVHPRDKQRMKQELSSELSTLLSSLSRYFRRGAPSSPATGVLPSPQGKSTSLSKASPESQEPLIQLVQAFVRHMQR(SEQ ID NO16)實施例16.表2中所示的人BFLP0169多肽序列的變體從存在于表2中的BFLP0169氨基酸序列變化一個氨基酸的多肽序列顯示如下。對于顯示的序列，表2中所示的BFLP0169序列的第1449位的C已經替換為Y，其以粗體顯示。
MIRKSKITSVLSFCRSSRELWTILLGRSALRELSQIEAELNKHWRRLLEGLSYYKPPSPSSAEKVKANKDVASPLKELGLRISKFLGLDEEQSVQLLQCYLQEDYRGTRDSVKTVLQDERQSQALILKIADYYYEERTCILRCVLHLLTYFQDERHPYRVEYADCVDKLEKELVSKYRQQFEELYKTEAPTWETHGNLMTERQVSRWFVQCLREQSMLLEIIFLYYAYFEMAPSDLLVLTKMFKEQGFGSRQTNRHLVDETMDPFVDRIGYFSALILVEGMDIESLHKCALDDRRELHQFAQDGLICQDMDCLMLTFGDIPHHAPVLLAWALLRHTLNPEETSSVVRKIGGTAIQLNVFQYLTRLLQSLASGGNDCTTSTACMCVYGLLSFVLTSLELHTLGNQQDIIDTACEVLADPSLPELFWGTEPTSGLGIILDSVCGMFPHLLSPLLQLLRALVSGKSTAKKVYSFLDKMSFYNELYKHKPHDVISHEDGTLWRRQTPKLLYPLGGQTNLRIPQGTVGQVMLDDRAYLVRWEYSYSSWTLFTCEIEMLLHVVSTADVIQHCQRVKPIIDLVHKVISTDLSIADCLLPITSRIYMLLQRLTTVISPPVDVIASCVNCLTVLAARNPAKVWTDLRHTGFLPFVAHPVSSLSQMISAEGMNAGGYGNLLMNSEQPQGEYGVTIAFLRLITTLVKGQLGSTQSQGLVPGVMFVLKEMLPSYHKWRYNSHGVREQIGCLILELIHAILNLCHETDLHSSHTPSLQFLCICSLAYTEAGQTVINIMGIGVDTIDMVMAAQPRSDGAEGQGQGQLLIKTVKLAFSVTNNVIRLKPPSNVVSPLEQALSQHGAHGNNLIAVLAKYIYHKHDPALPRLAIQLLKRLATVAPMSVYACLGNDAAAIRDAFLTRLQSKIEDMRIKVMILEFLTVAVETQPGLIELFLNLEVKDGSDGSKEFSLGMWSCLHAVLELIDSQQQDRYWCPPLLHRAAIAFLHALWQDRRDSAMLVLRTKPKFWENLTSPLFGTLSPPSETSEPSILETCALIMKIICLEIYYVVKGSLDQSLKDTLKKFSIEKRFAYWSGYVKSLAVHVAETEGSSCTSLLEYQMLVSAWRMLLIIATTHADIMHLTDSVVRRQLFLDVLDGTKALLLVPSSVNCLRLGSMKCTLLLILLRQWKRELGSVDEILGPLTEILEGVLQADQQLMEKTKAKVFSAFITVLQMKEMKVSDIPQYSQLVLNVCETLQEEVIALFDQTRHSLALGSATEDKDSMETDDCSRSRHRDQRDGVCVLGLHLAKELCEVDEDGDSWLQVTRRLPILPTLLTTLEVSLRMKQNLHFTEATLHLLLTLARTQQGATAVAGAGITQSICLPLLSVYQLSTNGTAQTPSASRKSLDAPSWPGVYRLSMSLMEQLLKTLRYNFLPEALDFVGVHQERTLQCLNAVRTVQSLAYLEEADHTVGFILQLSNFMKEWHFHLPQLMRDIQVNLGYLCQACTSLLHSRKMLQHYLQNKNGDGLPSAVAQRVQRPPSAASAAPSSSKQPAADTEASEQQALHTVQYGLLKILSKTLAALRHFTPDVCQILLDQSLDLAEYNFLFALSFTTPTFDSEVAPSFGTLLATVNVALNMLGELDKKKEPLTQAVGLSTQAEGTRTLKSLLMFTMENCFYLLISQAMRYLRDPAVHPRDKQRMKQELSSELSTLLSSLSRYFRRGAPSSPATGVLPSPQGKSTSLSKASPESQEPLIQLVQAFVRHMQR(SEQ ID NO17)實施例17.表2中所示的人BFLP0169多肽序列的變體從存在于表2中的BFLP0169氨基酸序列變化一個氨基酸的多肽序列顯示如下。對于顯示的序列，表2中所示的BFLP0169序列的第1542位的D已經替換為Q，其以粗體顯示。
MIRKSKITSVLSFCRSSRELWTILLGRSALRELSQIEAELNKHWRRLLEGLSYYKPPSPSSAEKVKANKDVASPLKELGLRISKFLGLDEEQSVQLLQCYLQEDYRGTRDSVKTVLQDERQSQALILKIADYYYEERTCILRCVLHLLTYFQDERHPYRVEYADCVDKLEKELVSKYRQQFEELYKTEAPTWETHGNLMTERQVSRWFVQCLREQSMLLEIIFLYYAYFEMAPSDLLVLTKMFKEQGFGSRQTNRHLVDETMDPFVDRIGYFSALILVEGMDIESLHKCALDDRRELHQFAQDGLICQDMDCLMLTFGDIPHHAPVLLAWALLRHTLNPEETSSVVRKIGGTAIQLNVFQYLTRLLQSLASGGNDCTTSTACMCVYGLLSFVLTSLELHTLGNQQDIIDTACEVLADPSLPELFWGTEPTSGLGIILDSVCGMFPHLLSPLLQLLRALVSGKSTAKKVYSFLDKMSFYNELYKHKPHDVISHEDGTLWRRQTPKLLYPLGGQTNLRIPQGTVGQVMLDDRAYLVRWEYSYSSWTLFTCEIEMLLHVVSTADVIQHCQRVKPIIDLVHKVISTDLSIADCLLPITSRIYMLLQRLTTVISPPVDVIASCVNCLTVLAARNPAKVWTDLRHTGFLPFVAHPVSSLSQMISAEGMNAGGYGNLLMNSEQPQGEYGVTIAFLRLITTLVKGQLGSTQSQGLVPCVMFVLKEMLPSYHKWRYNSHGVREQIGCLILELIHAILNLCHETDLHSSHTPSLQFLCICSLAYTEAGQTVINIMGIGVDTIDMVMAAQPRSDGAEGQGQGQLLIKTVKLAFSVTNNVIRLKPPSNVVSPLEQALSQHGAHGNNLIAVLAKYIYHKHDPALPRLAIQLLKRLATVAPMSVYACLGNDAAAIRDAFLTRLQSKIEDMRIKVMILEFLTVAVETQPGLIELFLNLEVKDGSDGSKEFSLGMWSCLHAVLELIDSQQQDRYWCPPLLHRAAIAFLHALWQDRRDSAMLVLRTKPKFWENLTSPLFGTLSPPSETSEPSILETCALIMKIICLEIYYVVKGSLDQSLKDTLKKFSIEKRFAYWSGYVKSLAVHVAETEGSSCTSLLEYQMLVSAWRMLLIIATTHADIMHLTDSVVRRQLFLDVLDGTKALLLVPSSVNCLRLGSMKCTLLLILLRQWKRELGSVDEILGPLTEILEGVLQADQQLMEKTKAKVFSAFITVLQMKEMKVSDIPQYSQLVLNVCETLQEEVIALFDQTRHSLALGSATEDKDSMETDDCSRSRHRDQRDGVCVLGLHLAKELCEVDEDGDSWLQVTRRLPILPTLLTTLEVSLRMKQNLHFTEATLHLLLTLARTQQGATAVAGAGITQSICLPLLSVYQLSTNGTAQTPSASRKSLDAPSWPGVYRLSMSLMEQLLKTLRYNFLPEALDFVGVHQERTLQCLNAVRTVQSLACLEEADHTVGFILQLSNFMKEWHFHLPQLMRDIQVNLGYLCQACTSLLHSRKMLQHYLQNKNGDGLPSAVAQRVQRPPSAASAAPSSSKQPAAQTEASEQQALHTVQYGLLKILSKTLAALRHFTPDVCQILLDQSLDLAEYNFLFALSFTTPTFDSEVAPSFGTLLATVNVALNMLGELDKKKEPLTQAVGLSTQAEGTRTLKSLLMFTMENCFYLLISQAMRYLRDPAVHPRDKQRMKQELSSELSTLLSSLSRYFRRGAPSSPATGVLPSPQGKSTSLSKASPESQEPLIQLVQAFVRHMQR(SEQ ID NO18)實施例18.表2中所示的人BFLP0169多肽序列的變體從存在于表2中的BFLP0169氨基酸序列變化一個氨基酸的多肽序列顯示如下。對于顯示的序列，表2中所示的BFLP0169序列的第1706位的F已經替換為H，其以粗體顯示。
MIRKSKITSVLSFCRSSRELWTILLGRSALRELSQIEAELNKHWRRLLEGLSYYKPPSPSSAEKVKANKDVASPLKELGLRISKFLGLDEEQSVQLLQCYLQEDYRGTRDSVKTVLQDERQSQALILKIADYYYEERTCILRCVLHLLTYFQDERHPYRVEYADCVDKLEKELVSKYRQQFEELYKTEAPTWETHGNLMTERQVSRWFVQCLREQSMLLEIIFLYYAYFEMAPSDLLVLTKMFKEQGFGSRQTNRHLVDETMDPFVDRIGYFSALILVEGMDIESLHKCALDDRRELHQFAQDGLICQDMDCLMLTFGDIPHHAPVLLAWALLRHTLNPEETSSVVRKIGGTAIQLNVFQYLTRLLQSLASGGNDCTTSTACMCVYGLLSFVLTSLELHTLGNQQDIIDTACEVLADPSLPELFWGTEPTSGLGIILDSVCGMFPHLLSPLLQLLRALVSGKSTAKKVYSFLDKMSFYNELYKHKPHDVISHEDGTLWRRQTPKLLYPLGGQTNLRIPQGTVGQVMLDDRAYLVRWEYSYSSWTLFTCEIEMLLHVVSTADVIQHCQRVKPIIDLVHKVISTDLSIADCLLPITSRIYMLLQRLTTVISPPVDVIASCVNCLTVLAARNPAKVWTDLRHTGFLPFVAHPVSSLSQMISAEGMNAGGYGNLLMNSEQPQGEYGVTIAFLRLITTLVKGQLGSTQSQGLVPCVMFVLKEMLPSYHKWRYNSHGVREQIGCLILELIHAILNLCHETDLHSSHTPSLQFLCICSLAYTEAGQTVINIMGIGVDTIDMVMAAQPRSDGAEGQGQGQLLIKTVKLAFSVTNNVIRLKPPSNVVSPLEQALSQHGAHGNNLIAVLAKYIYHKHDPALPRLAIQLLKRLATVAPMSVYACLGNDAAAIRDAFLTRLQSKIEDMRIKVMILEFLTVAVETQPGLIELFLNLEVKDGSDGSKEFSLGMWSCLHAVLELIDSQQQDRYWCPPLLHRAAIAFLHALWQDRRDSAMLVLRTKPKFWENLTSPLFGTLSPPSETSEPSILETCALIMKIICLEIYYVVKGSLDQSLKDTLKKFSIEKRFAYWSGYVKSLAVHVAETEGSSCTSLLEYQMLVSAWRMLLIIATTHADIMHLTDSVVRRQLFLDVLDGTKALLLVPSSVNCLRLGSMKCTLLLILLRQWKRELGSVDEILGPLTEILEGVLQADQQLMEKTKAKVFSAFITVLQMKEMKVSDIPQYSQLVLNVCETLQEEVIALFDQTRHSLALGSATEDKDSMETDDCSRSRHRDQRDGVCVLGLHLAKELCEVDEDGDSWLQVTRRLPILPTLLTTLEVSLRMKQNLHFTEATLHLLLTLARTQQGATAVAGAGITQSICLPLLSVYQLSTNGTAQTPSASRKSLDAPSWPGVYRLSMSLMEQLLKTLRYNFLPEALDFVGVHQERTLQCLNAVRTVQSLACLEEADHTVGFILQLSNFMKEWHFHLPQLMRDIQVNLGYLCQACTSLLHSRKMLQHYLQNKNGDGLPSAVAQRVQRPPSAASAAPSSSKQPAAQTEASEQQALHTVQYGLLKILSKTLAALRHFTPDVCQILLDQSLDLAEYNFLFALSFTTPTFDSEVAPSFGTLLATVNVALNMLGELDKKKEPLTQAVGLSTQAEGTRTLKSLLMFTMENCFYLLISQAMRYLRDPAVHPRDKQRMKQELSSELSTLLSSLSRYHRRGAPSSPATGVLPSPQGKSTSLSKASPESQEPLIQLVQAFVRHMQR(SEQ ID NO19)其他的實施方案本發明已經結合其發明詳述而進行了描述，上述說明書意在說明而非限制本發明的范圍，本發明的范圍通過所附的權利要求的范圍來加以限定。其他的方面、優勢和改變是在下列權利要求的范圍之內的。
序列表<110>Wyeth<120>用于治療狼瘡腎炎的組合物和方法<130>22058-582-061<140>PCT/US03/37339<141>2003-11-21<150>60/428,094<151>2002-11-21<160>26<170>PatentIn Ver.2.1<210>1<211>5987<212>DNA<213>人<400>1atgatcagaa agagcaaaat tacctctgtt ctctcatttt gcaggagcag tagagaactg 60tggactattc tgcttggaag gtcagctctg agagagctga gtcagattga ggcagaactg 120aataaacatt ggcggcgatt gttagagggg ctttcttact acaaacctcc cagtccaagt 180tcagctgaaa aagtgaaagc taataaagat gtagcttcac cattgaagga actgggttta 240agaatcagca agtttttggg tcttgatgaa gaacagagtg tgcagttact ccagtgttac 300ctgcaagagg actacagggg tactcgggac tcagtaaaga cagtactgca agatgagagg 360cagagccagg ccttaatcct gaagattgca gattattatt atgaagaaag aacctgtatt 420cttcgttgtg tcttacacct tctcacttac ttccaagatg aaagacaccc ctatagggtt 480gaatatgcag actgtgttga taaattggag aaggaactag tttcaaaata cagacagcag 540ttcgaagagc tttataaaac tgaagcacca acttgggaga cacatggaaa tctcatgaca 600gagcgccaag tgtctcgctg gtttgttcag tgccttcggg aacagtccat gctgctagaa 660attattttcc tttattatgc atactttgag atggcaccca gtgacttact tgtattaacc 720aagatgttta aagagcaagg atttggtagt aggcagacca ataggcacct ggtggatgag 780actatggatc cttttgtaga tcggattggc tacttcagtg ccctcatcct ggtggagggc 840atggatatcg agtccttgca taagtgtgct ttggatgaca gaagagaact gcatcagttt 900gcgcaggatg ggcttatttg tcaggatatg gactgtttaa tgttgacctt tggggacatt 960ccacatcatg ccccagtgct tttggcctgg gctctcctcc gtcacactct gaacccagaa 1020gagacaagca gtgtggtccg gaagataggt ggcacagcca tccagctgaa tgtgtttcag 1080tacttgaccc gattgctcca gtcccttgcc agtgggggaa atgattgcac caccagcact 1140gcatgcatgt gtgtctatgg actgctctct ttcgttctga cctcgttgga gctgcacacc 1200
ctgggcaatc agcaggatat aattgataca gcatgtgaag tattggccga cccttctctt 1260ccggaactgt tctggggaac agagccaact tctggccttg ggatcattct ggacagtgtg 1320tgtggaatgt ttccccacct tctctcccca ctcctgcaac tgctccgagc cctggtatca 1380gggaagtcca cagccaaaaa ggtgtatagc ttcttggata agatgtcttt ctacaatgaa 1440ctttataaac acaagcctca tgatgtgatc tcccatgaag atggaactct ttggcggaga 1500caaacaccca aactccttta tccccttggg ggtcaaacca accttcgcat acctcaaggc 1560actgtgggcc aagtaatgtt ggatgatagg gcatacctgg tacgctggga atactcctat 1620agcagctgga ccctctttac ctgcgagatt gaaatgttgc ttcatgttgt ttcaactgca 1680gatgtgattc agcactgcca gcgagtcaaa cccatcattg atctcgtcca taaggtcatc 1740agtacagacc tgtcgatagc agactgtctc ctgcccatca catctcgcat ctacatgctg 1800ctgcagcggt taacgacagt gatctcccca cctgtggatg tcattgcttc ttgtgtcaac 1860tgcttaactg ttttggctgc ccgcaatcca gcaaaggtct ggactgatct tcgtcacaca 1920ggttttttac catttgtggc ccatcctgtc tccagcctga gtcagatgat tagtgcggaa 1980gggatgaatg ctggagggta cggaaacctc ttgatgaaca gtgaacagcc tcagggcgag 2040tatggggtta ctattgcctt tctgcgcttg atcaccaccc ttgtcaaggg gcaacttggt 2100agtacccaga gccaaggact tgtaccctgt gtaatgtttg tgctgaagga gatgcttccc 2160agctaccata agtggcgcta caactctcat ggagtgaggg aacagattgg ttgcctgatc 2220ttggagctga ttcatgcgat actgaacctg tgccacgaga cagacctgca cagcagtcat 2280actcccagcc tgcagtttct ctgcatctgc agcctggcat acacagaagc aggacagaca 2340gttatcaata tcatgggcat tggcgtggac accattgaca tggtgatggc tgctcagcct 2400cgaagtgatg gggcagaggg ccaggggcag ggccagctgc tgatcaagac agtgaaactg 2460gcattctccg tcaccaacaa tgttattcgg ctgaaacctc cttctaatgt ggtgtccccc 2520ctggaacagg ctctctcaca acatggtgct catggaaaca acctcattgc tgttctagcc 2580aaatacatct accacaaaca tgaccctgct ttgccacgtc ttgccattca gctgctgaaa 2640cgtctggcca cggtggcccc aatgtcagtg tatgcttgtc tgggcaatga tgcggctgcc 2700attcgtgatg ccttcctgac ccgattgcag agcaaaattg aggacatgcg catcaaagtc 2760atgattctag agttcctcac tgttgcagta gagacccagc caggcctcat cgaactgttt 2820ctgaacctgg aagttaagga tggcagtgat ggctcaaagg aattcagcct tgggatgtgg 2880agctgtctcc atgcagtgct ggagctgatt gattcccaac agcaagatcg atactggtgc 2940ccacccctgc tgcatcgtgc cgccattgcc tttttgcatg ctctgtggca ggatcggagg 3000gacagtgcca tgctggtcct ccgaaccaaa cccaagtttt gggaaaattt aaccagtccg 3060ctgtttggaa ccctttctcc tccctctgaa acatcagagc ccagcatcct ggaaacctgt 3120gccctaatca tgaagataat ttgcttggag atatactatg tagtaaaggg ttcattagac 3180cagtcattaa aggatacact gaagaaattt tccatcgaga aacgctttgc ctactggtca 3240gggtatgtca agtcattggc agttcacgtg gccgaaacag aaggcagcag ctgcacctcc 3300ttgttagagt accagatgct ggtgtccgcc tggaggatgc ttctcatcat tgccaccact 3360catgcagata taatgcacct gactgactct gtggtgcgtc gccagctctt tcttgacgtg 3420cttgatggaa ccaaagcatt actcctagtt ccagcctcag tgaactgcct tcgccttggc 3480tccatgaagt gcactctgct gcttatcctc ctccggcagt ggaagagaga gttaggttct 3540gtggatgaaa tccttggacc cttgacggag atcctggagg gagtgctgca ggccgaccag 3600caactcatgg agaagaccaa ggccaaggtg ttctcagcat tcatcacagt gttgcaaatg 3660aaggagatga aagtaagtga catcccccag tactcccagc tggtgctgaa tgtctgtgag 3720accctccaag aggaagtgat tgcactcttc gaccagaccc gccacagtct ggcattaggc 3780agtgccacag aggacaagga cagcatggag actgacgact gttctcggtc ccggcacagg 3840
gaccagcgtg atggggtgtg tgtcctgggc ctgcacctgg ccaaggagct gtgtgaggta 3900gacgaggatg gtgactcctg gctgcaggta acccgcaggc tccccatcct acccaccctc 3960ctcaccactc tagaggtgag ccttcgcatg aagcagaacc tgcatttcac tgaggccaca 4020ttgcatctgc tcctcaccct ggctcgcact cagcagggag ccacagcagt ggctggagct 4080ggcatcaccc agagcatttg tttgcccctt ctgagtgtgt accagctgag caccaacggc 4140acagcacaga cacctagtgc ctctcggaag tccctggatg ccccctcttg gccaggagtc 4200taccgcctgt ccatgtccct gatggagcag ctgctcaaaa ctctgcgcta caacttcctg 4260cctgaggccc tggacttcgt gggtgtccac caggagcgga ccttacagtg cctcaacgca 4320gtgaggacag tgcagagtct ggcctgcctg gaggaggcgg accacaccgt gggttttatt 4380ctgcagctct ctaacttcat gaaggagtgg cacttccacc tgcctcagct catgcgtgat 4440atccaggtca acctgggtta cttgtgccag gcatgtacct ctctcctgca cagtcgaaag 4500atgctgcagc attacttaca gaacaaaaat ggggatggcc tcccctcagc tgttgcccag 4560cgagtccaga ggccaccgtc tgctgcttct gctgccccct cctcctcaaa gcagcccgct 4620gctgacacag aggcatcaga gcagcaggcc ttgcacacag tccagtatgg ccttctcaag 4680atcctcagca agacgctggc agccctgcgc cacttcaccc cagatgtctg ccagattctg 4740ctggatcagt ccctggacct tgctgaatac aacttcctgt ttgccctgag ctttaccact 4800cccacctttg actccgaagt ggccccctcc ttcgggaccc ttctggccac agtgaatgtg 4860gccctcaaca tgcttggaga gctggacaag aaaaaggagc ccctcaccca ggcagtgggg 4920ctcagcacac aggcagaagg gaccaggacg ttaaagtccc tcctgatgtt taccatggaa 4980aactgcttct acctgctcat ctctcaggcg atgcggtacc ttagggaccc ggctgtgcac 5040ccccgggaca aacagcggat gaagcaggag ctcagctctg agttgagcac gctgctgtcc 5100agcctctcgc gctacttccg ccggggagcc cccagctccc ctgccactgg tgtcctcccc 5160tcgccgcagg gcaagtccac ctctctctcc aaagccagcc ctgagagtca ggagcctctg 5220atccagttgg tgcaggcgtt tgtccggcat atgcaaagat agggcagtgc tgttctgccc 5280acctacccct ctccaccagc ctacactgca ccctggctgg caggggtgct gctggctgct 5340agggcctata caatggaggg cacctcctgt cacccccctc ccggagtagc cacgactcca 5400gccaccaccc actgacgtta tttttatact agatgaagag gtcaacagca ggcatgggga 5460gccgagtctt ctgtgctcag gtcctcacgc tgcagacgcc ccctagagga actttccttc 5520ctttccagca ttccccacag cactgccggc caggggagag gcggcagccc agcagagggc 5580tctatgcacg ggtttcaaac ctgttttcca cactctgtct ttgcagtttt ggtaattctg 5640tggtctattt atacagatat taaaatcttg tttatagaca gctgtgtgat gtttaacttc 5700aaagcccagg gatgacaacg tggctctcag aacctagaaa actcccctgg ccaggcgcct 5760gggagtgggg ctgcagcctc gggggaaggc aggtactgat ggatggctag ttcaccagca 5820tctcctcatt cctgtccttg ggctgagggt ttggctgggt gggcgctgtc agatattccc 5880ttccttggcc tgcgctggtc ctgtccttga ccctgctttc attggcccag tgggctgagc 5940tcatccctgg gtgagccttt cttgaagctc tgtgccttcc tatttat 5987<210>2<211>1753<212>PRT<213>人<400>2
Met Ile Arg Lys Ser Lys Ile Thr Ser Val Leu Ser Phe Cys Arg Ser1 5 10 15Ser Arg Glu Leu Trp Thr Ile Leu Leu Gly Arg Ser Ala Leu Arg Glu20 25 30Leu Ser Gln Ile Glu Ala Glu Leu Asn Lys His Trp Arg Arg Leu Leu35 40 45Glu Gly Leu Ser Tyr Tyr Lys Pro Pro Ser Pro Ser Ser Ala Glu Lys50 55 60Val Lys Ala Asn Lys Asp Val Ala Ser Pro Leu Lys Glu Leu Gly Leu65 70 75 80Arg Ile Ser Lys Phe Leu Gly Leu Asp Glu Glu Gln Ser Val Gln Leu85 90 95Leu Gln Cys Tyr Leu Gln Glu Asp Tyr Arg Gly Thr Arg Asp Ser Val100 105 110Lys Thr Val Leu Gln Asp Glu Arg Gln Ser Gln Ala Leu Ile Leu Lys115 120 125Ile Ala Asp Tyr Tyr Tyr Glu Glu Arg Thr Cys Ile Leu Arg Cys Val130 135 140Leu His Leu Leu Thr Tyr Phe Gln Asp Glu Arg His Pro Tyr Arg Val145 150 155 160Glu Tyr Ala Asp Cys Val Asp Lys Leu Glu Lys Glu Leu Val Ser Lys165 170 175Tyr Arg Gln Gln Phe Glu Glu Leu Tyr Lys Thr Glu Ala Pro Thr Trp180 185 190Glu Thr His Gly Asn Leu Met Thr Glu Arg Gln Val Ser Arg Trp Phe195 200 205Val Gln Cys Leu Arg Glu Gln Ser Met Leu Leu Glu Ile Ile Phe Leu210 215 220Tyr Tyr Ala Tyr Phe Glu Met Ala Pro Ser Asp Leu Leu Val Leu Thr225 230 235 240
Lys Met Phe Lys Glu Gln Gly Phe Gly Ser Arg Gln Thr Asn Arg His245 250 255Leu Val Asp Glu Thr Met Asp Pro Phe Val Asp Arg Ile Gly Tyr Phe260 265 270Ser Ala Leu Ile Leu Val Glu Gly Met Asp Ile Glu Ser Leu His Lys275 280 285Cys Ala Leu Asp Asp Arg Arg Glu Leu His Gln Phe Ala Gin Asp Gly290 295 300Leu Iie Cys Gln Asp Met Asp Cys Leu Met Leu Thr Phe Gly Asp Ile305 310 315 320Pro His His Ala Pro Val Leu Leu Ala Trp Ala Leu Leu Arg His Thr325 330 335Leu Asn Pro Glu Glu Thr Ser Ser Val Val Arg Lys Ile Gly Gly Thr340 345 350Ala Ile Gln Leu Asn Val Phe Gln Tyr Leu Thr Arg Leu Leu Gln Ser355 360 365Leu Ala Ser Gly Gly Asn Asp Cys Thr Thr Ser Thr Ala Cys Met Cys370 375 380Val Tyr Gly Leu Leu Ser Phe Val Leu Thr Ser Leu Glu Leu His Thr385 390 395 400Leu Gly Asn Gln Gln Asp Ile Ile Asp Thr Ala Cys Glu Val Leu Ala405 410 415Asp Pro Ser Leu Pro Glu Leu Phe Trp Gly Thr Glu Pro Thr Ser Gly420 425 430Leu Gly Ile Ile Leu Asp Ser Val Cys Gly Met Phe Pro His Leu Leu435 440 445Ser Pro Leu Leu Gln Leu Leu Arg Ala Leu Val Ser Gly Lys Ser Thr450 455 460Ala Lys Lys Val Tyr Ser Phe Leu Asp Lys Met Ser Phe Tyr Asn Glu
465 470 475 480Leu Tyr Lys His Lys Pro His Asp Val Ile Ser His Glu Asp Gly Thr485 490 495Leu Trp Arg Arg Gln Thr Pro Lys Leu Leu Tyr Pro Leu Gly Gly Gln500 505 510Thr Asn Leu Arg Ile Pro Gln Gly Thr Val Gly Gln Val Met Leu Asp515 520 525Asp Arg Ala Tyr Leu Val Arg Trp Glu Tyr Ser Tyr Ser Ser Trp Thr530 535 540Leu Phe Thr Cys Glu Ile Glu Met Leu Leu His Val Val Ser Thr Ala545 550 555 560Asp Val Ile Gln His Cys Gln Arg Val Lys Pro Ile Ile Asp Leu Val565 570 575His Lys Val Ile Ser Thr Asp Leu Ser Ile Ala Asp Cys Leu Leu Pro580 585 590Ile Thr Ser Arg Ile Tyr Met Leu Leu Gln Arg Leu Thr Thr Val Ile595 600 605Ser Pro Pro Val Asp Val Ile Ala Ser Cys Val Asn Cys Leu Thr Val610 615 620Leu Ala Ala Arg Asn Pro Ala Lys Val Trp Thr Asp Leu Arg His Thr625 630 635 640Gly Phe Leu Pro Phe Val Ala His Pro Val Ser Ser Leu Ser Gln Met645 650 655Ile Ser Ala Glu Gly Met Asn Ala Gly Gly Tyr Gly Asn Leu Leu Met660 665 670Asn Ser Glu Gln Pro Gln Gly Glu Tyr Gly Val Thr Ile Ala Phe Leu675 680 685Arg Leu Ile Thr Thr Leu Val Lys Gly Gln Leu Gly Ser Thr Gln Ser690 695 700
Gln Gly Leu Val Pro Cys Val Met Phe Val Leu Lys Glu Met Leu Pro705 710 715 720Ser Tyr His Lys Trp Arg Tyr Asn Ser His Gly Val Arg Glu Gln Ile725 730 735Gly Cys Leu Ile Leu Glu Leu Ile His Ala Ile Leu Asn Leu Cys His740 745 750Glu Thr Asp Leu His Ser Ser His Thr Pro Ser Leu Gln Phe Leu Cys755 760 765Ile Cys Ser Leu Ala Tyr Thr Glu Ala Gly Gln Thr Val Ile Asn Ile770 775 780Met Gly Ile Gly Val Asp Thr Ile Asp Met Val Met Ala Ala Gln Pro785 790 795 800Arg Ser Asp Gly Ala Glu Gly Gln Gly Gln Gly Gln Leu Leu Ile Lys805 810 815Thr ValLys Leu Ala Phe Ser Val Thr Asn Asn Val Ile Arg Leu Lys820 825 830Pro Pro Ser Asn Val Val Ser Pro Leu Glu Gln Ala Leu Ser Gln His835 840 845Gly Ala His Gly Asn Asn Leu Ile Ala Val Leu Ala Lys Tyr Ile Tyr850 855 860His Lys His Asp Pro Ala Leu Pro Arg Leu Ala Ile Gln Leu Leu Lys865 870 875 880Arg Leu Ala Thr Val Ala Pro Met Ser Val Tyr Ala Cys Leu Gly Asn885 890 895Asp Ala Ala Ala Ile Arg Asp Ala Phe Leu Thr Arg Leu Gln Ser Lys900 905 910Ile Glu Asp Met Arg Ile Lys Val Met Ile Leu Glu Phe Leu Thr Val915 920 925Ala Val Glu Thr Gln Pro Gly Leu Ile Glu Leu Phe Leu Asn Leu Glu930 935 940
Val Lys Asp Gly Ser Asp Gly Ser Lys Glu Phe Ser Leu Gly Met Trp945 950 955 960Ser Cys Leu His Ala Val Leu Glu Leu Ile Asp Ser Gln Gln Gln Asp965 970 975Arg Tyr Trp Cys Pro Pro Leu Leu His Arg Ala Ala Ile Ala Phe Leu980 985 990His Ala Leu Trp Gln Asp Arg Arg Asp Ser Ala Met Leu Val Leu Arg99510001005Thr Lys Pro Lys Phe Trp Glu Asn Leu Thr Ser Pro Leu Phe Gly Thr101010151020Leu Ser Pro Pro Ser Glu Thr Ser Glu Pro Ser Ile Leu Glu Thr Cys1025 103010351040Ala Leu Ile Met Lys Ile Ile Cys Leu Glu Ile Tyr Tyr Val Val Lys104510501055Gly Ser Leu Asp Gln Ser Leu Lys Asp Thr Leu Lys Lys Phe Ser Ile106010651070Glu Lys Arg Phe Ala Tyr Trp Ser Gly Tyr Val Lys Ser Leu Ala Val107510801085His Val Ala Glu Thr Glu Gly Ser Ser Cys Thr Ser Leu Leu Glu Tyr1090 1095 1100Gln Met Leu Val Ser Ala Trp Arg Met Leu Leu Ile Ile Ala Thr Thr1105 111011151120His Ala Asp Ile Met His Leu Thr Asp Ser Val Val Arg Arg Gln Leu112511301135Phe Leu Asp Val Leu Asp Gly Thr Lys Ala Leu Leu Leu Val Pro Ala114011451150Ser Val Asn Cys Leu Arg Leu Gly Ser Met Lys Cys Thr Leu Leu Leu115511601165Ile Leu Leu Arg Gln Trp Lys Arg Glu Leu Gly Ser Val Asp Glu Ile
117011751180Leu Gly Pro Leu Thr Glu Ile Leu Glu Gly Val Leu Gln Ala Asp Gln1185 119011951200Gln Leu Met Glu Lys Thr Lys Ala Lys Val Phe Ser Ala Phe Ile Thr120512101215Val Leu Gln Met Lys Glu Met Lys Val Ser Asp Ile Pro Gln Tyr Ser122012251230Gln Leu Val Leu Asn Val Cys Glu Thr Leu Gln Glu Glu ValIle Ala123512401245Leu Phe Asp Gln Thr Arg His Ser Leu Ala Leu Gly Ser Ala Thr Glu125012551260Asp Lys Asp Ser Mer Glu Thr Asp Asp Cys Ser Arg Ser Arg His Arg1265 127012751280Asp Gln Arg Asp Gly Val Cys Va1 Leu Gly Leu His Leu Ala Lys Glu128512901295Leu Cys Glu Val Asp Glu Asp Gly Asp Ser Trp Leu Gln Val Thr Arg130013051310Arg Leu Pro Ile Leu Pro Thr Leu Leu Thr Thr Leu Glu Val Ser Leu131513201325Arg Met Lys Gln Asn Leu His Phe Thr Glu Ala Thr Leu His Leu Leu133013351340Leu Thr Leu Ala Arg Thr Gln Gln Gly Ala Thr Ala Val Ala Gly Ala1345 135013551360Gly Ile Thr Gln Ser Ile Cys Leu Pro Leu Leu Ser Val Tyr Gln Leu136513701375Ser Thr Asn Gly Thr Ala Gln Thr Pro Ser Ala Ser Arg Lys Ser Leu138013851390Asp Ala Pro Ser Trp Pro Gly Val Tyr Arg Leu Ser Met Ser Leu Met139514001405
Glu Gln Leu Leu Lys Thr Leu Arg Tyr Asn Phe Leu Pro Glu Ala Leu141014151420Asp Phe Val Gly Val His Gln Glu Arg Thr Leu Gln Cys Leu Asn Ala1425 143014351440Val Arg Thr Val Gln Ser Leu Ala Cys Leu Glu Glu Ala Asp His Thr144514501455Val Gly Phe Ile Leu Gln Leu Ser Asn Phe Met Lys Glu Trp His Phe146014651470His Leu Pro Gln Leu Met Arg Asp Ile Gln Val Asn Leu Gly Tyr Leu147514801485Cys Gln Ala Cys Thr Ser Leu Leu His Ser Arg Lys Met Leu Gln His149014951500Tyr Leu Gln Asn Lys Asn Gly Asp Gly Leu Pro Ser Ala Val Ala Gln1505 151015151520Arg Val Gln Arg Pro Pro Ser Ala Ala Ser Ala Ala Pro Ser Ser Ser152515301535Lys Gln Pro Ala Ala Asp Thr G1u Ala Ser Glu Gln Gln Ala Leu His154015451550Thr Val Gln Tyr Gly Leu Leu Lys Ile Leu Ser Lys Thr Leu Ala Ala155515601565Leu Arg His Phe Thr Pro Asp Val Cys Gln Ile Leu Leu Asp Gln Ser157015751580Leu Asp Leu Ala Glu Tyr Asn Phe Leu Phe Ala Leu Ser Phe Thr Thr1585 159015951600Pro Thr Phe Asp Ser Glu Val Ala Pro Ser Phe Gly Thr Leu Leu Ala160516101615Thr ValAsn Val Ala Leu Asn Met Leu Gly Glu Leu Asp Lys Lys Lys162016251630Glu Pro Leu Thr Gln Ala Val Gly Leu Ser Thr Gln Ala Glu Gly Thr163516401645
Arg Thr Leu Lys Ser Leu Leu Met Phe Thr Met Glu Asn Cys Phe Tyr165016551660Leu Leu Ile Ser Gln Ala Met Arg Tyr Leu Arg Asp Pro Ala Val His1665 167016751680Pro Arg Asp Lys Gln Arg Met Lys Gln Glu Leu Ser Ser Glu Leu Ser168516901695Thr Leu Leu Ser Ser Leu Ser Arg Tyr Phe Arg Arg Gly Ala Pro Ser170017051710Ser Pro Ala Thr Gly Val Leu Pro Ser Pro Gln Gly Lys Ser Thr Ser171517201725Leu Ser Lys Ala Ser Pro Glu Ser Gln Glu Pro Leu Ile Gln Leu Val173017351740Gln Ala Phe Val Arg His Met Gln Arg1745 1750<210>3<211>1753<212>PRT<213>人<400>3Met Ile Arg Lys Ser Lys Ile Thr Ser Val Leu Ser Phe Cys Arg Ser1 5 10 15Ser Arg Glu Leu Trp Thr Ile Leu Leu Gly Arg Ser Ala Leu Arg Glu20 25 30Leu Ser Gln Ile Glu Ala Glu Leu Asn Lys His Trp Arg Arg Leu Leu35 40 45Glu Gly Leu Ser Tyr Tyr Lys Pro Pro Ser Pro Ser Ser Ala Glu Lys50 55 60Val Lys Ala Asn Lys Asp Val Ala Ser Pro Leu Lys Glu Val Gly Leu65 70 75 80
Arg Ile Ser Lys Phe Leu Gly Leu Asp Glu Glu Gln Ser Val Gln Leu85 90 95Leu Gln Cys Tyr Leu Gln Glu Asp Tyr Arg Gly Thr Arg Asp Ser Val100 105 110Lys Thr Val Leu Gln Asp Glu Arg Gln Ser Gln Ala Leu Ile Leu Lys115 120 125Ile Ala Asp Tyr Tyr Tyr Glu Glu Arg Thr Cys Ile Leu Arg Cys Val130 135 140Leu His Leu Leu Thr Tyr Phe Gln Asp Glu Arg His Pro Tyr Arg Val145 150 155 160Glu Tyr Ala Asp Cys Val Asp Lys Leu Glu Lys Glu Leu Val Ser Lys165 170 175Tyr Arg Gln Gln Phe Glu Glu Leu Tyr Lys Thr Glu Ala Pro Thr Trp180 185 190Glu Thr His Gly Asn Leu Met Thr Glu Arg Gln Val Ser Arg Trp Phe195 200 205Val Gln Cys Leu Arg Glu Gln Ser Met Leu Leu Glu Ile Ile Phe Leu210 215 220Tyr Tyr Ala Tyr Phe Glu Met Ala Pro Ser Asp Leu Leu Val Leu Thr225 230 235 240Lys Met Phe Lys Glu Gln Gly Phe Gly Ser Arg Gln Thr Asn Arg His245 250 255Leu Val Asp Glu Thr Met Asp Pro Phe Val Asp Arg Ile Gly Tyr Phe260 265 270Ser Ala Leu Ile Leu Val Glu Gly Met Asp Ile Glu Ser Leu His Lys275 280 285Cys Ala Leu Asp Asp Arg Arg Glu Leu His Gln Phe Ala Gln Asp Gly290 295 300Leu Ile Cys Gln Asp Met Asp Cys Leu Met Leu Thr Phe Gly Asp Ile305 310 315 320
Pro His His Ala Pro Val Leu Leu Ala Trp Ala Leu Leu Arg His Thr325 330 335Leu Asn Pro Glu Glu Thr Ser Ser Val Val Arg Lys Ile Gly Gly Thr340 345 350Ala Ile Gln Leu Asn Val Phe Gln Tyr Leu Thr Arg Leu Leu Gln Ser355 360 365Leu Ala Ser Gly Gly Asn Asp Cys Thr Thr Ser Thr Ala Cys Met Cys370 375 380Val Tyr Gly Leu Leu Ser Phe Val Leu Thr Ser Leu Glu Leu His Thr385 390 395 400Leu Gly Asn Gln Gln Asp Ile Ile Asp Thr Ala Cys Glu Val Leu Ala405 410 415Asp Pro Ser Leu Pro Glu Leu Phe Trp Gly Thr Glu Pro Thr Ser Gly420 425 430Leu Gly Ile Ile Leu Asp Ser Val Cys Gly Met Phe Pro His Leu Leu435 440 445Ser Pro Leu Leu Gln Leu Leu Arg Ala Leu Val Ser Gly Lys Ser Thr450 455 460Ala Lys Lys Val Tyr Ser Phe Leu Asp Lys Met Ser Phe Tyr Asn Glu465 470 475 480Leu Tyr Lys His Lys Pro His Asp Val Ile Ser His Glu Asp Gly Thr485 490 495Leu Trp Arg Arg Gln Thr Pro Lys Leu Leu Tyr Pro Leu Gly Gly Gln500 505 510Thr Asn Leu Arg Ile Pro Gln Gly Thr Val Gly Gln Val Met Leu Asp515 520 525Asp Arg Ala Tyr Leu Val Arg Trp Glu Tyr Ser Tyr Ser Ser Trp Thr530 535 540Leu Phe Thr Cys Glu Ile Glu Met Leu Leu His Val Val Ser Thr Ala
545 550 555 560Asp Val Ile Gln His Cys Gln Arg Val Lys Pro Ile Ile Asp Leu Val565 570 575His Lys Val Ile Ser Thr Asp Leu Ser Ile Ala Asp Cys Leu Leu Pro580 585 590Ile Thr Ser Arg Ile Tyr Met Leu Leu Gln Arg Leu Thr Thr Val Ile595 600 605Ser Pro Pro Val Asp Val Ile Ala Ser Cys Val Asn Cys Leu Thr Val610 615 620Leu Ala Ala Arg Asn Pro Ala Lys Val Trp Thr Asp Leu Arg His Thr625 630 635 640Gly Phe Leu Pro Phe Val Ala His Pro Val Ser Ser Leu Ser Gln Met645 650 655Ile Ser Ala Glu Gly Met Asn Ala Gly Gly Tyr Gly Asn Leu Leu Met660 665 670Asn Ser Glu Gln Pro Gln Gly Glu Tyr Gly Val Thr Ile Ala Phe Leu675 680 685Arg Leu Ile Thr Thr Leu Val Lys Gly Gln Leu Gly Ser Thr Gln Ser690 695 700Gln Gly Leu Val Pro Cys Val Met Phe Val Leu Lys Glu Met Leu Pro705 710 715 720Ser Tyr His Lys Trp Arg Tyr Asn Ser His Gly Val Arg Glu Gln Ile725 730 735Gly Cys Leu Ile Leu Glu Leu Ile His Ala Ile Leu Asn Leu Cys His740 745 750Glu Thr Asp Leu His Ser Ser His Thr Pro Ser Leu Gln Phe Leu Cys755 760 765Ile Cys Ser Leu Ala Tyr Thr Glu Ala Gly Gln Thr Val Ile Asn Ile770 775 780
Met Gly Ile Gly Val Asp Thr Ile Asp Met Val Met Ala Ala Gln Pro785 790 795 800Arg Ser Asp Gly Ala Glu Gly Gln Gly Gln Gly Gln Leu Leu Ile Lys805 810 815Thr Val Lys Leu Ala Phe Ser Val Thr Asn Asn Val Ile Arg Leu Lys820 825 830Pro Pro Ser Asn Val Val Ser Pro Leu Glu Gln Ala Leu Ser Gln His835 840 845Gly Ala His Gly Asn Asn Leu Ile Ala Val Leu Ala Lys Tyr Ile Tyr850 855 860His Lys His Asp Pro Ala Leu Pro Arg Leu Ala Ile Gln Leu Leu Lys865 870 875 880Arg Leu Ala Thr Val Ala Pro Met Ser Val Tyr Ala Cys Leu Gly Asn885 890 895Asp Ala Ala Ala Ile Arg Asp Ala Phe Leu Thr Arg Leu Gln Ser Lys900 905 910Ile Glu Asp Met Arg Ile Lys Val Met Ile Leu Glu Phe Leu Thr Val915 920 925Ala Val Glu Thr Gln Pro Gly Leu Ile Glu Leu Phe Leu Asn Leu Glu930 935 940Val Lys Asp Gly Ser Asp Gly Ser Lys Glu Phe Ser Leu Gly Met Trp945 950 955 960Ser Cys Leu His Ala Val Leu Glu Leu Ile Asp Ser Gln Gln Gln Asp965 970 975Arg Tyr Trp Cys Pro Pro Leu Leu His Arg Ala Ala Ile Ala Phe Leu980 985 990His Ala Leu Trp Gln Asp Arg Arg Asp Ser Ala Met Leu Val Leu Arg99510001005Thr Lys Pro Lys Phe Trp Glu Asn Leu Thr Ser Pro Leu Phe Gly Thr101010151020
Leu Ser Pro Pro Ser Glu Thr Ser Glu Pro Ser Ile Leu Glu Thr Cys1025 103010351040Ala Leu Ile Met Lys Ile Ile Cys Leu Glu Ile Tyr Tyr Val Val Lys104510501055Gly Ser Leu Asp Gln Ser Leu Lys Asp Thr Leu Lys Lys Phe Ser Ile106010651070Glu Lys Arg Phe Ala Tyr Trp Ser Gly Tyr Val Lys Ser Leu Ala Val107510801085His Val Ala Glu Thr Glu Gly Ser Ser Cys Thr Ser Leu Leu Glu Tyr109010951100Gln Met Leu Val Ser Ala Trp Arg Met Leu Leu Ile Ile Ala Thr Thr1105 111011151120His Ala Asp Ile Met His Leu Thr Asp Ser Val Val Arg Arg Gln Leu112511301135Phe Leu Asp Val Leu Asp Gly Thr Lys Ala Leu Leu Leu Val Pro Ala114011451150Ser Val Asn Cys Leu Arg Leu Gly Ser Met Lys Cys Thr Leu Leu Leu115511601165Ile Leu Leu Arg Gln Trp Lys Arg Glu Leu Gly Ser Val Asp Glu Ile117011751180Leu Gly Pro Leu Thr Glu Ile Leu Glu Gly Val Leu Gln Ala Asp Gln1185 119011951200Gln Leu Met Glu Lys Thr Lys Ala Lys Val Phe Ser Ala Phe Ile Thr120512101215Val Leu Gln Met Lys Glu Met Lys Val Ser Asp Ile Pro Gln Tyr Ser122012251230Gln Leu Val Leu Asn Val Cys Glu Thr Leu Gln Glu Glu Val Ile Ala123512401245Leu Phe Asp Gln Thr Arg His Ser Leu Ala Leu Gly Ser Ala Thr Glu
125012551260Asp Lys Asp Ser Met Glu Thr Asp Asp Cys Ser Arg Ser Arg His Arg1265 127012751280Asp Gln Arg Asp Gly Val Cys Val Leu Gly Leu His Leu Ala Lys Glu128512901295Leu Cys Glu Val Asp Glu Asp Gly Asp Ser Trp Leu Gln Val Thr Arg130013051310Arg Leu Pro Ile Leu Pro Thr Leu Leu Thr Thr Leu Glu Val Ser Leu131513201325Arg Met Lys Gln Asn Leu His Phe Thr Glu Ala Thr Leu His Leu Leu133013351340Leu Thr Leu Ala Arg Thr Gln Gln Gly Ala Thr Ala Val Ala Gly Ala1345 135013551360Gly Ile Thr Gln Ser Ile Cys Leu Pro Leu Leu Ser Val Tyr Gln Leu136513701375Ser Thr Asn Gly Thr Ala Gln Thr Pro Ser Ala Ser Arg Lys Ser Leu138013851390Asp Ala Pro Ser Trp Pro Gly Val Tyr Arg Leu Ser Met Ser Leu Met139514001405Glu Gln Leu Leu Lys Thr Leu Arg Tyr Asn Phe Leu Pro Glu Ala Leu141014151420Asp Phe Val Gly Val His Gln Glu Arg Thr Leu Gln Cys Leu Asn Ala1425 143014351440Val Arg Thr Val Gln Ser Leu Ala Cys Leu Glu Glu Ala Asp His Thr144514501455Val Gly Phe Ile Leu Gln Leu Ser Asn Phe Met Lys Glu Trp His Phe146014651470His Leu Pro Gln Leu Met Arg Asp Ile Gln Val Asn Leu Gly Tyr Leu147514801485
Cys Gln Ala Cys Thr Ser Leu Leu His Ser Arg Lys Met Leu Gln His14901495 1500Tyr Leu Gln Asn Lys Asn Gly Asp Gly Leu Pro Ser Ala Val Ala Gln1505 151015151520Arg ValGln Arg Pro Pro Ser Ala Ala Ser Ala Ala Pro Ser Ser Ser152515301535Lys Gln Pro Ala Ala Asp Thr Glu Ala Ser Glu Gln Gln Ala Leu His154015451550Thr Val Gln Tyr Gly Leu Leu Lys Ile Leu Ser Lys Thr Leu Ala Ala155515601565Leu Arg His Phe Thr Pro Asp Val Cys Gln Ile Leu Leu Asp Gln Ser157015751580Leu Asp Leu Ala Glu Tyr Asn Phe Leu Phe Ala Leu Ser Phe Thr Thr158159015951600Pro Thr Phe Asp Ser Glu Val Ala Pro Ser Phe Gly Thr Leu Leu Ala160516101615Thr Val Asn Val Ala Leu Asn Met Leu Gly Glu Leu Asp Lys Lys Lys162016251630Glu Pro Leu Thr Gln Ala Val Gly Leu Ser Thr Gln Ala Glu Gly Thr163516401645Arg Thr Leu Lys Ser Leu Leu Met Phe Thr Met Glu Asn Cys Phe Tyr165016551660Leu Leu Ile Ser Gln Ala Met Arg Tyr Leu Arg Asp Pro Ala Val His1665 167016751680Pro Arg Asp Lys Gln Arg Met Lys Gln Glu Leu Ser Ser Glu Leu Ser168516901695Thr Leu Leu Ser Ser Leu Ser Arg Tyr Phe Arg Arg Gly Ala Pro Ser170017051710Ser Pro Ala Thr Gly Val Leu Pro Ser Pro Gln Gly Lys Ser Thr Ser171517201725
Leu Ser Lys Ala Ser Pro Glu Ser Gln Glu Pro Leu Ile Gln Leu Val173017351740Gln Ala Phe Val Arg His Met Gln Arg1745 1750<210>4<211>1753<212>PRT<213>人<400>4Met Ile Arg Lys Ser Lys Ile Thr Ser Val Leu Ser Phe Cys Arg Ser1 5 10 15Ser Arg Glu Leu Trp Thr Ile Leu Leu Gly Arg Ser Ala Leu Arg Glu20 25 30Leu Ser Gln Ile Glu Ala Glu Leu Asn Lys His Trp Arg Arg Leu Leu35 40 45Glu Gly Leu Ser Tyr Tyr Lys Pro Pro Ser Pro Ser Ser Ala Glu Lys50 55 60Val Lys Ala Asn Lys Asp Val Ala Ser Pro Leu Lys Glu Leu Gly Leu65 70 75 80Arg Ile Ser Lys Phe Leu Gly Leu Asp Glu Glu Gln Ser Val Gln Leu85 90 95Leu Gln Cys Tyr Leu Gln Glu Asp Tyr Arg Gly Thr Arg Asp Ser Val100 105 110Lys Thr Val Leu Gln Asp Glu Arg Gln Ser Gln Ala Leu Ile Leu Lys115 120 125Ile Ala Asp Tyr Tyr Tyr Glu Glu Arg Thr Cys Ile Leu Arg Cys Val130 135 140Leu His Leu Leu Thr Tyr Phe Gln Asp Glu Arg His Pro Tyr Arg Val145 150 155 160
Glu Tyr Ala Asp Cys Val Asp Lys Leu Glu Lys Glu Leu Val Ser Lys165 170 175Tyr Arg Gln Gln Phe Glu Glu Leu Tyr Lys Thr Glu Ala Pro Thr Trp180 185 190Glu Thr His Gly Asn Ile Met Thr Glu Arg Gln Val Ser Arg Trp Phe195 200 205Val Gln Cys Leu Arg Glu Gln Ser Met Leu Leu Glu Ile Ile Phe Leu210 215 220Tyr Tyr Ala Tyr Phe Glu Met Ala Pro Ser Asp Leu Leu Val Leu Thr225 230 235 240Lys Met Phe Lys Glu Gln Gly Phe Gly Ser Arg Gln Thr Asn Arg His245 250 255Leu Val Asp Glu Thr Met Asp Pro Phe Val Asp Arg Ile Gly Tyr Phe260 265 270Ser Ala Leu Ile Leu Val Glu Gly Met Asp Ile Glu Ser Leu His Lys275 280 285Cys Ala Leu Asp Asp Arg Arg Glu Leu His Gln Phe Ala Gln Asp Gly290 295 300Leu Ile Cys Gln Asp Met Asp Cys Leu Met Leu Thr Phe Gly Asp Ile305 310 315 320Pro His His Ala Pro Val Leu Leu Ala Trp Ala Leu Leu Arg His Thr325 330 335Leu Asn Pro Glu Glu Thr Ser Ser Val Val Arg Lys Ile Gly Gly Thr340 345 350Ala Ile Gln Leu Asn Val Phe Gln Tyr Leu Thr Arg Leu Leu Gln Ser355 360 365Leu Ala Ser Gly Gly Asn Asp Cys Thr Thr Ser Thr Ala Cys Met Cys370 375 380Val Tyr Gly Leu Leu Ser Phe Val Leu Thr Ser Leu Glu Leu His Thr385 390 395 400
Leu Gly Asn Gln Gln Asp Ile Ile Asp Thr Ala Cys Glu Val Leu Ala405 410 415Asp Pro Ser Leu Pro Glu Leu Phe Trp Gly Thr Glu Pro Thr Ser Gly420 425 430Leu Gly Ile Ile Leu Asp Ser Val Cys Gly Met Phe Pro His Leu Leu435 440 445Ser Pro Leu Leu Gln Leu Leu Arg Ala Leu Val Ser Gly Lys Ser Thr450 455 460Ala Lys Lys Val Tyr Ser Phe Leu Asp Lys Met Ser Phe Tyr Asn Glu465 470 475 480Leu Tyr Lys His Lys Pro His Asp Val Ile Ser His Glu Asp Gly Thr485 490 495Leu Trp Arg Arg Gln Thr Pro Lys Leu Leu Tyr Pro Leu Gly Gly Gln500 505 510Thr Asn Leu Arg Ile Pro Gln Gly Thr Val Gly Gln Val Met Leu Asp515 520 525Asp Arg Ala Tyr Leu Val Arg Trp Glu Tyr Ser Tyr Ser Ser Trp Thr530 535 540Leu Phe Thr Cys Glu Ile Glu Met Leu Leu His Val Val Ser Thr Ala545 550 555 560Asp Val Ile Gln His Cys Gln Arg Val Lys Pro Ile Ile Asp Leu Val565 570 575His Lys Val Ile Ser Thr Asp Leu Ser Ile Ala Asp Cys Leu Leu Pro580 585 590Ile Thr Ser Arg Ile Tyr Met Leu Leu Gln Arg Leu Thr Thr Val Ile595 600 605Ser Pro Pro Val Asp Val Ile Ala Ser Cys Val Asn Cys Leu Thr Val610 615 620Leu Ala Ala Arg Asn Pro Ala Lys Val Trp Thr Asp Leu Arg His Thr
625 630 635 640Gly Phe Leu Pro Phe Val Ala His Pro Val Ser Ser Leu Ser Gln Met645 650 655Ile Ser Ala Glu Gly Met Asn Ala Gly Gly Tyr Gly Asn Leu Leu Met660 665 670Asn Ser Glu Gln Pro Gln Gly Glu Tyr Gly Val Thr Ile Ala Phe Leu675 680 685Arg Leu Ile Thr Thr Leu Val Lys Gly Gln Leu Gly Ser Thr Gln Ser690 695 700Gln Gly Leu Val Pro Cys Val Met Phe Val Leu Lys Glu Met Leu Pro705 710 715 720Ser Tyr His Lys Trp Arg Tyr Asn Ser His Gly Val Arg Glu Gln Ile725 730 735Gly Cys Leu Ile Leu Glu Leu Ile His Ala Ile Leu Asn Leu Cys His740 745 750Glu Thr Asp Leu His Ser Ser His Thr Pro Ser Leu Gln Phe Leu Cys755 760 765Ile Cys Ser Leu Ala Tyr Thr Glu Ala Gly Gln Thr Val Ile Asn Ile770 775 780Met Gly Ile Gly Val Asp Thr Ile Asp Met Val Met Ala Ala Gln Pro785 790 795 800Arg Ser Asp Gly Ala Glu Gly Gln Gly Gln Gly Gln Leu Leu Ile Lys805 810 815Thr ValLys Leu Ala Phe Ser Val Thr Asn Asn Val Ile Arg Leu Lys820 825 830Pro Pro Ser Asn Val Val Ser Pro Leu Glu Gln Ala Leu Ser Gln His835 840 845Gly Ala His Gly Asn Asn Leu Ile Ala Val Leu Ala Lys Tyr Ile Tyr850 855 860
His Lys His Asp Pro Ala Leu Pro Arg Leu Ala Ile Gln Leu Leu Lys865 870 875 880Arg Leu Ala Thr Val Ala Pro Met Ser Val Tyr Ala Cys Leu Gly Asn885 890 895Asp Ala Ala Ala Ile Arg Asp Ala Phe Leu Thr Arg Leu Gln Ser Lys900 905 910Ile Glu Asp Met Arg Ile Lys Val Met Ile Leu Glu Phe Leu Thr Val915 920 925Ala Val Glu Thr Gln Pro Gly Leu Ile Glu Leu Phe Leu Asn Leu Glu930 935 940Val Lys Asp Gly Ser Asp Gly Ser Lys Glu Phe Ser Leu Gly Met Trp945 950 955 960Ser Cys Leu His Ala Val Leu Glu Leu Ile Asp Ser Gln Gln Gln Asp965 970 975Arg Tyr Trp Cys Pro Pro Leu Leu His Arg Ala Ala Ile Ala Phe Leu980 985 990His Ala Leu Trp Gln Asp Arg Arg Asp Ser Ala Met Leu Val Leu Arg99510001005Thr Lys Pro Lys Phe Trp Glu Asn Leu Thr Ser Pro Leu Phe Gly Thr101010151020Leu Ser Pro Pro Ser Glu Thr Ser Glu Pro Ser Ile Leu Glu Thr Cys1025 103010351040Ala Leu Ile Met Lys Ile Ile Cys Leu Glu Ile Tyr Tyr Val Val Lys104510501055Gly Ser Leu Asp Gln Ser Leu Lys Asp Thr Leu Lys Lys Phe Ser Ile106010651070Glu Lys Arg Phe Ala Tyr Trp Ser Gly Tyr Val Lys Ser Leu Ala Val107510801085His Val Ala Glu Thr Glu Gly Ser Ser Cys Thr Ser Leu Leu Glu Tyr109010951100
Gln Met Leu Val Ser Ala Trp Arg Met Leu Leu Ile Ile Ala Thr Thr1105 111011151120His Ala Asp Ile Met His Leu Thr Asp Ser Val Val Arg Arg Gln Leu112511301135Phe Leu Asp Val Leu Asp Gly Thr Lys Ala Leu Leu Leu Val Pro Ala114011451150Ser Val Asn Cys Leu Arg Leu Gly Ser Met Lys Cys Thr Leu Leu Leu115511601165Ile Leu Leu Arg Gln Trp Lys Arg Glu Leu Gly Ser Val Asp Glu Ile117011751180Leu Gly Pro Leu Thr Glu Ile Leu Glu G1y Val Leu Gln Ala Asp Gln1185 119011951200Gln Leu Met Glu Lys Thr Lys Ala Lys Val Phe Ser Ala Phe Ile Thr120512101215Val Leu Gln Met Lys Glu Met Lys Val Ser Asp Ile Pro Gln Tyr Ser122012251230Gln Leu Val Leu Asn Val Cys Glu Thr Leu Gln Glu Glu Val Ile Ala123512401245Leu Phe Asp Gln Thr Arg His Ser Leu Ala Leu Gly Ser Ala Thr Glu125012551260Asp Lys Asp Ser Met Glu Thr Asp Asp Cys Ser Arg Ser Arg His Arg1265 127012751280Asp Gln Arg Asp Gly Val Cys Val Leu Gly Leu His Leu Ala Lys Glu128512901295Leu Cys Glu Val Asp Glu Asp Gly Asp Ser Trp Leu Gln Val Thr Arg130013051310Arg Leu Pro Ile Leu Pro Thr Leu Leu Thr Thr Leu Glu Val Ser Leu131513201325Arg Met Lys Gln Asn Leu His Phe Thr Glu Ala Thr Leu His Leu Leu
133013351340Leu Thr Leu Ala Arg Thr Gln Gln Gly Ala Thr Ala Val Ala Gly Ala1345 135013551360Gly Ile Thr Gln Ser Ile Cys Leu Pro Leu Leu Ser Val Tyr Gln Leu136513701375Ser Thr Asn Gly Thr Ala Gln Thr Pro Ser Ala Ser Arg Lys Ser Leu138013851390Asp Ala Pro Ser Trp Pro Gly Val Tyr Arg Leu Ser Met Ser Leu Met139514001405Glu Gln Leu Leu Lys Thr Leu Arg Tyr Asn Phe Leu Pro Glu Ala Leu141014151420Asp Phe Val Gly Val His Gln Glu Arg Thr Leu Gln Cys Leu Asn Ala1425 143014351440Val Arg Thr Val Gln Ser Leu Ala Cys Leu Glu Glu Ala Asp His Thr144514501455Val Gly Phe Ile Leu Gln Leu Ser Asn Phe Met Lys Glu Trp His Phe146014651470His Leu Pro Gln Leu Met Arg Asp Ile Gln Val Asn Leu Gly Tyr Leu147514801485Cys Gln Ala Cys Thr Ser Leu Leu His Ser Arg Lys Met Leu Gln His149014951500Tyr Leu Gln Asn Lys Asn Gly Asp Gly Leu Pro Ser Ala Val Ala Gln1505 151015151520Arg Val Gln Arg Pro Pro Ser Ala Ala Ser Ala Ala Pro Ser Ser Ser152515301535Lys Gln Pro Ala Ala Asp Thr Glu Ala Ser Glu Gln Gln Ala Leu His154015451550Thr Val Gln Tyr Gly Leu Leu Lys Ile Leu Ser Lys Thr Leu Ala Ala155515601565
Leu Arg His Phe Thr Pro Asp Val Cys Gln Ile Leu Leu Asp Gln Ser157015751580Leu Asp Leu Ala Glu Tyr Ash Phe Leu Phe Ala Leu Ser Phe Thr Thr1585 159015951600Pro Thr Phe Asp Ser Glu Val Ala Pro Ser Phe Gly Thr Leu Leu Ala160516101615Thr Val Asn Val Ala Leu Asn Met Leu Gly Glu Leu Asp Lys Lys Lys162016251630Glu Pro Leu Thr Gln Ala Val Gly Leu Ser Thr Gln Ala Glu Gly Thr163516401645Arg Thr Leu Lys Ser Leu Leu Met Phe Thr Met Glu Asn Cys Phe Tyr165016551660Leu Leu Ile Ser Gln Ala Met Arg Tyr Leu Arg Asp Pro Ala Val His1665 167016751680Pro Arg Asp Lys Gln Arg Met Lys Gln Glu Leu Ser Ser Glu Leu Ser168516901695Thr Leu Leu Ser Ser Leu Ser Arg Tyr Phe Arg Arg Gly Ala Pro Ser170017051710Ser Pro Ala Thr Gly Val Leu Pro Ser Pro Gln Gly Lys Ser Thr Ser171517201725Leu Ser Lys Ala Ser Pro Glu Ser Gln Glu Pro Leu Ile Gln Leu Val173017351740Gln Ala Phe Val Arg His Met Gln Arg1745 1750<210>5<211>1752<212>PRT<213>人<400>5Met Ile Arg Lys Ser Lys Ile Thr Ser Val Leu Ser Phe Cys Arg Ser
1 5 10 15Ser Arg Glu Leu Trp Thr Ile Leu Leu Gly Arg Ser Ala Leu Ara Glu20 25 30Leu Ser Gln Ile Glu Ala Glu Leu Asn Lys His Trp Arg Arg Leu Leu35 40 45Glu Gly Leu Ser Tyr Tyr Lys Pro Pro Ser Pro Ser Ser Ala Glu Lys50 55 60Val Lys Ala Asn Lys Asp Val Ala Ser Pro Leu Lys Glu Leu Gly Leu65 70 75 80Arg Ile Ser Lys Phe Leu Gly Leu Asp Glu Glu Gln Ser Val Gln Leu85 90 95Leu Gln Cys Tyr Leu Gln Glu Asp Tyr Arg Gly Thr Arg Asp Ser Val100 105 110Lys Thr Val Leu Gln Asp Glu Arg Gln Ser Gln Ala Leu Ile Leu Lys115 120 125Ile Ala Asp Tyr Tyr Tyr Glu Glu Arg Thr Cys Ile Leu Arg Cys Val130 135 140Leu His Leu Leu Thr Tyr Phe Gln Asp Glu Arg Pro Tyr Arg Val Glu145 150 155 160Tyr Ala Asp Cys Val Asp Lys Leu Glu Lys Glu Leu Val Ser Lys Tyr165 170 175Arg Gln Gln Phe Glu Glu Leu Tyr Lys Thr Glu Ala Pro Thr Trp Glu180 185 190Thr His Gly Asn Leu Met Thr Glu Arg Gln Val Ser Arg Trp Phe Val195 200 205Gln Cys Leu Arg Glu Gln Ser Met Leu Leu Glu Ile Ile Phe Leu Tyr210 215 220Tyr Ala Tyr Phe Glu Met Ala Pro Ser Asp Leu Leu Val Leu Thr Lys225 230 235 240
Met Phe Lys Glu Gln Gly Phe Gly Ser Arg Gln Thr Asn Arg His Leu245 250 255Val Asp Glu Thr Met Asp Pro Phe Val Asp Lys Ile Gly Tyr Phe Ser260 265 270Ala Leu Ile Leu Val Glu Gly Met Asp Ile Glu Ser Leu His Lys Cys275 280 285Ala Leu Asp Asp Arg Arg Glu Leu His Gln Phe Ala Gln Asp Gly Leu290 295 300Ile Cys Gln Asp Met Asp Cys Leu Met Leu Thr Phe Gly Asp Ile Pro305 310 315 320His His Ala Pro Val Leu Leu Ala Trp Ala Leu Leu Arg His Thr Leu325 330 335Asn Pro Glu Glu Thr Ser Ser Val Val Arg Lys Ile Gly Gly Thr Ala340 345 350Ile Gln Leu Asn Val Phe Gln Tyr Leu Thr Arg Leu Leu Gln Ser Leu355 360 365Ala Ser Gly Gly Asn Asp Cys Thr Thr Ser Thr Ala Cys Met Cys Val370 375 380Tyr Gly Leu Leu Ser Phe Val Leu Thr Ser Leu Glu Leu His Thr Leu385 390 395 400Gly Asn Gln Gln Asp Ile Ile Asp Thr Ala Cys Glu Val Leu Ala Asp405 410 415Pro Ser Leu Pro Glu Leu Phe Trp Gly Thr Glu Pro Thr Ser Gly Leu420 425 430Gly Ile Ile Leu Asp Ser Val Cys Gly Met Phe Pro His Leu Leu Ser435 440 445Pro Leu Leu Gln Leu Leu Arg Ala Leu Val Ser Gly Lys Ser Thr Ala450 455 460Lys Lys Val Tyr Ser Phe Leu Asp Lys Met Ser Phe Tyr Asn Glu Leu465 470 475 480
Tyr Lys His Lys Pro His Asp Val Ile Ser His Glu Asp Gly Thr Leu485 490 495Trp Arg Arg Gln Thr Pro Lys Leu Leu Tyr Pro Leu Gly Gly Gln Thr500 505 510Asn Leu Arg Ile Pro Gln Gly Thr Val Gly Gln Val Met Leu Asp Asp515 520 525Arg Ala Tyr Leu Val Arg Trp Glu Tyr Ser Tyr Ser Ser Trp Thr Leu530 535 540Phe Thr Cys Glu Ile Glu Met Leu Leu His Val Val Ser Thr Ala Asp545 550 555 560Val Ile Gln His Cys Gln Arg Val Lys Pro Ile Ile Asp Leu Val His565 570 575Lys Val Ile Ser Thr Asp Leu Ser Ile Ala Asp Cys Leu Leu Pro Ile580 585 590Thr Ser Arg Ile Tyr Met Leu Leu Gln Arg Leu Thr Thr Val Ile Ser595 600 605Pro Pro Val Asp Val Ile Ala Ser Cys Val Asn Cys Leu Thr Val Leu610 615 620Ala Ala Arg Asn Pro Ala Lys Val Trp Thr Asp Leu Arg His Thr Gly625 630 635 640Phe Leu Pro Phe Val Ala His Pro Val Ser Ser Leu Ser Gln Met Ile645 650 655Ser Ala Glu Gly Met Asn Ala Gly Gly Tyr Gly Asn Leu Leu Met Asn660 665 670Ser Glu Gln Pro Gln Gly Glu Tyr Gly Val Thr Ile Ala Phe Leu Arg675 680 685Leu Ile Thr Thr Leu Val Lys Gly Gln Leu Gly Ser Thr Gln Ser Gln690 695 700Gly Leu Val Pro Cys Val Met Phe Val Leu Lys Glu Met Leu Pro Ser
705 710 715 720Tyr His Lys Trp Arg Tyr Asn Ser His Gly Val Arg Glu Gln Ile Gly725 730 735Cys Leu Ile Leu Glu Leu Ile His Ala Ile Leu Asn Leu Cys His Glu740 745 750Thr Asp Leu His Ser Ser His Thr Pro Ser Leu Gln Phe Leu Cys Ile755 760 765Cys Ser Leu Ala Tyr Thr Glu Ala Gly Gln Thr Val Ile Asn Ile Met770 775 780Gly Ile Gly Val Asp Thr Ile Asp Met Val Met Ala Ala Gln Pro Arg785 790 795 800Ser Asp Gly Ala Glu Gly Gln Gly Gln Gly Gln Leu Leu Ile Lys Thr805 810 815ValLys Leu Ala Phe Ser Val Thr Asn Asn Val Ile Arg Leu Lys Pro820 825 830Pro Ser Asn Val Val Ser Pro Leu Glu Gln Ala Leu Ser Gln His Gly835 840 845Ala His Gly Asn Asn Leu Ile Ala Val Leu Ala Lys Tyr Ile Tyr His850 855 860Lys His Asp Pro Ala Leu Pro Arg Leu Ala Ile Gln Leu Leu Lys Arg865 870 875 880Leu Ala Thr Val Ala Pro Met Ser Val Tyr Ala Cys Leu Gly Asn Asp885 890 895Ala Ala Ala Ile Arg Asp Ala Phe Leu Thr Arg Leu Gln Ser Lys Ile900 905 910Glu Asp Met Arg Ile Lys Val Met Ile Leu Glu Phe Leu Thr Val Ala915 920 925Val Glu Thr Gln Pro Gly Leu Ile Glu Leu Phe Leu Asn Leu Glu Val930 935 940
Lys Asp Gly Ser Asp Gly Ser Lys Glu Phe Ser Leu Gly Met Trp Ser945 950 955 960Cys Leu His Ala Val Leu Glu Leu Ile Asp Ser Gln Gln Gln Asp Arg965 970 975Tyr Trp Cys Pro Pro Leu Leu His Arg Ala Ala Ile Ala Phe Leu His980 985 990Ala Leu Trp Gln Asp Arg Arg Asp Ser Ala Met Leu Val Leu Arg Thr99510001005Lys Pro Lys Phe Trp Glu Asn Leu Thr Ser Pro Leu Phe Gly Thr Leu101010151020Ser Pro Pro Ser Glu Thr Ser Glu Pro Ser Ile Leu Glu Thr Cys Ala1025 103010351040Leu Ile Met Lys Ile Ile Cys Leu Glu Ile Tyr Tyr Val Val Lys Gly104510501055Ser Leu Asp Gln Ser Leu Lys Asp Thr Leu Lys Lys Phe Ser Ile Glu106010651070Lys Arg Phe Ala Tyr Trp Ser Gly Tyr Val Lys Ser Leu Ala Val His107510801085Val Ala Glu Thr Glu Gly Ser Ser Cys Thr Ser Leu Leu Glu Tyr Gln109010951100Met Leu Val Ser Ala Trp Arg Met Leu Leu Ile Ile Ala Thr Thr His1105 111011151120Ala Asp Ile Met His Leu Thr Asp Ser Val Val Arg Arg Gln Leu Phe112511301135Leu Asp Val Leu Asp Gly Thr Lys Ala Leu Leu Leu Val Pro Ala Ser114011451150Val Asn Cys Leu Arg Leu Gly Ser Met Lys Cys Thr Leu Leu Leu Ile115511601165Leu Leu Arg Gln Trp Lys Arg Glu Leu G1y Ser Val Asp Glu Ile Leu117011751180
Gly Pro Leu Thr Glu Ile Leu Glu Gly Val Leu Gln Ala Asp Gln Gln1185 119011951200Leu Met Glu Lys Thr Lys Ala Lys Val Phe Ser Ala Phe Ile Thr Val120512101215Leu Gln Met Lys Glu Met Lys Val Ser Asp Ile Pro Gln Tyr Ser Gln122012251230Leu Val Leu Asn Val Cys Glu Thr Leu Gln Glu Glu Val Ile Ala Leu123512401245Phe Asp Gln Thr Arg His Ser Leu Ala Leu Gly Ser Ala Thr Glu Asp125012551260Lys Asp Ser Met Glu Thr Asp Asp Cys Ser Arg Ser Arg His Arg Asp1265 127012751280Gln Arg Asp Gly Val Cys Val Leu Gly Leu His Leu Ala Lys Glu Leu128512901295Cys Glu Val Asp Glu Asp Gly Asp Ser Trp Leu Gln Val Thr Arg Arg130013051310Leu Pro Ile Leu Pro Thr Leu Leu Thr Thr Leu Glu Val Ser Leu Arg131513201325Met Lys Gln Asn Leu His Phe Thr Glu Ala Thr Leu His Leu Leu Leu133013351340Thr Leu Ala Arg Thr Gln Gln Gly Ala Thr Ala Val Ala Gly Ala Gly1345 135013551360Ile Thr Gln Ser Ile Cys Leu Pro Leu Leu Ser Val Tyr Gln Leu Ser136513701375Thr Asn Gly Thr Ala Gln Thr Pro Ser Ala Ser Arg Lys Ser Leu Asp138013851390Ala Pro Ser Trp Pro Gly Val Tyr Arg Leu Ser Met Ser Leu Met Glu139514001405Gln Leu Leu Lys Thr Leu Arg Tyr Asn Phe Leu Pro Glu Ala Leu Asp
141014151420Phe Val Gly Val His Gln Glu Arg Thr Leu Gln Cys Leu Asn Ala Val1425 143014351440Arg Thr Val Gln Ser Leu Ala Cys Leu Glu Glu Ala Asp His Thr Val144514501455Gly Phe Ile Leu Gln Leu Ser Asn Phe Met Lys Glu Trp His Phe His146014651470Leu Pro Gln Leu Met Arg Asp Ile Gln Val Asn Leu Gly Tyr Leu Cys147514801485Gln Ala Cys Thr Ser Leu Leu His Ser Arg Lys Met Leu Gln His Tyr149014951500Leu Gln Asn Lys Asn Gly Asp Gly Leu Pro Ser Ala Val Ala Gln Arg1505 151015151520Val Gln Arg Pro Pro Ser Ala Ala Ser Ala Ala Pro Ser Ser Ser Lys152515301535Gln Pro Ala Ala Asp Thr Glu Ala Ser Glu Gln Gln Ala Leu His Thr154015451550Val Gln Tyr Gly Leu Leu Lys Ile Leu Ser Lys Thr Leu Ala Ala Leu155515601565Arg His Phe Thr Pro Asp Val Cys Gln Ile Leu Leu Asp Gln Ser Leu157015751580Asp Leu Ala Glu Tyr Asn Phe Leu Phe Ala Leu Ser Phe Thr Thr Pro1585 159015951600Thr Phe Asp Ser Glu Val Ala Pro Ser Phe Gly Thr Leu Leu Ala Thr160516101615Val Asn Val Ala Leu Asn Met Leu Gly Glu Leu Asp Lys Lys Lys Glu162016251630Pro Leu Thr Gln Ala Val Gly Leu Ser Thr Gln Ala Glu Gly Thr Arg163516401645
Thr Leu Lys Ser Leu Leu Met Phe Thr Met Glu Asn Cys Phe Tyr Leu165016551660Leu Ile Ser Gln Ala Met Arg Tyr Leu Arg Asp Pro Ala Val His Pro1665 167016751680Arg Asp Lys Gln Arg Met Lys Gln Glu Leu Ser Ser Glu Leu Ser Thr168516901695Leu Leu Ser Ser Leu Ser Arg Tyr Phe Arg Arg Gly Ala Pro Ser Ser170017051710Pro Ala Thr Gly Val Leu Pro Ser Pro Gln Gly Lys Ser Thr Ser Leu171517201725Ser Lys Ala Ser Pro Glu Ser Gln Glu Pro Leu Ile Gln Leu Val Gln173017351740Ala Phe Val Arg His Met Gln Arg1745 1750<210>6<211>1753<212>PRT<213>人<400>6Met Ile Arg Lys Ser Lys Ile Thr Ser Val Leu Ser Phe Cys Arg Ser1 5 10 15Ser Arg Glu Leu Trp Thr Ile Leu Leu Gly Arg Ser Ala Leu Arg Glu20 25 30Leu Ser Gln Ile Glu Ala Glu Leu Asn Lys His Trp Arg Arg Leu Leu35 40 45Glu Gly Leu Ser Tyr Tyr Lys Pro Pro Ser Pro Ser Ser Ala Glu Lys50 55 60Val Lys Ala Asn Lys Asp Val Ala Ser Pro Leu Lys Glu Leu Gly Leu65 70 75 80Arg Ile Ser Lys Phe Leu Gly Leu Asp Glu Glu Gln Ser Val Gln Leu
85 90 95Leu Gln Cys Tyr Leu Gln Glu Asp Tyr Arg Gly Thr Arg Asp Ser Val100 105 110Lys Thr Val Leu Gln Asp Glu Arg Gln Ser Gln Ala Leu Ile Leu Lys115 120 125Ile Ala Asp Tyr Tyr Tyr Glu Glu Arg Thr Cys Ile Leu Arg Cys Val130 135 140Leu His Leu Leu Thr Tyr Phe Gln Asp Glu Arg His Pro Tyr Arg Val145 150 155 160Glu Tyr Ala Asp Cys Val Asp Lys Leu Glu Lys Glu Leu Val Ser Lys165 170 175Tyr Arg Gln Gln Phe Glu Glu Leu Tyr Lys Thr Glu Ala Pro Thr Trp180 185 190Glu Thr His Gly Asn Leu Met Thr Glu Arg Gln Val Ser Arg Trp Phe195 200 205Val Gln Cys Leu Ara Glu Gln Ser Met Leu Leu Glu Ile Ile Phe Leu210 215 220Tyr Tyr Ala Tyr Phe Glu Met Ala Pro Ser Asp Leu Leu Val Leu Thr225 230 235 240Lys Met Phe Lys Glu Gln Gly Phe Gly Ser Arg Gln Thr Asn Arg His245 250 255Leu Val Asp Glu Thr Met Asp Pro Phe Val Asp Arg Ile Gly Tyr Phe260 265 270Ser Ala Leu Ile Leu ValGlu Gly Met Asp Ile Glu Ser Leu His Lys275 280 285Cys Ala Leu Asp Asp Arg Arg Glu Leu His Gln Phe Ala Gln Asp Gly290 295 300Leu Ile Cys Gln Asp Met Asp Cys Leu Met Leu Thr Phe Gly Asp Ile305 310 315 320
Pro His His Ala Pro Val Leu Leu Ala Trp Ala Leu Leu Arg His Thr325 330 335Leu Asn Pro Glu Glu Thr Ser Ser Val Val Arg Lys Ile Gly Gly Thr340 345 350Ala Ile Asn Leu Asn Val Phe Gln Tyr Leu Thr Arg Leu Leu Gln Ser355 360 365Leu Ala Ser Gly Gly Asn Asp Cys Thr Thr Ser Thr Ala Cys Met Cys370 375 380Val Tyr Gly Leu Leu Ser Phe Val Leu Thr Ser Leu Glu Leu His Thr385 390 395 400Leu Gly Asn Gln Gln Asp Ile Ile Asp Thr Ala Cys Glu Val Leu Ala405 410 415Asp Pro Ser Leu Pro Glu Leu Phe Trp Gly Thr Glu Pro Thr Ser Gly420 425 430Leu Gly Ile Ile Leu Asp Ser Val Cys Gly Met Phe Pro His Leu Leu435 440 445Ser Pro Leu Leu Gln Leu Leu Arg Ala Leu Val Ser Gly Lys Ser Thy450 455 460Ala Lys Lys Val Tyr Ser Phe Leu Asp Lys Met Ser Phe Tyr Asn Glu465 470 475 480Leu Tyr Lys His Lys Pro His Asp Val Ile Ser His Glu Asp Gly Thr485 490 495Leu Trp Arg Arg Gln Thr Pro Lys Leu Leu Tyr Pro Leu Gly Gly Gln500 505 510Thr Asn Leu Arg Ile Pro Gln Gly Thr Val Gly Gln Val Met Leu Asp515 520 525Asp Arg Ala Tyr Leu Val Arg Trp Glu Tyr Ser Tyr Ser Ser Trp Thr530 535 540Leu Phe Thr Cys Glu Ile Glu Met Leu Leu His Val Val Ser Thr Ala545 550 555 560
Asp Val Ile Gln His Cys Gln Arg Val Lys Pro Ile Ile Asp Leu Val565 570 575His Lys Val Ile Ser Thr Asp Leu Ser Ile Ala Asp Cys Leu Leu Pro580 585 590Ile Thr Ser Arg Ile Tyr Met Leu Leu Gln Arg Leu Thr Thr Val Ile595 600 605Ser Pro Pro Val Asp Val Ile Ala Ser Cys Val Asn Cys Leu Thr Val610 615 620Leu Ala Ala Arg Asn Pro Ala Lys Val Trp Thr Asp Leu Arg His Thr625 630 635 640Gly Phe Leu Pro Phe Val Ala His Pro Val Ser Ser Leu Ser Gln Met645 650 655Ile Ser Ala Glu Gly Met Asn Ala Gly Gly Tyr Gly Asn Leu Leu Met660 665 670Asn Ser Glu Gln Pro Gln Gly Glu Tyr Gly Val Thr Ile Ala Phe Leu675 680 685Arg Leu Ile Thr Thr Leu Val Lys Gly Gln Leu Gly Ser Thr Gln Ser690 695 700Gln Gly Leu Val Pro Cys Val Met Phe Val Leu Lys Glu Met Leu Pro705 710 715 720Ser Tyr His Lys Trp Arg Tyr Asn Ser His Gly Val Arg Glu Gln Ile725 730 735Gly Cys Leu Ile Leu Glu Leu Ile His Ala Ile Leu Asn Leu Cys His740 745 750Glu Thr Asp Leu His Ser Ser His Thr Pro Ser Leu Gln Phe Leu Cys755 760 765Ile Cys Ser Leu Ala Tyr Thr Glu Ala Gly Gln Thr Val Ile Asn Ile770 775 780Met Gly Ile Gly Val Asp Thr Ile Asp Met Val Met Ala Ala Gln Pro
785 790 795 800Arg Ser Asp Gly Ala Glu Gly Gln Gly Gln Gly Gln Leu Leu Ile Lys805 810 815Thr Val Lys Leu Ala Phe Ser Val Thr Asn Asn Val Ile Arg Leu Lys820 825 830Pro Pro Ser Asn Val Val Ser Pro Leu Glu Gln Ala Leu Ser Gln His835 840 845Gly Ala His Gly Asn Asn Leu Ile Ala Val Leu Ala Lys Tyr Ile Tyr850 855 860His Lys His Asp Pro Ala Leu Pro Arg Leu Ala Ile Gln Leu Leu Lys865 870 875 880Arg Leu Ala Thr Val Ala Pro Met Ser Val Tyr Ala Cys Leu Gly Asn885 890 895Asp Ala Ala Ala Ile Arg Asp Ala Phe Leu Thr Arg Leu Gln Ser Lys900 905 910Ile Glu Asp Met Arg Ile Lys Val Met Ile Leu Glu Phe Leu Thr Val915 920 925Ala Val Glu Thr Gln Pro Gly Leu Ile Glu Leu Phe Leu Asn Leu Glu930 935 940Val Lys Asp Gly Ser Asp Gly Ser Lys Glu Phe Ser Leu Gly Met Trp945 950 955 960Ser Cys Leu His Ala Val Leu Glu Leu Ile Asp Ser Gln Gln Gln Asp965 970 975Arg Tyr Trp Cys Pro Pro Leu Leu His Arg Ala Ala Ile Ala Phe Leu980 985 990His Ala Leu Trp Gln Asp Arg Arg Asp Ser Ala Met Leu Val Leu Arg99510001005Thr Lys Pro Lys Phe Trp Glu Asn Leu Thr Ser Pro Leu Phe Gly Thr101010151020
Leu Ser Pro Pro Ser Glu Thr Ser Glu Pro Ser Ile Leu Glu Thr Cys1025 103010351040Ala Leu Ile Met Lys Ile Ile Cys Leu Glu Ile Tyr Tyr Val Val Lys104510501055Gly Ser Leu Asp Gln Ser Leu Lys Asp Thr Leu Lys Lys Phe Ser Ile106010651070Glu Lys Arg Phe Ala Tyr Trp Ser Gly Tyr Val Lys Ser Leu Ala Val107510801085His Val Ala Glu Thr Glu Gly Ser Ser Cys Thr Ser Leu Leu Glu Tyr109010951100Gln Met Leu Val Ser Ala Trp Arg Met Leu Leu Ile Ile Ala Thr Thr1105 111011151120His Ala Asp Ile Met His Leu Thr Asp Ser Val Val Arg Arg Gln Leu112511301135Phe Leu Asp Val Leu Asp Gly Thr Lys Ala Leu Leu Leu Val Pro Ala114011451150Ser Val Asn Cys Leu Arg Leu Gly Ser Met Lys Cys Thr Leu Leu Leu115511601165Ile Leu Leu Arg Gln Trp Lys Arg Glu Leu Gly Ser Val Asp Glu Ile117011751180Leu Gly Pro Leu Thr Glu Ile Leu Glu Gly Val Leu Gln Ala Asp Gln1185 119011951200Gln Leu Met Glu Lys Thr Lys Ala Lys Val Phe Ser Ala Phe Ile Thr120512101215Val Leu Gln Met Lys Glu Met Lys Val Ser Asp Ile Pro Gln Tyr Ser122012251230Gln Leu Val Leu Asn Val Cys Glu Thr Leu Gln Glu Glu Val Ile Ala123512401245Leu Phe Asp Gln Thr Arg His Ser Leu Ala Leu Gly Ser Ala Thr Glu125012551260
Asp Lys Asp Ser Met Glu Thr Asp Asp Cys Ser Arg Ser Arg His Arg1265 127012751280Asp Gln Arg Asp Gly Val Cys Val Leu Gly Leu His Leu Ala Lys Glu128512901295Leu Cys Glu Val Asp Glu Asp Gly Asp Ser Trp Leu Gln Val Thr Arg130013051310Arg Leu Pro Ile Leu Pro Thr Leu Leu Thr Thr Leu Glu Val Ser Leu131513201325Arg Met Lys Gln Asn Leu His Phe Thr Glu Ala Thr Leu His Leu Leu133013351340Leu Thr Leu Ala Arg Thr Gln Gln Gly Ala Thr Ala Val Ala Gly Ala1345 135013551360Gly Ile Thr Gln Ser Ile Cys Leu Pro Leu Leu Ser Val Tyr Gln Leu136513701375Ser Thr Asn Gly Thr Ala Gln Thr Pro Ser Ala Ser Arg Lys Ser Leu138013851390Asp Ala Pro Ser Trp Pro Gly Val Tyr Arg Leu Ser Met Ser Leu Met139514001405Glu Gln Leu Leu Lys Thr Leu Arg Tyr Asn Phe Leu Pro Glu Ala Leu141014151420Asp Phe Val Gly Val His Gln Glu Arg Thr Leu Gln Cys Leu Asn Ala1425 143014351440Val Arg Thr Val Gln Ser Leu Ala Cys Leu Glu Glu Ala Asp His Thr144514501455Val Gly Phe Ile Leu Gln Leu Ser Asn Phe Met Lys Glu Trp His Phe146014651470His Leu Pro Gln Leu Met Arg Asp Ile Gln Val Asn Leu Gly Tyr Leu147514801485Cys Gln Ala Cys Thr Ser Leu Leu His Ser Arg Lys Met Leu Gln His
1490 1495 1500Tyr Leu Gln Asn Lys Asn Gly Asp Gly Leu Pro Ser Ala Val Ala Gln1505 1510 1515 1520Arg Val Gln Arg Pro Pro Ser Ala Ala Ser Ala Ala Pro Ser Ser Ser1525 1530 1535Lys Gln Pro Ala Ala Asp Thr Glu Ala Ser Glu Gln Gln Ala Leu His1540 1545 1550Thr Val Gln Tyr Gly Leu Leu Lys Ile Leu Ser Lys Thr Leu Ala Ala1555 1560 1565Leu Arg His Phe Thr Pro Asp Val Cys Gln Ile Leu Leu Asp Gln Ser1570 1575 1580Leu Asp Leu Ala Glu Tyr Asn Phe Leu Phe Ala Leu Ser Phe Thr Thr1585 1590 1595 1600Pro Thr Phe Asp Ser Glu Val Ala Pro Ser Phe Gly Thr Leu Leu Ala1605 1610 1615Thr Val Asn Val Ala Leu Asn Met Leu Gly Glu Leu Asp Lys Lys Lys1620 1625 1630Glu Pro Leu Thr Gln Ala Val Gly Leu Ser Thr Gln Ala Glu Gly Thr1635 1640 1645Arg Thr Leu Lys Ser Leu Leu Met Phe Thr Met Glu Asn Cys Phe Tyr1650 1655 1660Leu Leu Ile Ser Gln Ala Met Arg Tyr Leu Arg Asp Pro Ala Val His1665 1670 1675 1680Pro Arg Asp Lys Gln Arg Met Lys Gln Glu Leu Ser Ser Glu Leu Ser1685 1690 1695Thr Leu Leu Ser Ser Leu Ser Arg Tyr Phe Arg Arg Gly Ala Pro Ser1700 1705 1710Ser Pro Ala Thr Gly Val Leu Pro Ser Pro Gln Gly Lys Ser Thr Ser1715 1720 1725
Leu Ser Lys Ala Ser Pro Glu Ser Gln Glu Pro Leu Ile Gln Leu Val1730 1735 1740Gln Ala Phe Val Arg His Met Gln Arg1745 1750<210>7<211>1753<212>PRT<213>人<400>7Met Ile Arg Lys Ser Lys Ile Thr Ser Val Leu Ser Phe Cys Arg Ser1 5 10 15Ser Arg Glu Leu Trp Thr Ile Leu Leu Gly Arg Ser Ala Leu Arg Glu20 25 30Leu Ser Gln Ile Glu Ala Glu Leu Asn Lys His Trp Arg Arg Leu Leu35 40 45Glu Gly Leu Ser Tyr Tyr Lys Pro Pro Ser Pro Ser Ser Ala Glu Lys50 55 60Val Lys Ala Asn Lys Asp Val Ala Ser Pro Leu Lys Glu Leu Gly Leu65 70 75 80Arg Ile Ser Lys Phe Leu Gly Leu Asp Glu Glu Gln Ser Val Gln Leu85 90 95Leu Gln Cys Tyr Leu Gln Glu Asp Tyr Arg Gly Thr Arg Asp Ser Val100 105 110Lys Thr Val Leu Gln Asp Glu Arg Gln Ser Gln Ala Leu Ile Leu Lys115 120 125Ile Ala Asp Tyr Tyr Tyr Glu Glu Arg Thr Cys Ile Leu Arg Cys Val130 135 140Leu His Leu Leu Thr Tyr Phe Gln Asp Glu Arg His Pro Tyr Arg Val145 150 155 160Glu Tyr Ala Asp Cys Val Asp Lys Leu Glu Lys Glu Leu Val Ser Lys
165 170 175Tyr Arg Gln Gln Phe Glu Glu Leu Tyr Lys Thr Glu Ala Pro Thr Trp180 185 190Glu Thr His Gly Asn Leu Met Thr Glu Arg Gln Val Ser Arg Trp Phe195 200 205Val Gln Cys Leu Arg Glu Gln Ser Met Leu Leu Glu Ile Ile Phe Leu210 215 220Tyr Tyr Ala Tyr Phe Glu Met Ala Pro Ser Asp Leu Leu Val Leu Thr225 230 235 240Lys Met Phe Lys Glu Gln Gly Phe Gly Ser Arg Gln Thr Asn Arg His245 250 255Leu Val Asp Glu Thr Met Asp Pro Phe Val Asp Arg Ile Gly Tyr Phe260 265 270Ser Ala Leu Ile Leu Val Glu Gly Met Asp Ile Glu Ser Leu His Lys275 280 285Cys Ala Leu Asp Asp Arg Arg Glu Leu His Gln Phe Ala Gln Asp Gly290 295 300Leu Ile Cys Gln Asp Met Asp Cys Leu Met Leu Thr Phe Gly Asp Ile305 310 315 320Pro His His Ala Pro Val Leu Leu Ala Trp Ala Leu Leu Arg His Thr325 330 335Leu Asn Pro Glu Glu Thr Ser Ser Val Val Arg Lys Ile Gly Gly Thr340 345 350Ala Ile Gln Leu Asn Val Phe Gln Tyr Leu Thr Arg Leu Leu Gln Ser355 360 365Leu Ala Ser Gly Gly Asn Asp Cys Thr Thr Ser Thr Ala Cys Met Cys370 375 380Val Tyr Gly Leu Leu Ser Phe Val Leu Thr Ser Leu Glu Leu His Thr385 390 395 400
Leu Gly Asn Gln Gln Asp Ile Ile Asp Thr Ala Cys Glu Val Leu Ala405 410 415Asp Pro Ser Leu Pro Glu Leu Phe Trp Gly Thr Glu Pro Thr Ser Gly420 425 430Leu Gly Ile Ile Leu Asp Ser Val Cys Gly Met Phe Pro Arg Leu Leu435 440 445Ser Pro Leu Leu Gln Leu Leu Arg Ala Leu Val Ser Gly Lys Ser Thr450 455 460Ala Lys Lys Val Tyr Ser Phe Leu Asp Lys Met Ser Phe Tyr Asn Glu465 470 475 480Leu Tyr Lys His Lys Pro His Asp Val Ile Ser His Glu Asp Gly Thr485 490 495Leu Trp Arg Arg Gln Thr Pro Lys Leu Leu Tyr Pro Leu Gly Gly Gln500 505 510Thr Asn Leu Arg Ile Pro Gln Gly Thr ValGly Gln Val Met Leu Asp515 520 525Asp Arg Ala Tyr Leu Val Arg Trp Glu Tyr Ser Tyr Ser Ser Trp Thr530 535 540Leu Phe Thr Cys Glu Ile Glu Met Leu Leu His Val Val Ser Thr Ala545 550 555 560Asp Val Ile Gln His Cys Gln Arg ValLys Pro He Ile Asp Leu Val565 570 575His Lys Val Ile Ser Thr Asp Leu Ser Ile Ala Asp Cys Leu Leu Pro580 585 590Ile Thr Ser Arg Ile Tyr Met Leu Leu Gln Arg Leu Thr Thr Val Ile595 600 605Ser Pro Pro Val Asp Val Ile Ala Ser Cys Val Asn Cys Leu Thr Val610 615 620Leu Ala Ala Arg Asn Pro Ala Lys Val Trp Thr Asp Leu Arg His Thr625 630 635 640
Gly Phe Leu Pro Phe Val Ala His Pro Val Ser Ser Leu Ser Gln Met645 650 655Ile Ser Ala Glu Gly Met Asn Ala Gly Gly Tyr Gly Asn Leu Leu Met660 665 670Asn Ser Glu Gln Pro Gln Gly Glu Tyr Gly Val Thr Ile Ala Phe Leu675 680 685Arg Leu Ile Thr Thr Leu Val Lys Gly Gln Leu Gly Ser Thr Gln Ser690 695 700Gln Gly Leu Val Pro Cys Val Met Phe Val Leu Lys Glu Met Leu Pro705 710 715 720Ser Tyr His Lys Trp Arg Tyr Asn Ser His Gly Val Arg Glu Gln Ile725 730 735Gly Cys Leu Ile Leu Glu Leu Ile His Ala Ile Leu Asn Leu Cys His740 745 750Glu Thr Asp Leu His Ser Ser His Thr Pro Ser Leu Gln Phe Leu Cys755 760 765Ile Cys Ser Leu Ala Tyr Thr Glu Ala Gly Gln Thr Val Ile Asn Ile770 775 780Met Gly Ile Gly Val Asp Thr Ile Asp Met Val Met Ala Ala Gln Pro785 790 795 800Arg Ser Asp Gly Ala Glu Gly Gln Gly Gln Gly Gln Leu Leu Ile Lys805 810 815Thr Val Lys Leu Ala Phe Ser Val Thr Asn Asn Val Ile Arg Leu Lys820 825 830Pro Pro Ser Asn Val Val Ser Pro Leu Glu Gln Ala Leu Ser Gln His835 840 845Gly Ala His Gly Asn Asn Leu Ile Ala Val Leu Ala Lys Tyr Ile Tyr850 855 860His Lys His Asp Pro Ala Leu Pro Arg Leu Ala Ile Gln Leu Leu Lys
865 870 875 880Arg Leu Ala Thr Val Ala Pro Met Ser Val Tyr Ala Cys Leu Gly Asn885 890 895Asp Ala Ala Ala Ile Arg Asp Ala Phe Leu Thr Arg Leu Gln Ser Lys900 905 910Ile Glu Asp Met Arg Ile Lys Val Met Ile Leu Glu Phe Leu Thr Val915 920 925Ala Val Glu Thr Gln Pro Gly Leu Ile Glu Leu Phe Leu Asn Leu Glu930 935 940Val Lys Asp Gly Ser Asp Gly Ser Lys Glu Phe Ser Leu Gly Met Trp945 950 955 960Ser Cys Leu His Ala Val Leu Glu Leu Ile Asp Ser Gln Gln Gln Asp965 970 975Arg Tyr Trp Cys Pro Pro Leu Leu His Arg Ala Ala Ile Ala Phe Leu980 985 990His Ala Leu Trp Gln Asp Arg Arg Asp Ser Ala Met Leu Val Leu Arg99510001005Thr Lys Pro Lys Phe Trp Glu Asn Leu Thr Ser Pro Leu Phe Gly Thr101010151020Leu Ser Pro Pro Ser Glu Thr Ser Glu Pro Ser Ile Leu Glu Thr Cys1025 103010351040Ala Leu Ile Met Lys Ile Ile Cys Leu Glu Ile Tyr Tyr Val Val Lys104510501055Gly Ser Leu Asp Gln Ser Leu Lys Asp Thr Leu Lys Lys Phe Ser Ile106010651070Glu Lys Arg Phe Ala Tyr Trp Ser Gly Tyr Val Lys Ser Leu Ala Val107510801085His Val Ala Glu Thr Glu Gly Ser Ser Cys Thr Ser Leu Leu Glu Tyr109010951100
Gln Met Leu Val Ser Ala Trp Arg Met Leu Leu Ile Ile Ala Thr Thr1105 111011151120His Ala Asp Ile Met His Leu Thr Asp Ser Val Val Arg Arg Gln Leu112511301135Phe Leu Asp Val Leu Asp Gly Thr Lys Ala Leu Leu Leu Val Pro Ala114011451150Ser Val Asn Cys Leu Arg Leu Gly Ser Met Lys Cys Thr Leu Leu Leu115511601165Ile Leu Leu Arg Gln Trp Lys Arg Glu Leu Gly Ser Val Asp Glu Ile117011751180Leu Gly Pro Leu Thr Glu Ile Leu Glu Gly Val Leu Gln Ala Asp Gln1185 119011951200Gln Leu Met Glu Lys Thr Lys Ala Lys Val Phe Ser Ala Phe Ile Thr120512101215Val Leu Gln Met Lys Glu Met Lys Val Ser Asp Ile Pro Gln Tyr Ser122012251230Gln Leu Val Leu Asn Val Cys Glu Thr Leu Gln Glu Glu Val Ile Ala123512401245Leu Phe Asp Gln Thr Arg His Ser Leu Ala Leu Gly Ser Ala Thr Glu125012551260Asp Lys Asp Ser Met Glu Thr Asp Asp Cys Ser Arg Ser Arg His Arg1265 127012751280Asp Gln Arg Asp Gly Val Cys Val Leu Gly Leu His Leu Ala Lys Glu128512901295Leu Cys Glu Val Asp Glu Asp Gly Asp Ser Trp Leu Gln Val Thr Arg130013051310Arg Leu Pro Ile Leu Pro Thr Leu Leu Thr Thr Leu Glu Val Ser Leu131513201325Arg Met Lys Gln Asn Leu His Phe Thr Glu Ala Thr Leu His Leu Leu133013351340
Leu Thr Leu Ala Arg Thr Gln Gln Gly Ala Thr Ala Val Ala Gly Ala1345 135013551360Gly Ile Thr Gln Ser Ile Cys Leu Pro Leu Leu Ser Val Tyr Gln Leu136513701375Ser Thr Asn Gly Thr Ala Gln Thr Pro Ser Ala Ser Arg Lys Ser Leu138013851390Asp Ala Pro Ser Trp Pro Gly Val Tyr Arg Leu Ser Met Ser Leu Met139514001405Glu Gln Leu Leu Lys Thr Leu Arg Tyr Asn Phe Leu Pro Glu Ala Leu141014151420Asp Phe Val Gly Val His Gln Glu Arg Thr Leu Gln Cys Leu Asn Ala1425 143014351440Val Arg Thr Val Gln Ser Leu Ala Cys Leu Glu Glu Ala Asp His Thr144514501455Va1Gly Phe Ile Leu Gln Leu Ser Asn Phe Met Lys Glu Trp His Phe146014651470His Leu Pro Gln Leu Met Arg Asp Ile Gln Val Asn Leu Gly Tyr Leu147514801485Cys Gln Ala Cys Thr Ser Leu Leu His Ser Arg Lys Met Leu Gln His149014951500Tyr Leu Gln Asn Lys Asn Gly Asp Gly Leu Pro Ser Ala Val Ala Gln1505 151015151520Arg Val Gln Arg Pro Pro Ser Ala Ala Ser Ala Ala Pro Ser Ser Ser152515301535Lys Gln Pro Ala Ala Asp Thr Glu Ala Ser Glu Gln Gln Ala Leu His154015451550Thr Val Gln Tyr Gly Leu Leu Lys Ile Leu Ser Lys Thr Leu Ala Ala155515601565Leu Arg His Phe Thr Pro Asp Val Cys Gln Ile Leu Leu Asp Gln Ser
157015751580Leu Asp Leu Ala Glu Tyr Asn Phe Leu Phe Ala Leu Ser Phe Thr Thr1585 159015951600Pro Thr Phe Asp Ser Glu Val Ala Pro Ser Phe Gly Thr Leu Leu Ala160516101615Thr Val Asn Val Ala Leu Asn Met Leu Gly Glu Leu Asp Lys Lys Lys162016251630Glu Pro Leu Thr Gln Ala Val Gly Leu Ser Thr Gln Ala Glu Gly Thr163516401645Arg Thr Leu Lys Ser Leu Leu Met Phe Thr Met Glu Asn Cys Phe Tyr165016551660Leu Leu Ile Ser Gln Ala Met Arg Tyr Leu Arg Asp Pro Ala Val His1665 167016751680Pro Arg Asp Lys Gln Arg Met Lys Gln Glu Leu Ser Ser Glu Leu Ser168516901695Thr Leu Leu Ser Ser Leu Ser Arg Tyr Phe Arg Arg Gly Ala Pro Ser170017051710Ser Pro Ala Thr Gly Val Leu Pro Ser Pro Gln Gly Lys Ser Thr Ser171517201725Leu Ser Lys Ala Ser Pro Glu Ser Gln Glu Pro Leu Ile Gln Leu Val173017351740Gln Ala Phe Val Arg His Met Gln Arg1745 1750<210>8<211>1753<212>PRT<213>人<400>8Met Ile Arg Lys Ser Lys Ile Thr Ser Val Leu Ser Phe Cys Arg Ser1 5 10 15
Ser Arg Glu Leu Trp Thr Ile Leu Leu Gly Arg Ser Ala Leu Arg Glu20 25 30Leu Ser Gln Ile Glu Ala Glu Leu Asn Lys His Trp Arg Arg Leu Leu35 40 45Glu Gly Leu Ser Tyr Tyr Lys Pro Pro Ser Pro Ser Ser Ala Glu Lys50 55 60Val Lys Ala Asn Lys Asp Val Ala Ser Pro Leu Lys Glu Leu Gly Leu65 70 75 80Arg Ile Ser Lys Phe Leu Gly Leu Asp Glu Glu Gln Ser Val Gln Leu85 90 95Leu Gln Cys Tyr Leu Gln Glu Asp Tyr Arg Gly Thr Arg Asp Ser Val100 105 110Lys Thr Val Leu Gln Asp Glu Arg Gln Ser Gln Ala Leu Ile Leu Lys115 120 125Ile Ala Asp Tyr Tyr Tyr Glu Glu Arg Thr Cys Ile Leu Arg Cys Val130 135 140Leu His Leu Leu Thr Tyr Phe Gln Asp Glu Arg His Pro Tyr Arg Val145 150 155 160Glu Tyr Ala Asp Cys Val Asp Lys Leu Glu Lys Glu Leu Val Ser Lys165 170 175Tyr Arg Gln Gln Phe Glu Glu Leu Tyr Lys Thr Glu Ala Pro Thr Trp180 185 190Glu Thr His Gly Asn Leu Met Thr Glu Arg Gln Val Ser Arg Trp Phe195 200 205Val Gln Cys Leu Arg Glu Gln Ser Met Leu Leu Glu Ile Ile Phe Leu210 215 220Tyr Tyr Ala Tyr Phe Glu Met Ala Pro Ser Asp Leu Leu Val Leu Thr225 230 235 240Lys Met Phe Lys Glu Gln Gly Phe Gly Ser Arg Gln Thr Asn Arg His
245 250 255Leu Val Asp Glu Thr Met Asp Pro Phe Val Asp Arg Ile Gly Tyr Phe260 265 270Ser Ala Leu Ile Leu Val Glu Gly Met Asp Ile Glu Ser Leu His Lys275 280 285Cys Ala Leu Asp Asp Arg Arg Glu Leu His Gln Phe Ala Gln Asp Gly290 295 300Leu Ile Cys Gln Asp Met Asp Cys Leu Met Leu Thr Phe Gly Asp Ile305 310 315 320Pro His His Ala Pro Val Leu Leu Ala Trp Ala Leu Leu Arg His Thr325 330 335Leu Asn Pro Glu Glu Thr Ser Ser Val Val Arg Lys Ile Gly Gly Thr340 345 350Ala Ile Gln Leu Asn Val Phe Gln Tyr Leu Thr Arg Leu Leu Gln Ser355 360 365Leu Ala Ser Gly Gly Asn Asp Cys Thr Thr Ser Thr Ala Cys Met Cys370 375 380Val Tyr Gly Leu Leu Ser Phe Val Leu Thr Ser Leu Glu Leu His Thr385 390 395 400Leu Gly Asn Gln Gln Asp Ile Ile Asp Thr Ala Cys Glu Val Leu Ala405 410 415Asp Pro Ser Leu Pro Glu Leu Phe Trp Gly Thr Glu Pro Thr Ser Gly420 425 430Leu Gly Ile Ile Leu Asp Ser Val Cys Gly Met Phe Pro His Leu Leu435 440 445Ser Pro Leu Leu Gln Leu Leu Arg Ala Leu Val Ser Gly Lys Ser Thr450 455 460Ala Lys Lys Val Tyr Ser Phe Leu Asp Lys Met Ser Phe Tyr Asn Glu465 470 475 480
Leu Tyr Lys His Lys Pro His Asp Val Ile Ser His Glu Asp Gly Thr485 490 495Leu Trp Arg Arg Gln Thr Pro Lys Leu Leu Tyr Pro Leu Gly Gly Gln500 505 510Thr Asn Leu Arg Ile Pro Gln Gly Thr Val Gly Gln Val Met Leu Asp515 520 525Asp Arg Ala Tyr Leu Val Arg Trp Glu Tyr Ser Tyr Ser Ser Trp Thr530 535 540Leu Phe Thr Cys Glu Ile Glu Met Ile Leu His Val Val Ser Thr Ala545 550 555 560Asp Val Ile Gln His Cys Gln Arg Val Lys Pro Ile Ile Asp Leu Val565 570 575His Lys Val Ile Ser Thr Asp Leu Ser Ile Ala Asp Cys Leu Leu Pro580 585 590Ile Thr Ser Arg Ile Tyr Met Leu Leu Gln Arg Leu Thr Thr Val Ile595 600 605Ser Pro Pro Val Asp Val Ile Ala Ser Cys Val Asn Cys Leu Thr Val610 615 620Leu Ala Ala Arg Asn Pro Ala Lys Val Trp Thr Asp Leu Arg His Thr625 630 635 640Gly Phe Leu Pro Phe Val Ala His Pro Val Ser Ser Leu Ser Gln Met645 650 655Ile Ser Ala Glu Gly Met Asn Ala Gly Gly Tyr Gly Asn Leu Leu Met660 665 670Asn Ser Glu Gln Pro Gln Gly Glu Tyr Gly Val Thr Ile Ala Phe Leu675 680 685Arg Leu Ile Thr Thr Leu Val Lys Gly Gln Leu Gly Ser Thr Gln Ser690 695 700Gln Gly Leu Val Pro Cys Val Met Phe Val Leu Lys Glu Met Leu Pro705 710 715 720
Ser Tyr His Lys Trp Arg Tyr Asn Ser His Gly Val Arg Glu Gln Ile725 730 735Gly Cys Leu Ile Leu Glu Leu Ile His Ala Ile Leu Asn Leu Cys His740 745 750Glu Thr Asp Leu His Ser Ser His Thr Pro Ser Leu Gln Phe Leu Cys755 760 765Ile Cys Ser Leu Ala Tyr Thr Glu Ala Gly Gln Thr Val Ile Asn Ile770 775 780Met Gly Ile Gly Val Asp Thr Ile Asp Met Val Met Ala Ala Gln Pro785 790 795 800Arg Ser Asp Gly Ala Glu Gly Gln Gly Gln Gly Gln Leu Leu Ile Lys805 810 815Thr Val Lys Leu Ala Phe Ser Val Thr Asn Asn Val Ile Arg Leu Lys820 825 830Pro Pro Ser Asn Val ValSer Pro Leu Glu Gln Ala Leu Ser Gln His835 840 845Gly Ala His Gly Asn Asn Leu Ile Ala Val Leu Ala Lys Tyr Ile Tyr850 855 860His Lys His Asp Pro Ala Leu Pro Arg Leu Ala Ile Gln Leu Leu Lys865 870 875 880Arg Leu Ala Thr Val Ala Pro Met Ser Val Tyr Ala Cys Leu Gly Asn885 890 895Asp Ala Ala Ala Ile Arg Asp Ala Phe Leu Thr Arg Leu Gln Ser Lys900 905 910Ile Glu Asp Met Arg Ile Lys Val Met Ile Leu Glu Phe Leu Thr Val915 920 925Ala Val Glu Thr Gln Pro Gly Leu Ile Glu Leu Phe Leu Asn Leu Glu930 935 940Val Lys Asp Gly Ser Asp Gly Ser Lys Glu Phe Ser Leu Gly Met Trp
945 950 955 960Ser Cys Leu His Ala Val Leu Glu Leu Ile Asp Ser Gln Gln Gln Asp965 970 975Arg Tyr Trp Cys Pro Pro Leu Leu His Arg Ala Ala Ile Ala Phe Leu980 985 990His Ala Leu Trp Gln Asp Arg Arg Asp Ser Ala Met Leu Val Leu Arg99510001005Thr Lys Pro Lys Phe Trp Glu Asn Leu Thr Ser Pro Leu Phe Gly Thr101010151020Leu Ser Pro Pro Ser Glu Thr Ser Glu Pro Ser Ile Leu Glu Thr Cys1025 103010351040Ala Leu Ile Met Lys Ile Ile Cys Leu Glu Ile Tyr Tyr Val Val Lys104510501055Gly Ser Leu Asp Gln Ser Leu Lys Asp Thr Leu Lys Lys Phe Ser Ile106010651070Glu Lys Arg Phe Ala Tyr Trp Ser Gly Tyr Val Lys Ser Leu Ala Val107510801085His Val Ala Glu Thr Glu Gly Ser Ser Cys Thr Ser Leu Leu Glu Tyr109010951100Gln Met Leu Val Ser Ala Trp Arg Met Leu Leu Ile Ile Ala Thr Thr1105 111011151120His Ala Asp Ile Met His Leu Thr Asp Ser Val Val Arg Arg Gln Leu112511301135Phe Leu Asp Val Leu Asp Gly Thr Lys Ala Leu Leu Leu Val Pro Ala114011451150Ser Val Asn Cys Leu Arg Leu Gly Ser Met Lys Cys Thr Leu Leu Leu115511601165Ile Leu Leu Arg Gln Trp Lys Arg Glu Leu Gly Ser Val Asp Glu Ile117011751180
Leu Gly Pro Leu Thr Glu Ile Leu Glu Gly Val Leu Gln Ala Asp Gln1185 119011951200Gln Leu Met Glu Lys Thr Lys Ala Lys Val Phe Ser Ala Phe Ile Thr120512101215Val Leu Gln Met Lys Glu Met Lys Val Ser Asp Ile Pro Gln Tyr Ser122012251230Gln Leu Val Leu Asn Val Cys Glu Thr Leu Gln Glu Glu Val Ile Ala123512401245Leu Phe Asp Gln Thr Arg His Ser Leu Ala Leu Gly Ser Ala Thr Glu125012551260Asp Lys Asp Ser Met Glu Thr Asp Asp Cys Ser Arg Ser Arg His Arg1265 127012751280Asp Gln Arg Asp Gly Val Cys Val Leu Gly Leu His Leu Ala Lys Glu128512901295Leu Cys Glu Val Asp Glu Asp Gly Asp Ser Trp Leu Gln Val Thr Arg130013051310Arg Leu Pro Ile Leu Pro Thr Leu Leu Thr Thr Leu Glu Val Ser Leu131513201325Arg Met Lys Gln Asn Leu His Phe Thr Glu Ala Thr Leu His Leu Leu133013351340Leu Thr Leu Ala Arg Thr Gln Gln Gly Ala Thr Ala Val Ala Gly Ala1345 135013551360Gly Ile Thr Gln Ser Ile Cys Leu Pro Leu Leu Ser Val Tyr Gln Leu136513701375Ser Thr Asn Gly Thr Ala Gln Thr Pro Ser Ala Ser Arg Lys Ser Leu138013851390Asp Ala Pro Ser Trp Pro Gly Val Tyr Arg Leu Ser Met Ser Leu Met139514001405Glu Gln Leu Leu Lys Thr Leu Arg Tyr Asn Phe Leu Pro Glu Ala Leu141014151420
Asp Phe Val Gly Val His Gln Glu Arg Thr Leu Gln Cys Leu Asn Ala1425 143014351440Val Arg Thr Val Gln Ser Leu Ala Cys Leu Glu Glu Ala Asp His Thr144514501455Val Gly Phe Ile Leu Gln Leu Ser Asn Phe Met Lys Glu Trp His Phe146014651470His Leu Pro Gln Leu Met Arg Asp Ile Gln Val Asn Leu Gly Tyr Leu147514801485Cys Gln Ala Cys Thr Ser Leu Leu His Ser Arg Lys Met Leu Gln His149014951500Tyr Leu Gln Asn Lys Asn Gly Asp Gly Leu Pro Ser Ala Val Ala Gln1505 151015151520Arg Val Gln Arg Pro Pro Ser Ala Ala Ser Ala Ala Pro Ser Ser Ser152515301535Lys Gln Pro Ala Ala Asp Thr Glu Ala Ser Glu Gln Gln Ala Leu His154015451550Thr Val Gln Tyr Gly Leu Leu Lys Ile Leu Ser Lys Thr Leu Ala Ala155515601565Leu Arg His Phe Thr Pro Asp Val Cys Gln Ile Leu Leu Asp Gln Ser157015751580Leu Asp Leu Ala Glu Tyr Asn Phe Leu Phe Ala Leu Ser Phe Thr Thr1585 159015951600Pro Thr Phe Asp Ser Glu Val Ala Pro Ser Phe Gly Thr Leu Leu Ala160516101615Thr Val Asn Val Ala Leu Asn Met Leu Gly Glu Leu Asp Lys Lys Lys162016251630Glu Pro Leu Thr Gln Ala ValGly Leu Ser Thr Gln Ala Glu Gly Thr163516401645Arg Thr Leu Lys Ser Leu Leu Met Phe Thr Met Glu Asn Cys Phe Tyr
165016551660Leu Leu Ile Ser Gln Ala Met Arg Tyr Leu Arg Asp Pro Ala Val His1665 167016751680Pro Arg Asp Lys Gln Arg Met Lys Gln Glu Leu Ser Ser Glu Leu Ser168516901695Thr Leu Leu Ser Ser Leu Ser Arg Tyr Phe Arg Arg Gly Ala Pro Ser170017051710Ser Pro Ala Thr Gly Val Leu Pro Ser Pro Gln Gly Lys Ser Thr Ser171517201725Leu Ser Lys Ala Ser Pro Glu Ser Gln Glu Pro Leu Ile Gln Leu Val173017351740Gln Ala Phe Val Arg His Met Gln Arg1745 1750<210>9<211>1753<212>PRT<213>人<400>9Met Ile Arg Lys Ser Lys Ile Thr Ser Val Leu Ser Phe Cys Arg Ser1 5 10 15Ser Arg Glu Leu Trp Thr Ile Leu Leu Gly Arg Ser Ala Leu Arg Glu20 25 30Leu Ser Gln Ile Glu Ala Glu Leu Asn Lys His Trp Arg Arg Leu Leu35 40 45Glu Gly Leu Ser Tyr Tyr Lys Pro Pro Ser Pro Ser Ser Ala Glu Lys50 55 60Val Lys Ala Asn Lys Asp Val Ala Ser Pro Leu Lys Glu Leu Gly Leu65 70 75 80Arg Ile Ser Lys Phe Leu Gly Leu Asp Glu Glu Gln Ser Val Gln Leu85 90 95
Leu Gln Cys Tyr Leu Gln Glu Asp Tyr Arg Gly Thr Arg Asp Ser Val100 105 110Lys Thr Val Leu Gln Asp Glu Arg Gln Ser Gln Ala Leu Ile Leu Lys115 120 125Ile Ala Asp Tyr Tyr Tyr Glu Glu Arg Thr Cys Ile Leu Arg Cys Val130 135 140Leu His Leu Leu Thr Tyr Phe Gln Asp Glu Arg His Pro Tyr Arg Val145 150 155 160Glu Tyr Ala Asp Cys Val Asp Lys Leu Glu Lys Glu Leu Val Ser Lys165 170 175Tyr Arg Gln Gln Phe Glu Glu Leu Tyr Lys Thr Glu Ala Pro Thr Trp180 185 190Glu Thr His Gly Asn Leu Met Thr Glu Arg Gln Val Ser Arg Trp Phe195 200 205Val Gln Cys Leu Arg Glu Gln Ser Met Leu Leu Glu Ile Ile Phe Leu210 215 220Tyr Tyr Ala Tyr Phe Glu Met Ala Pro Ser Asp Leu Leu Val Leu Thr225 230 235 240Lys Met Phe Lys Glu Gln Gly Phe Gly Ser Arg Gln Thr Asn Arg His245 250 255Leu Val Asp Glu Thr Met Asp Pro Phe Val Asp Arg Ile Gly Tyr Phe260 265 270Ser Ala Leu Ile Leu Val Glu Gly Met Asp Ile Glu Ser Leu His Lys275 280 285Cys Ala Leu Asp Asp Arg Arg Glu Leu His Gln Phe Ala Gln Asp Gly290 295 300Leu Ile Cys Gln Asp Met Asp Cys Leu Met Leu Thr Phe Gly Asp Ile305 310 315 320Pro His His Ala Pro Val Leu Leu Ala Trp Ala Leu Leu Arg His Thr
325 330 335Leu Asn Pro Glu Glu Thr Ser Ser Val Val Arg Lys Ile Gly Gly Thr340 345 350Ala Ile Gln Leu Asn ValPhe Gln Tyr Leu Thr Arg Leu Leu Gln Ser355 360 365Leu Ala Ser Gly Gly Asn Asp Cys Thr Thr Ser Thr Ala Cys Met Cys370 375 380Val Tyr Gly Leu Leu Ser Phe Val Leu Thr Ser Leu Glu Leu His Thr385 390 395 400Leu Gly Asn Gln Gln Asp Ile Ile Asp Thr Ala Cys Glu Val Leu Ala405 410 415Asp Pro Ser Leu Pro Glu Leu Phe Trp Gly Thr Glu Pro Thr Ser Gly420 425 430Leu Gly Ile Ile Leu Asp Ser Val Cys Gly Met Phe Pro His Leu Leu435 440 445Ser Pro Leu Leu Gln Leu Leu Arg Ala Leu Val Ser Gly Lys Ser Thr450 455 460Ala Lys Lys ValTyr Ser Phe Leu Asp Lys Met Ser Phe Tyr Asn Glu465 470 475 480Leu Tyr Lys His Lys Pro His Asp Val Ile Ser His Glu Asp Gly Thr485 490 495Leu Trp Arg Arg Gln Thr Pro Lys Leu Leu Tyr Pro Leu Gly Gly Gln500 505 510Thr Asn Leu Arg Ile Pro Gln Gly Thr Val Gly Gln Val Met Leu Asp515 520 525Asp Arg Ala Tyr Leu Val Arg Trp Glu Tyr Ser Tyr Ser Ser Trp Thr530 535 540Leu Phe Thr Cys Glu Ile Glu Met Leu Leu His Val Val Ser Thr Ala545 550 555 560
Asp Val Ile Gln His Cys Gln Arg Val Lys Pro Ile Ile Asp Leu Val565 570 575His Lys Val Ile Ser Thr Asp Leu Ser Ile Ala Asp Cys Leu Leu Pro580 585 590Ile Thr Ser Arg Ile Tyr Met Leu Leu Gln Arg Leu Thr Thr Val Ile595 600 605Ser Pro Pro Val Asp Val Ile Ala Ser Cys Val Asn Cys Leu Thr Val610 615 620Leu Ala Ala Arg Asn Pro Ala Lys Val Phe Thr Asp Leu Arg His Thr625 630 635 640Gly Phe Leu Pro Phe Val Ala His Pro Val Ser Ser Leu Ser Gln Met645 650 655Ile Ser Ala Glu Gly Met Asn Ala Gly Gly Tyr Gly Asn Leu Leu Met660 665 670Asn Ser Glu Gln Pro Gln Gly Glu Tyr Gly Val Thr Ile Ala Phe Leu675 680 685Arg Leu Ile Thr Thr Leu Val Lys Gly Gln Leu Gly Ser Thr Gln Ser690 695 700Gln Gly Leu Val Pro Cys Val Met Phe Val Leu Lys Glu Met Leu Pro705 710 715 720Ser Tyr His Lys Trp Arg Tyr Asn Ser His Gly Val Arg Glu Gln Ile725 730 735Gly Cys Leu Ile Leu Glu Leu Ile His Ala Ile Leu Asn Leu Cys His740 745 750Glu Thr Asp Leu His Ser Ser His Thr Pro Ser Leu Gln Phe Leu Cys755 760 765Ile Cys Ser Leu Ala Tyr Thr Glu Ala Gly Gln Thr Val Ile Asn Ile770 775 780Met Gly Ile Gly Val Asp Thr Ile Asp Met Val Met Ala Ala Gln Pro785 790 795 800
Arg Ser Asp Gly Ala Glu Gly Gln Gly Gln Gly Gln Leu Leu Ile Lys805 810 815Thr Val Lys Leu Ala Phe Ser Val Thr Asn Asn Val Ile Arg Leu Lys820 825 830Pro Pro Ser Asn Val Val Ser Pro Leu Glu Gln Ala Leu Ser Gln His835 840 845Gly Ala His Gly Asn Asn Leu Ile Ala Val Leu Ala Lys Tyr Ile Tyr850 855 860His Lys His Asp Pro Ala Leu Pro Arg Leu Ala Ile Gln Leu Leu Lys865 870 875 880Arg Leu Ala Thr Val Ala Pro Met Ser Val Tyr Ala Cys Leu Gly Asn885 890 895Asp Ala Ala Ala Ile Arg Asp Ala Phe Leu Thr Arg Leu Gln Ser Lys900 905 910Ile Glu Asp Met Arg Ile Lys Val Met Ile Leu Glu Phe Leu Thr Val915 920 925Ala Val Glu Thr Gln Pro Gly Leu Ile Glu Leu Phe Leu Asn Leu Glu930 935 940Val Lys Asp Gly Ser Asp Gly Ser Lys Glu Phe Ser Leu Gly Met Trp945 950 955 960Ser Cys Leu His Ala Val Leu Glu Leu Ile Asp Ser Gln Gln Gln Asp965 970 975Arg Tyr Trp Cys Pro Pro Leu Leu His Arg Ala Ala Ile Ala Phe Leu980 985 990His Ala Leu Trp Gln Asp Arg Arg Asp Ser Ala Met Leu Val Leu Arg99510001005Thr Lys Pro Lys Phe Trp Glu Asn Leu Thr Ser Pro Leu Phe Gly Thr101010151020Leu Ser Pro Pro Ser Glu Thr Ser Glu Pro Ser Ile Leu Glu Thr Cys
1025 103010351040Ala Leu Ile Met Lys Ile Ile Cys Leu Glu Ile Tyr Tyr Val Val Lys104510501055Gly Ser Leu Asp Gln Ser Leu Lys Asp Thr Leu Lys Lys Phe Ser Ile106010651070Glu Lys Arg Phe Ala Tyr Trp Ser Gly Tyr Val Lys Ser Leu Ala Val107510801085His Val Ala Glu Thr Glu Gly Ser Ser Cys Thr Ser Leu Leu Glu Tyr109010951100Gln Met Leu Val Ser Ala Trp Arg Met Leu Leu Ile Ile Ala Thr Thr1105 111011151120His Ala Asp Ile Met His Leu Thr Asp Ser Val Val Arg Arg Gln Leu112511301135Phe Leu Asp Val Leu Asp Gly Thr Lys Ala Leu Leu Leu Val Pro Ala114011451150Ser Val Asn Cys Leu Arg Leu Gly Ser Met Lys Cys Thr Leu Leu Leu115511601165Ile Leu Leu Arg Gln Trp Lys Arg Glu Leu Gly Ser Val Asp Glu Ile117011751180Leu Gly Pro Leu Thr Glu Ile Leu Glu Gly Val Leu Gln Ala Asp Gln1185 119011951200Gln Leu Met Glu Lys Thr Lys Ala Lys Val Phe Ser Ala Phe Ile Thr120512101215Val Leu Gln Met Lys Glu Met Lys Val Ser Asp Ile Pro Gln Tyr Ser122012251230Gln Leu Val Leu Asn ValCys Glu Thr Leu Gln Glu Glu Val Ile Ala123512401245Leu Phe Asp Gln Thr Arg His Ser Leu Ala Leu Gly Ser Ala Thr Glu125012551260
Asp Lys Asp Ser Met Glu Thr Asp Asp Cys Ser Arg Ser Arg His Arg1265 127012751280Asp Gln Arg Asp Gly Val Cys Val Leu Gly Leu His Leu Ala Lys Glu128512901295Leu Cys Glu Val Asp Glu Asp Gly Asp Ser Trp Leu Gln Val Thr Arg130013051310Arg Leu Pro Ile Leu Pro Thr Leu Leu Thr Thr Leu Glu Val Ser Leu131513201325Arg Met Lys Gln Asn Leu His Phe Thr Glu Ala Thr Leu His Leu Leu133013351340Leu Thr Leu Ala Arg Thr Gln Gln Gly Ala Thr Ala Val Ala Gly Ala1345 135013551360Gly Ile Thr Gln Ser Ile Cys Leu Pro Leu Leu Ser Val Tyr Gln Leu136513701375Ser Thr Asn Gly Thr Ala Gln Thr Pro Ser Ala Ser Arg Lys Ser Leu138013851390Asp Ala Pro Ser Trp Pro Gly Val Tyr Arg Leu Ser Met Ser Leu Met139514001405Glu Gln Leu Leu Lys Thr Leu Arg Tyr Asn Phe Leu Pro Glu Ala Leu141014151420Asp Phe Val Gly Val His Gln Glu Arg Thr Leu Gln Cys Leu Asn Ala1425 143014351440Val Arg Thr Val Gln Ser Leu Ala Cys Leu Glu Glu Ala Asp His Thr144514501455Val Gly Phe Ile Leu Gln Leu Ser Asn Phe Met Lys Glu Trp His Phe146014651470His Leu Pro Gln Leu Met Arg Asp Ile Gln Val Asn Leu Gly Tyr Leu147514801485Cys Gln Ala Cys Thr Ser Leu Leu His Ser Arg Lys Met Leu Gln His149014951500
Tyr Leu Gln Asn Lys Asn Gly Asp Gly Leu Pro Ser Ala Val Ala Gln1505 151015151520Arg Val Gln Arg Pro Pro Ser Ala Ala Ser Ala Ala Pro Ser Ser Ser152515301535Lys Gln Pro Ala Ala Asp Thr Glu Ala Ser Glu Gln Gln Ala Leu His154015451550Thr Val Gln Tyr Gly Leu Leu Lys Ile Leu Ser Lys Thr Leu Ala Ala155515601565Leu Arg His Phe Thr Pro Asp Val Cys Gln Ile Leu Leu Asp Gln Ser157015751580Leu Asp Leu Ala Glu Tyr Asn Phe Leu Phe Ala Leu Ser Phe Thr Thr1585 159015951600Pro Thr Phe Asp Ser Glu Val Ala Pro Ser Phe Gly Thr Leu Leu Ala160516101615Thr Val Asn Val Ala Leu Asn Met Leu Gly Glu Leu Asp Lys Lys Lys162016251630Glu Pro Leu Thr Gln Ala Val Gly Leu Ser Thr Gln Ala Glu Gly Thr163516401645Arg Thr Leu Lys Ser Leu Leu Met Phe Thr Met Glu Asn Cys Phe Tyr165016551660Leu Leu Ile Ser Gln Ala Met Arg Tyr Leu Arg Asp Pro Ala Val His1665 167016751680Pro Arg Asp Lys Gln Arg Met Lys Gln Glu Leu Ser Ser Glu Leu Ser168516901695Thr Leu Leu Ser Ser Leu Ser Arg Tyr Phe Arg Arg Gly Ala Pro Ser170017051710Ser Pro Ala Thr Gly Val Leu Pro Ser Pro Gln Gly Lys Ser Thr Ser171517201725Leu Ser Lys Ala Ser Pro Glu Ser Gln Glu Pro Leu Ile Gln Leu Val
173017351740Gln Ala Phe Val Arg His Met Gln Arg1745 1750<210>10<211>1753<212>PRT<213>人<400>10Met Ile Arg Lys Ser Lys Ile Thr Ser Val Leu Ser Phe Cys Arg Ser1 5 10 15Ser Arg Glu Leu Trp Thr Ile Leu Leu Gly Arg Ser Ala Leu Arg Glu20 25 30Leu Ser Gln Ile Glu Ala Glu Leu Asn Lys His Trp Arg Arg Leu Leu35 40 45Glu Gly Leu Ser Tyr Tyr Lys Pro Pro Ser Pro Ser Ser Ala Glu Lys50 55 60Val Lys Ala Asn Lys Asp Val Ala Ser Pro Leu Lys Glu Leu Gly Leu65 70 75 80Arg Ile Ser Lys Phe Leu Gly Leu Asp Glu Glu Gln Ser Val Gln Leu85 90 95Leu Gln Cys Tyr Leu Gln Glu Asp Tyr Arg Gly Thr Arg Asp Ser Val100 105 110Lys Thr Val Leu Gln Asp Glu Arg Gln Ser Gln Ala Leu Ile Leu Lys115 120 125Ile Ala Asp Tyr Tyr Tyr Glu Glu Arg Thr Cys Ile Leu Arg Cys Val130 135 140Leu His Leu Leu Thr Tyr Phe Gln Asp Glu Arg His Pro Tyr Arg Val145 150 155 160Glu Tyr Ala Asp Cys Val Asp Lys Leu Glu Lys Glu Leu Val Ser Lys165 170 175
Tyr Arg Gln Gln Phe Glu Glu Leu Tyr Lys Thr Glu Ala Pro Thr Trp180 185 190Glu Thr His Gly Asn Leu Met Thr Glu Arg Gln Val Ser Arg Trp Phe195 200 205Val Gln Cys Leu Arg Glu Gln Ser Met Leu Leu Glu Ile Ile Phe Leu210 215 220Tyr Tyr Ala Tyr Phe Glu Met Ala Pro Ser Asp Leu Leu Val Leu Thr225 230 235 240Lys Met Phe Lys Glu Gln Gly Phe Gly Ser Arg Gln Thr Asn Arg His245 250 255Leu Val Asp Glu Thr Met Asp Pro Phe Val Asp Arg Ile Gly Tyr Phe260 265 270Ser Ala Leu Ile Leu Val Glu Gly Met Asp Ile Glu Ser Leu His Lys275 280 285Cys Ala Leu Asp Asp Arg Arg Glu Leu His Gln Phe Ala Gln Asp Gly290 295 300Leu Ile Cys Gln Asp Met Asp Cys Leu Met Leu Thr Phe Gly Asp Ile305 310 315 320Pro His His Ala Pro Val Leu Leu Ala Trp Ala Leu Leu Arg His Thr325 330 335Leu Asn Pro Glu Glu Thr Ser Ser Val Val Arg Lys Ile Gly Gly Thr340 345 350Ala Ile Gln Leu Asn Val Phe Gln Tyr Leu Thr Arg Leu Leu Gln Ser355 360 365Leu Ala Ser Gly Gly Asn Asp Cys Thr Thr Ser Thr Ala Cys Met Cys370 375 380Val Tyr Gly Leu Leu Ser Phe Val Leu Thr Ser Leu Glu Leu His Thr385 390 395 400Leu Gly Asn Gln Gln Asp Ile Ile Asp Thr Ala Cys Glu Val Leu Ala
405 410 415Asp Pro Ser Leu Pro Glu Leu Phe Trp Gly Thr Glu Pro Thr Ser Gly420 425 430Leu Gly Ile Ile Leu Asp Ser Val Cys Gly Met Phe Pro His Leu Leu435 440 445Ser Pro Leu Leu Gln Leu Leu Arg Ala Leu Val Ser Gly Lys Ser Thr450 455 460Ala Lys Lys Val Tyr Ser Phe Leu Asp Lys Met Ser Phe Tyr Asn Glu465 470 475 480Leu Tyr Lys His Lys Pro His Asp Val Ile Ser His Glu Asp Gly Thr485 490 495Leu Trp Arg Arg Gln Thr Pro Lys Leu Leu Tyr Pro Leu Gly Gly Gln500 505 510Thr Asn Leu Arg Ile Pro Gln Gly Thr Val Gly Gln Val Met Leu Asp515 520 525Asp Arg Ala Tyr Leu Val Arg Trp Glu Tyr Ser Tyr Ser Ser Trp Thr530 535 540Leu Phe Thr Cys Glu Ile Glu Met Leu Leu His Val Val Ser Thr Ala545 550 555 560Asp Val Ile Gln His Cys Gln Arg Val Lys Pro Ile Ile Asp Leu Val565 570 575His Lys Val Ile Ser Thr Asp Leu Ser Ile Ala Asp Cys Leu Leu Pro580 585 590Ile Thr Ser Arg Ile Tyr Met Leu Leu Gln Arg Leu Thr Thr Val Ile595 600 605Ser Pro Pro Val Asp Val Ile Ala Ser Cys Val Asn Cys Leu Thr Val610 615 620Leu Ala Ala Arg Asn Pro Ala Lys Val Trp Thr Asp Leu Arg His Thr625 630 635 640
Gly Phe Leu Pro Phe Val Ala His Pro Val Ser Ser Leu Ser Gln Met645 650 655Ile Ser Ala Glu Gly Met Asn Ala Gly Gly Tyr Gly Asn Leu Leu Met660 665 670Asn Ser Glu Gln Pro Gln Gly Glu Tyr Gly Val Thr Ile Ala Phe Leu675 680 685Arg Leu Ile Thr Thr Leu Val Lys Gly Gln Leu Gly Ser Thr Gln Ser690 695 700Gln Gly Leu Val Pro Cys Val Met Phe Val Leu Lys Glu Met Leu Pro705 710 715 720Ser Tyr His Lys Trp Arg Tyr Asn Ser His Gly Val Arg Glu Gln Ile725 730 735Gly Cys Leu Ile Leu Glu Leu Ile His Ala Ile Leu Asp Leu Cys His740 745 750Glu Thr Asp Leu His Ser Ser His Thr Pro Ser Leu Gln Phe Leu Cys755 760 765Ile Cys Ser Leu Ala Tyr Thr Glu Ala Gly Gln Thr Val Ile Asn Ile770 775 780Met Gly Ile Gly Val Asp Thr Ile Asp Met Val Met Ala Ala Gln Pro785 790 795 800Arg Ser Asp Gly Ala Glu Gly Gln Gly Gln Gly Gln Leu Leu Ile Lys805 810 815Thr Val Lys Leu Ala Phe Ser Val Thr Asn Asn Val Ile Arg Leu Lys820 825 830Pro Pro Ser Asn Val Val Ser Pro Leu Glu Gln Ala Leu Ser Gln His835 840 845Gly Ala His Gly Asn Asn Leu Ile Ala Val Leu Ala Lys Tyr Ile Tyr850 855 860His Lys His Asp Pro Ala Leu Pro Arg Leu Ala Ile Gln Leu Leu Lys865 870 875 880
Arg Leu Ala Thr Val Ala Pro Met Ser Val Tyr Ala Cys Leu Gly Asn885 890 895Asp Ala Ala Ala Ile Arg Asp Ala Phe Leu Thr Arg Leu Gln Ser Lys900 905 910Ile Glu Asp Met Arg Ile Lys Val Met Ile Leu Glu Phe Leu Thr Val915 920 925Ala Val Glu Thr Gln Pro Gly Leu Ile Glu Leu Phe Leu Asn Leu Glu930 935 940Val Lys Asp Gly Ser Asp Gly Ser Lys Glu Phe Ser Leu Gly Met Trp945 950 955 960Ser Cys Leu His Ala Val Leu Glu Leu Ile Asp Ser Gln Gln Gln Asp965 970 975Arg Tyr Trp Cys Pro Pro Leu Leu His Arg Ala Ala Ile Ala Phe Leu980 985 990His Ala Leu Trp Gln Asp Arg Arg Asp Ser Ala Met Leu Val Leu Arg99510001005Thr Lys Pro Lys Phe Trp Glu Asn Leu Thr Ser Pro Leu Phe Gly Thr101010151020Leu Ser Pro Pro Ser Glu Thr Ser Glu Pro Ser Ile Leu Glu Thr Cys1025 103010351040Ala Leu Ile Met Lys Ile Ile Cys Leu Glu Ile Tyr Tyr Val Val Lys104510501055Gly Ser Leu Asp Gln Ser Leu Lys Asp Thr Leu Lys Lys Phe Ser Ile106010651070Glu Lys Arg Phe Ala Tyr Trp Ser Gly Tyr Val Lys Ser Leu Ala Val10751080 1085His Val Ala Glu Thr Glu Gly Ser Ser Cys Thr Ser Leu Leu Glu Tyr109010951100Gln Met Leu ValSer Ala Trp Arg Met Leu Leu Ile Ile Ala Thr Thr
110111011151120His Ala Asp Ile Met His Leu Thr Asp Ser Val Val Arg Arg Gln Leu112511301135Phe Leu Asp Val Leu Asp Gly Thr Lys Ala Leu Leu Leu Val Pro Ala114011451150Ser Val Asn Cys Leu Arg Leu Gly Ser Met Lys Cys Thr Leu Leu Leu115511601165Ile Leu Leu Arg Gln Trp Lys Arg Glu Leu Gly Ser Val Asp Glu Ile117011751180Leu Gly Pro Leu Thr Glu Ile Leu Glu Gly Val Leu Gln Ala Asp Gln1185 119011951200Gln Leu Met Glu Lys Thr Lys Ala Lys Val Phe Ser Ala Phe Ile Thr120512101215Val Leu Gln Met Lys Glu Met Lys Val Ser Asp Ile Pro Gln Tyr Ser122012251230Gln Leu Val Leu Asn Val Cys Glu Thr Leu Gln Glu Glu Val Ile Ala123512401245Leu Phe Asp Gln Thr Arg His Ser Leu Ala Leu Gly Ser Ala Thr Glu125012551260Asp Lys Asp Ser Met Glu Thr Asp Asp Cys Ser Arg Ser Arg His Arg1265 127012751280Asp Gln Arg Asp Gly Val Cys Val Leu Gly Leu His Leu Ala Lys Glu128512901295Leu Cys Glu Val Asp Glu Asp Gly Asp Ser Trp Leu Gln Val Thr Arg130013051310Arg Leu Pro Ile Leu Pro Thr Leu Leu Thr Thr Leu Glu Val Ser Leu131513201325Arg Met Lys Gln Asn Leu His Phe Thr Glu Ala Thr Leu His Leu Leu133013351340
Leu Thr Leu Ala Arg Thr Gln Gln Gly Ala Thr Ala Val Ala Gly Ala1345 135013551360Gly Ile Thr Gln Ser Ile Cys Leu Pro Leu Leu Ser Val Tyr Gln Leu136513701375Ser Thr Asn Gly Thr Ala Gln Thr Pro Ser Ala Ser Arg Lys Ser Leu138013851390Asp Ala Pro Ser Trp Pro Gly Val Tyr Arg Leu Ser Met Ser Leu Met139514001405Glu Gln Leu Leu Lys Thr Leu Arg Tyr Asn Phe Leu Pro Glu Ala Leu141014151420Asp Phe Val Gly Val His Gln Glu Arg Thr Leu Gln Cys Leu Asn Ala1425 143014351440Val Arg Thr Val Gln Ser Leu Ala Cys Leu Glu Glu Ala Asp His Thr144514501455Val Gly Phe Ile Leu Gln Leu Ser Asn Phe Met Lys Glu Trp His Phe146014651470His Leu Pro Gln Leu Met Arg Asp Ile Gln Val Asn Leu Gly Tyr Leu147514801485Cys Gln Ala Cys Thr Ser Leu Leu His Ser Arg Lys Met Leu Gln His149014951500Tyr Leu Gln Asn Lys Asn Gly Asp Gly Leu Pro Ser Ala Val Ala Gln1505 151015151520Arg Val Gln Arg Pro Pro Ser Ala Ala Ser Ala Ala Pro Ser Ser Ser152515301535Lys Gln Pro Ala Ala Asp Thr Glu Ala Ser Glu Gln Gln Ala Leu His154015451550Thr Val Gln Tyr Gly Leu Leu Lys Ile Leu Ser Lys Thr Leu Ala Ala155515601565Leu Arg His Phe Thr Pro Asp Val Cys Gln Ile Leu Leu Asp Gln Ser157015751580
Leu Asp Leu Ala Glu Tyr Asn Phe Leu Phe Ala Leu Ser Phe Thr Thr1585 159015951600Pro Thr Phe Asp Ser G1u Val Ala Pro Ser Phe G1y Thr Leu Leu Ala160516101615Thr Val Asn Val Ala Leu Asn Met Leu Gly Glu Leu Asp Lys Lys Lys162016251630Glu Pro Leu Thr Gln Ala Val Gly Leu Ser Thr Gln Ala Glu Gly Thr163516401645Arg Thr Leu Lys Ser Leu Leu Met Phe Thr Met Glu Asn Cys Phe Tyr165016551660Leu Leu Ile Ser Gln Ala Met Arg Tyr Leu Arg Asp Pro Ala Val His1665 167016751680Pro Arg Asp Lys Gln Arg Met Lys Gln Glu Leu Ser Ser Glu Leu Ser168516901695Thr Leu Leu Ser Ser Leu Ser Arg Tyr Phe Arg Arg Gly Ala Pro Ser170017051710Ser Pro Ala Thr Gly Val Leu Pro Ser Pro Gln Gly Lys Ser Thr Ser171517201725Leu Ser Lys Ala Ser Pro Glu Ser Gln Glu Pro Leu Ile Gln Leu Val173017351740Gln Ala Phe Val Arg His Met Gln Arg1745 1750<210>11<211>1753<212>PRT<213>人<400>11Met Ile Arg Lys Ser Lys Ile Thr Ser Val Leu Ser Phe Cys Arg Ser1 5 10 15
Ser Arg Glu Leu Trp Thr Ile Leu Leu Gly Arg Ser Ala Leu Arg Glu20 25 30Leu Ser Gln Ile Glu Ala Glu Leu Asn Lys His Trp Arg Arg Leu Leu35 40 45Glu Gly Leu Ser Tyr Tyr Lys Pro Pro Ser Pro Ser Ser Ala Glu Lys50 55 60Val Lys Ala Asn Lys Asp Val Ala Ser Pro Leu Lys Glu Leu Gly Leu65 70 75 80Arg Ile Ser Lys Phe Leu Gly Leu Asp Glu Glu Gln Ser Val Gln Leu85 90 95Leu Gln Cys Tyr Leu Gln Glu Asp Tyr Arg Gly Thr Arg Asp Ser Val100 105 110Lys Thr Val Leu Gln Asp Glu Arg Gln Ser Gln Ala Leu Ile Leu Lys115 120 125Ile Ala Asp Tyr Tyr Tyr Glu Glu Arg Thr Cys Ile Leu Arg Cys Val130 135 140Leu His Leu Leu Thr Tyr Phe Gln Asp Glu Arg His Pro Tyr Arg Val145 150 155 160Glu Tyr Ala Asp Cys Val Asp Lys Leu Glu Lys Glu Leu Val Ser Lys165 170 175Tyr Arg Gln Gln Phe Glu Glu Leu Tyr Lys Thr Glu Ala Pro Thr Trp180 185 190Glu Thr His Gly Asn Leu Met Thr Glu Arg Gln Val Ser Arg Trp Phe195 200 205Val Gln Cys Leu Arg Glu Gln Ser Met Leu Leu Glu Ile Ile Phe Leu210 215 220Tyr Tyr Ala Tyr Phe Glu Met Ala Pro Ser Asp Leu Leu Val Leu Thr225 230 235 240Lys Met Phe Lys Glu Gln Gly Phe Gly Ser Arg Gln Thr Asn Arg His245 250 255
Leu Val Asp Glu Thr Met Asp Pro Phe Val Asp Arg Ile Gly Tyr Phe260 265 270Ser Ala Leu Ile Leu Val Glu Gly Met Asp Ile Glu Ser Leu His Lys275 280 285Cys Ala Leu Asp Asp Arg Arg Glu Leu His Gln Phe Ala Gln Asp Gly290 295 300Leu Ile Cys Gln Asp Met Asp Cys Leu Met Leu Thr Phe Gly Asp Ile305 310 315 320Pro His His Ala Pro Val Leu Leu Ala Trp Ala Leu Leu Arg His Thr325 330 335Leu Asn Pro Glu Glu Thr Ser Ser Val Val Arg Lys Ile Gly Gly Thr340 345 350Ala Ile Gln Leu Asn Val Phe Gln Tyr Leu Thr Arg Leu Leu Gln Ser355 360 365Leu Ala Ser Gly Gly Asn Asp Cys Thr Thr Ser Thr Ala Cys Met Cys370 375 380Val Tyr Gly Leu Leu Ser Phe Val Leu Thr Ser Leu Glu Leu His Thr385 390 395 400Leu Gly Asn Gln Gln Asp Ile Ile Asp Thr Ala Cys Glu Val Leu Ala405 410 415Asp Pro Ser Leu Pro Glu Leu Phe Trp Gly Thr Glu Pro Thr Ser Gly420 425 430Leu Gly Ile Ile Leu Asp Ser ValCys Gly Met Phe Pro His Leu Leu435 440 445Ser Pro Leu Leu Gln Leu Leu Arg Ala Leu Val Ser Gly Lys Ser Thr450 455 460Ala Lys Lys Val Tyr Ser Phe Leu Asp Lys Met Ser Phe Tyr Asn Glu465 470 475 480Leu Tyr Lys His Lys Pro His Asp Val Ile Ser His Glu Asp Gly Thr
485 490 495Leu Trp Arg Arg Gln Thr Pro Lys Leu Leu Tyr Pro Leu Gly Gly Gln500 505 510Thr Asn Leu Arg Ile Pro Gln Gly Thr Val Gly Gln Val Met Leu Asp515 520 525Asp Arg Ala Tyr Leu Val Arg Trp Glu Tyr Ser Tyr Ser Ser Trp Thr530 535 540Leu Phe Thr Cys Glu Ile Glu Met Leu Leu His Val Val Ser Thr Ala545 550 555 560Asp Val Ile Gln His Cys Gln Arg Val Lys Pro Ile Ile Asp Leu Val565 570 575His Lys Val Ile Ser Thr Asp Leu Ser Ile Ala Asp Cys Leu Leu Pro580 585 590Ile Thr Ser Arg Ile Tyr Met Leu Leu Gln Arg Leu Thr Thr Val Ile595 600 605Ser Pro Pro Val Asp Val Ile Ala Ser Cys Val Asn Cys Leu Thr Val610 615 620Leu Ala Ala Arg Asn Pro Ala Lys Val Trp Thr Asp Leu Arg His Thr625 630 635 640Gly Phe Leu Pro Phe Val Ala His Pro Val Ser Ser Leu Ser Gln Met645 650 655Ile Ser Ala Glu Gly Met Asn Ala Gly Gly Tyr Gly Asn Leu Leu Met660 665 670Asn Ser Glu Gln Pro Gln Gly Glu Tyr Gly Val Thr Ile Ala Phe Leu675 680 685Arg Leu Ile Thr Thr Leu Val Lys Gly Gln Leu Gly Ser Thr Gln Ser690 695 700Gln Gly Leu Val Pro Cys Val Met Phe Val Leu Lys Glu Met Leu Pro705 710 715 720
Ser Tyr His Lys Trp Arg Tyr Asn Ser His Gly Val Arg Glu Gln Ile725 730 735Gly Cys Leu Ile Leu Glu Leu Ile His Ala Ile Leu Asn Leu Cys His740 745 750Glu Thr Asp Leu His Ser Ser His Thr Pro Ser Leu Gln Phe Leu Cys755 760 765Ile Cys Ser Leu Ala Tyr Thr Glu Ala Gly Gln Thr Val Ile Asn Ile770 775 780Met Gly Ile Gly Val Asp Thr Ile Asp Met Val Met Ala Ala Gln Pro785 790 795 800Arg Ser Asp Gly Ala Glu Gly Gln Gly Gln Gly Gln Leu Leu Ile Lys805 810 815Thr Val Lys Leu Ala Phe Ser Val Thr Asn Asn Val Ile Arg Leu Lys820 825 830Pro Pro Ser Asn Val Met Ser Pro Leu Glu Gln Ala Leu Ser Gln His835 840 845Gly Ala His Gly Asn Asn Leu Ile Ala Val Leu Ala Lys Tyr Ile Tyr850 855 860His Lys His Asp Pro Ala Leu Pro Arg Leu Ala Ile Gln Leu Leu Lys865 870 875 880Arg Leu Ala Thr Val Ala Pro Met Ser Val Tyr Ala Cys Leu Gly Asn885 890 895Asp Ala Ala Ala Ile Arg Asp Ala Phe Leu Thr Arg Leu Gln Ser Lys900 905 910Ile Glu Asp Met Arg Ile Lys Val Met Ile Leu Glu Phe Leu Thr Val915 920 925Ala Val Glu Thr Gln Pro Gly Leu Ile Glu Leu Phe Leu Asn Leu Glu930 935 940Val Lys Asp Gly Ser Asp Gly Ser Lys Glu Phe Ser Leu Gly Met Trp945 950 955 960
Ser Cys Leu His Ala Val Leu Glu Leu Ile Asp Ser Gln Gln Gln Asp965 970 975Arg Tyr Trp Cys Pro Pro Leu Leu His Arg Ala Ala Ile Ala Phe Leu980 985 990His Ala Leu Trp Gln Asp Arg Arg Asp Ser Ala Met Leu Val Leu Arg99510001005Thr Lys Pro Lys Phe Trp Glu Asn Leu Thr Ser Pro Leu Phe Gly Thr101010151020Leu Ser Pro Pro Ser Glu Thr Ser Glu Pro Ser Ile Leu Glu Thr Cys1025 103010351040Ala Leu Ile Met Lys Ile Ile Cys Leu Glu Ile Tyr Tyr Val Val Lys104510501055Gly Ser Leu Asp Gln Ser Leu Lys Asp Thr Leu Lys Lys Phe Ser Ile106010651070Glu Lys Arg Phe Ala Tyr Trp Ser Gly Tyr Val Lys Ser Leu Ala Val107510801085His Val Ala Glu Thr Glu Gly Ser Ser Cys Thr Ser Leu Leu Glu Tyr109010951100Gln Met Leu Val Ser Ala Trp Arg Met Leu Leu Ile Ile Ala Thr Thr1105 111011151120His Ala Asp Ile Met His Leu Thr Asp Ser Val Val Arg Arg Gln Leu112511301135Phe Leu Asp Val Leu Asp Gly Thr Lys Ala Leu Leu Leu Val Pro Ala114011451150Ser Val Asn Cys Leu Arg Leu Gly Ser Met Lys Cys Thr Leu Leu Leu115511601165Ile Leu Leu Arg Gln Trp Lys Arg Glu Leu Gly Ser Val Asp Glu Ile117011751180Leu Gly Pro Leu Thr Glu Ile Leu Glu Gly Val Leu Gln Ala Asp Gln
1185 119011951200Gln Leu Met Glu Lys Thr Lys Ala Lys Val Phe Ser Ala Phe Ile Thr120512101215Val Leu Gln Met Lys Glu Met Lys Val Ser Asp Ile Pro Gln Tyr Ser122012251230Gln Leu Val Leu Asn Val Cys Glu Thr Leu Gln Glu Glu Val Ile Ala123512401245Leu Phe Asp Gln Thr Arg His Ser Leu Ala Leu Gly Ser Ala Thr Glu125012551260Asp Lys Asp Ser Met Glu Thr Asp Asp Cys Ser Arg Ser Arg His Arg1265 127012751280Asp Gln Arg Asp Gly Val Cys Val Leu Gly Leu His Leu Ala Lys Glu128512901295Leu Cys Glu Val Asp Glu Asp Gly Asp Ser Trp Leu Gln Val Thr Arg130013051310Arg Leu Pro Ile Leu Pro Thr Leu Leu Thr Thr Leu Glu Val Ser Leu131513201325Arg Met Lys Gln Asn Leu His Phe Thr Glu Ala Thr Leu His Leu Leu133013351340Leu Thr Leu Ala Arg Thr Gln Gln Gly Ala Thr Ala Val Ala Gly Ala1345 135013551360Gly Ile Thr Gln Ser Ile Cys Leu Pro Leu Leu Ser Val Tyr Gln Leu136513701375Ser Thr Asn Gly Thr Ala Gln Thr Pro Ser Ala Ser Arg Lys Ser Leu138013851390Asp Ala Pro Ser Trp Pro Gly Val Tyr Arg Leu Ser Met Ser Leu Met139514001405Glu Gln Leu Leu Lys Thr Leu Arg Tyr Asn Phe Leu Pro Glu Ala Leu141014151420
Asp Phe Val Gly Val His Gln Glu Arg Thr Leu Gln Cys Leu Asn Ala1425 143014351440Val Arg Thr Val Gln Ser Leu Ala Cys Leu Glu Glu Ala Asp His Thr144514501455Val Gly Phe Ile Leu Gln Leu Ser Asn Phe Met Lys Glu Trp His Phe146014651470His Leu Pro Gln Leu Met Arg Asp Ile Gln Val Asn Leu Gly Tyr Leu147514801485Cys Gln Ala Cys Thr Ser Leu Leu His Ser Arg Lys Met Leu Gln His149014951500Tyr Leu Gln Asn Lys Asn Gly Asp Gly Leu Pro Ser Ala Val Ala Gln150151015151520Arg Val Gln Arg Pro Pro Ser Ala Ala Ser Ala Ala Pro Ser Ser Ser152515301535Lys Gln Pro Ala Ala Asp Thr Glu Ala Ser Glu Gln Gln Ala Leu His154015451550Thr Val Gln Tyr Gly Leu Leu Lys Ile Leu Ser Lys Thr Leu Ala Ala155515601565Leu Arg His Phe Thr Pro Asp Val Cys Gln Ile Leu Leu Asp Gln Ser157015751580Leu Asp Leu Ala Glu Tyr Asn Phe Leu Phe Ala Leu Ser Phe Thr Thr1585 159015951600Pro Thr Phe Asp Ser Glu Val Ala Pro Ser Phe Gly Thr Leu Leu Ala160516101615Thr Val Asn Val Ala Leu Asn Met Leu Gly Glu Leu Asp Lys Lys Lys162016251630Glu Pro Leu Thr Gln Ala Val Gly Leu Ser Thr Gln Ala Glu Gly Thr163516401645Arg Thr Leu Lys Ser Leu Leu Met Phe Thr Met Glu Asn Cys Phe Tyr165016551660
Leu Leu Ile Ser Gln Ala Met Arg Tyr Leu Arg Asp Pro Ala Val His1665 167016751680Pro Arg Asp Lys Gln Arg Met Lys Gln Glu Leu Ser Ser Glu Leu Ser168516901695Thr Leu Leu Ser Ser Leu Ser Arg Tyr Phe Arg Arg Gly Ala Pro Ser170017051710Ser Pro Ala Thr Gly Val Leu Pro Ser Pro Gln Gly Lys Ser Thr Ser171517201725Leu Ser Lys Ala Ser Pro Glu Ser Gln Glu Pro Leu Ile Gln Leu Val173017351740Gln Ala Phe Val Arg His Met Gln Arg1745 1750<210>12<211>1753<212>PRT<213>人<400>12Met Ile Arg Lys Ser Lys Ile Thr Ser Val Leu Ser Phe Cys Arg Ser1 5 10 15Ser Arg Glu Leu Trp Thr Ile Leu Leu Gly Arg Ser Ala Leu Arg Glu20 25 30Leu Ser Gln Ile Glu Ala Glu Leu Asn Lys His Trp Arg Arg Leu Leu35 40 45Glu Gly Leu Ser Tyr Tyr Lys Pro Pro Ser Pro Ser Ser Ala Glu Lys50 55 60Val Lys Ala Asn Lys Asp Val Ala Ser Pro Leu Lys Glu Leu Gly Leu65 70 75 80Arg Ile Ser Lys Phe Leu Gly Leu Asp Glu Glu Gln Ser Val Gln Leu85 90 95
Leu Gln Cys Tyr Leu Gln Glu Asp Tyr Arg Gly Thr Arg Asp Ser Val100 105 110Lys Thr Val Leu Gln Asp Glu Arg Gln Ser Gln Ala Leu Ile Leu Lys115 120 125Ile Ala Asp Tyr Tyr Tyr Glu Glu Arg Thr Cys Ile Leu Arg Cys Val130 135 140Leu His Leu Leu Thr Tyr Phe Gln Asp Glu Arg His Pro Tyr Arg Val145 150 155 160Glu Tyr Ala Asp Cys Val Asp Lys Leu Glu Lys Glu Leu Val Ser Lys165 170 175Tyr Arg Gln Gln Phe Glu Glu Leu Tyr Lys Thr Glu Ala Pro Thr Trp180 185 190Glu Thr His Gly Asn Leu Met Thr Glu Arg Gln Val Ser Arg Trp Phe195 200 205Val Gln Cys Leu Arg Glu Gln Ser Met Leu Leu Glu Ile Ile Phe Leu210 215 220Tyr Tyr Ala Tyr Phe Glu Met Ala Pro Ser Asp Leu Leu Val Leu Thr225 230 235 240Lys Met Phe Lys Glu Gln Gly Phe Gly Ser Arg Gln Thr Asn Arg His245 250 255Leu Val Asp Glu Thr Met Asp Pro Phe Val Asp Arg Ile Gly Tyr Phe260 265 270Ser Ala Leu Ile Leu ValGlu Gly Met Asp Ile Glu Ser Leu His Lys275 280 285Cys Ala Leu Asp Asp Arg Arg Glu Leu His Gln Phe Ala Gln Asp Gly290 295 300Leu Ile Cys Gln Asp Met Asp Cys Leu Met Leu Thr Phe Gly Asp Ile305 310 315 320Pro His His Ala Pro Val Leu Leu Ala Trp Ala Leu Leu Arg His Thr325 330 335
Leu Asn Pro Glu Glu Thr Ser Ser Val Val Arg Lys Ile Gly Gly Thr340 345 350Ala Ile Gln Leu Asn Val Phe Gln Tyr Leu Thr Arg Leu Leu Gln Ser355 360 365Leu Ala Ser Gly Gly Asn Asp Cys Thr Thr Ser Thr Ala Cys Met Cys370 375 380Val Tyr Gly Leu Leu Ser Phe Val Leu Thr Ser Leu Glu Leu His Thr385 390 395 400Leu Gly Asn Gln Gln Asp Ile Ile Asp Thr Ala Cys Glu Val Leu Ala405 410 415Asp Pro Ser Leu Pro Glu Leu Phe Trp Gly Thr Glu Pro Thr Ser Gly420 425 430Leu Gly Ile Ile Leu Asp Ser Val Cys Gly Met Phe Pro His Leu Leu435 440 445Ser Pro Leu Leu Gln Leu Leu Arg Ala Leu Val Ser Gly Lys Ser Thr450 455 460Ala Lys Lys Val Tyr Ser Phe Leu Asp Lys Met Ser Phe Tyr Asn Glu465 470 475 480Leu Tyr Lys His Lys Pro His Asp Val Ile Ser His Glu Asp Gly Thr485 490 495Leu Trp Arg Arg Gln Thr Pro Lys Leu Leu Tyr Pro Leu Gly Gly Gln500 505 510Thr Asn Leu Arg Ile Pro Gln Gly Thr Val Gly Gln Val Met Leu Asp515 520 525Asp Arg Ala Tyr Leu Val Arg Trp Glu Tyr Ser Tyr Ser Ser Trp Thr530 535 540Leu Phe Thr Cys Glu Ile Glu Met Leu Leu His Val Val Ser Thr Ala545 550 555 560Asp Val Ile Gln His Cys Gln Arg Val Lys Pro Ile Ile Asp Leu Val
565 570 575His Lys Val Ile Ser Thr Asp Leu Ser Ile Ala Asp Cys Leu Leu Pro580 585 590Ile Thr Ser Arg Ile Tyr Met Leu Leu Gln Arg Leu Thr Thr Val Ile595 600 605Ser Pro Pro Val Asp Val Ile Ala Ser Cys ValAsn Cys Leu Thr Val610 615 620Leu Ala Ala Arg Asn Pro Ala Lys Val Trp Thr Asp Leu Arg His Thr625 630 635 640Gly Phe Leu Pro Phe Val Ala His Pro Val Ser Ser Leu Ser Gln Met645 650 655Ile Ser Ala Glu Gly Met Asn Ala Gly Gly Tyr Gly Asn Leu Leu Met660 665 670Asn Ser Glu Gln Pro Gln Gly Glu Tyr Gly Val Thr Ile Ala Phe Leu675 680 685Arg Leu Ile Thr Thr Leu ValLys Gly Gln Leu Gly Ser Thr Gln Ser690 695 700Gln Gly Leu Val Pro Cys Val Met Phe Val Leu Lys Glu Met Leu Pro705 710 715 720Ser Tyr His Lys Trp Arg Tyr Asn Ser His Gly Val Arg Glu Gln Ile725 730 735Gly Cys Leu Ile Leu Glu Leu Ile His Ala Ile Leu Asn Leu Cys His740 745 750Glu Thr Asp Leu His Ser Ser His Thr Pro Ser Leu Gln Phe Leu Cys755 760 765Ile Cys Ser Leu Ala Tyr Thr Glu Ala Gly Gln Thr Val Ile Asn Ile770 775 780Met Gly Ile Gly Val Asp Thr Ile Asp Met Val Met Ala Ala Gln Pro785 790 795 800
Arg Ser Asp Gly Ala Glu Gly Gln Gly Gln Gly Gln Leu Leu Ile Lys805 810 815Thr Val Lys Leu Ala Phe Ser Val Thr Asn Asn ValI le Arg Leu Lys820 825 830Pro Pro Ser Asn Val Val Ser Pro Leu Glu Gln Ala Leu Ser Gln His835 840 845Gly Ala His Gly Asn Asn Leu Ile Ala Val Leu Ala Lys Tyr Ile Tyr850 855 860His Lys His Asp Pro Ala Leu Pro Arg Leu Ala Ile Gln Leu Leu Lys865 870 875 880Arg Leu Ala Thr Val Ala Pro Met Ser Val Tyr Ala Cys Leu Gly Asn885 890 895Asp Ala Ala Ala Ile Arg Asp Ala Phe Leu Thr Arg Leu Gln Ser Lys900 905 910Ile Glu Asp Met Arg Ile Lys Val Met Ile Leu Glu Phe Leu Thr Val915 920 925Ala Val Glu Thr Gln Pro Gly Leu Ile Glu Leu Phe Leu Asn Leu Glu930 935 940Val Lys Asp Gly Ser Asp Gly Ser Lys Glu Phe Ser Leu Thr Met Trp945 950 955 960Ser Cys Leu His Ala Val Leu Glu Leu Ile Asp Ser Gln Gln Gln Asp965 970 975Arg Tyr Trp Cys Pro Pro Leu Leu His Arg Ala Ala Ile Ala Phe Leu980 985 990His Ala Leu Trp Gln Asp Arg Arg Asp Ser Ala Met Leu Val Leu Arg99510001005Thr Lys Pro Lys Phe Trp Glu Asn Leu Thr Ser Pro Leu Phe Gly Thr101010151020Leu Ser Pro Pro Ser Glu Thr Ser Glu Pro Ser Ile Leu Glu Thr Cys1025 103010351040
Ala Leu Ile Met Lys Ile Ile Cys Leu Glu Ile Tyr Tyr Val Val Lys104510501055Gly Ser Leu Asp Gln Ser Leu Lys Asp Thr Leu Lys Lys Phe Ser Ile106010651070Glu Lys Arg Phe Ala Tyr Trp Ser Gly Tyr Val Lys Ser Leu Ala Val107510801085His Val Ala Glu Thr Glu Gly Ser Ser Cys Thr Ser Leu Leu Glu Tyr109010951100Gln Met Leu Val Ser Ala Trp Arg Met Leu Leu Ile Ile Ala Thr Thr1105 111011151120His Ala Asp Ile Met His Leu Thr Asp Ser Val Val Arg Arg Gln Leu112511301135Phe Leu Asp Val Leu Asp Gly Thr Lys Ala Leu Leu Leu Val Pro Ala114011451150Ser Val Asn Cys Leu Arg Leu Gly Ser Met Lys Cys Thr Leu Leu Leu115511601165Ile Leu Leu Arg Gln Trp Lys Arg Glu Leu Gly Ser Val Asp Glu Ile117011751180Leu Gly Pro Leu Thr Glu Ile Leu Glu Gly Val Leu Gln Ala Asp Gln1185 119011951200Gln Leu Met Glu Lys Thr Lys Ala Lys Val Phe Ser Ala Phe Ile Thr120512101215Val Leu Gln Met Lys Glu Met Lys Val Ser Asp Ile Pro Gln Tyr Ser122012251230Gln Leu Val Leu Asn Val Cys Glu Thr Leu Gln Glu Glu Val Ile Ala123512401245Leu Phe Asp Gln Thr Arg His Ser Leu Ala Leu Gly Ser Ala Thr Glu125012551260Asp Lys Asp Ser Met Glu Thr Asp Asp Cys Ser Arg Ser Arg His Arg
1265 127012751280Asp Gln Arg Asp Gly Val Cys Val Leu Gly Leu His Leu Ala Lys Glu128512901295Leu Cys Glu Val Asp Glu Asp Gly Asp Ser Trp Leu Gln Val Thr Arg130013051310Arg Leu Pro Ile Leu Pro Thr Leu Leu Thr Thr Leu Glu Val Ser Leu131513201325Arg Met Lys Gln Asn Leu His Phe Thr Glu Ala Thr Leu His Leu Leu133013351340Leu Thr Leu Ala Arg Thr Gln Gln Gly Ala Thr Ala Val Ala Gly Ala1345 135013551360Gly Ile Thr Gln Ser Ile Cys Leu Pro Leu Leu Ser Val Tyr Gln Leu136513701375Ser Thr Asn Gly Thr Ala Gln Thr Pro Ser Ala Ser Arg Lys Ser Leu138013851390Asp Ala Pro Ser Trp Pro Gly ValTyr Arg Leu Ser Met Ser Leu Met139514001405Glu Gln Leu Leu Lys Thr Leu Arg Tyr Asn Phe Leu Pro Glu Ala Leu141014151420Asp Phe ValGly Val His Gln Glu Arg Thr Leu Gln Cys Leu Asn Ala1425 143014351440Val Arg Thr Val Gln Ser Leu Ala Cys Leu Glu Glu Ala Asp His Thr144514501455Val Gly Phe Ile Leu Gln Leu Ser Asn Phe Met Lys Glu Trp His Phe146014651470His Leu Pro Gln Leu Met Arg Asp Ile Gln Val Asn Leu Gly Tyr Leu147514801485Cys Gln Ala Cys Thr Ser Leu Leu His Ser Arg Lys Met Leu Gln His149014951500
Tyr Leu Gln Asn Lys Asn Gly Asp Gly Leu Pro Ser Ala Val Ala Gln1505 151015151520Arg Val Gln Arg Pro Pro Ser Ala Ala Ser Ala Ala Pro Ser Ser Ser152515301535Lys Gln Pro Ala Ala Asp Thr Glu Ala Ser Glu Gln Gln Ala Leu His154015451550Thr Val Gln Tyr Gly Leu Leu Lys Ile Leu Ser Lys Thr Leu Ala Ala155515601565Leu Arg His Phe Thr Pro Asp Val Cys Gln Ile Leu Leu Asp Gln Ser157015751580Leu Asp Leu Ala Glu Tyr Asn Phe Leu Phe Ala Leu Ser Phe Thr Thr1585 159015951600Pro Thr Phe Asp Ser Glu Val Ala Pro Ser Phe Gly Thr Leu Leu Ala160516101615Thr Val Asn Val Ala Leu Asn Met Leu Gly Glu Leu Asp Lys Lys Lys162016251630Glu Pro Leu Thr Gln Ala Val Gly Leu Ser Thr Gln Ala Glu Gly Thr163516401645Arg Thr Leu Lys Ser Leu Leu Met Phe Thr Met Glu Asn Cys Phe Tyr165016551660Leu Leu Ile Ser Gln Ala Met Arg Tyr Leu Arg Asp Pro Ala Val His1665 167016751680Pro Arg Asp Lys Gln Arg Met Lys Gln Glu Leu Ser Ser Glu Leu Ser168516901695Thr Leu Leu Ser Ser Leu Ser Arg Tyr Phe Arg Arg Gly Ala Pro Ser170017051710Ser Pro Ala Thr Gly Val Leu Pro Ser Pro Gln Gly Lys Ser Thr Ser171517201725Leu Ser Lys Ala Ser Pro Glu Ser Gln Glu Pro Leu Ile Gln Leu Val173017351740
Gln Ala Phe Val Arg His Met Gln Arg1745 1750<210>13<211>1753<212>PRT<213>人<400>13Met Ile Arg Lys Ser Lys Ile Thr Ser Val Leu Ser Phe Cys Arg Ser1 5 10 15Ser Arg Glu Leu Trp Thr Ile Leu Leu Gly Arg Ser Ala Leu Arg Glu20 25 30Leu Ser Gln Ile Glu Ala Glu Leu Asn Lys His Trp Arg Arg Leu Leu35 40 45Glu Gly Leu Ser Tyr Tyr Lys Pro Pro Ser Pro Ser Ser Ala Glu Lys50 55 60Val Lys Ala Asn Lys Asp Val Ala Ser Pro Leu Lys Glu Leu Gly Leu65 70 75 80Arg Ile Ser Lys Phe Leu Gly Leu Asp Glu Glu Gln Ser Val Gln Leu85 90 95Leu Gln Cys Tyr Leu Gln Glu Asp Tyr Arg Gly Thr Arg Asp Ser Val100 105 110Lys Thr Val Leu Gln Asp Glu Arg Gln Ser Gln Ala Leu Ile Leu Lys115 120 125Ile Ala Asp Tyr Tyr Tyr Glu Glu Arg Thr Cys Ile Leu Arg Cys Val130 135 140Leu His Leu Leu Thr Tyr Phe Gln Asp Glu Arg His Pro Tyr Arg Val145 150 155 160Glu Tyr Ala Asp Cys Val Asp Lys Leu Glu Lys Glu Leu Val Ser Lys165 170 175
Tyr Arg Gln Gln Phe Glu Glu Leu Tyr Lys Thr Glu Ala Pro Thr Trp180 185 190Glu Thr His Gly Asn Leu Met Thr Glu Arg Gln Val Ser Arg Trp Phe195 200 205Val Gln Cys Leu Arg Glu Gln Ser Met Leu Leu Glu Ile Ile Phe Leu210 215 220Tyr Tyr Ala Tyr Phe Glu Met Ala Pro Ser Asp Leu Leu Val Leu Thr225 230 235 240Lys Met Phe Lys Glu Gln Gly Phe Gly Ser Arg Gln Thr Asn Arg His245 250 255Leu Val Asp Glu Thr Met Asp Pro Phe Val Asp Arg Ile Gly Tyr Phe260 265 270Ser Ala Leu Ile Leu Val Glu Gly Met Asp Ile Glu Ser Leu His Lys275 280 285Cys Ala Leu Asp Asp Arg Arg Glu Leu His Gln Phe Ala Gln Asp Gly290 295 300Leu Ile Cys Gln Asp Met Asp Cys Leu Met Leu Thr Phe Gly Asp Ile305 310 315 320Pro His His Ala Pro Val Leu Leu Ala Trp Ala Leu Leu Arg His Thr325 330 335Leu Asn Pro Glu Glu Thr Ser Ser Val Val Arg Lys Ile Gly Gly Thr340 345 350Ala Ile Gln Leu Asn Val Phe Gln Tyr Leu Thr Arg Leu Leu Gln Ser355 360 365Leu Ala Ser Gly Gly Asn Asp Cys Thr Thr Ser Thr Ala Cys Met Cys370 375 380Val Tyr Gly Leu Leu Ser Phe Val Leu Thr Ser Leu Glu Leu His Thr385 390 395 400Leu Gly Asn Gln Gln Asp Ile Ile Asp Thr Ala Cys Glu Val Leu Ala405 410 415
Asp Pro Ser Leu Pro Glu Leu Phe Trp Gly Thr Glu Pro Thr Ser Gly420 425 430Leu Gly Ile Ile Leu Asp Ser Val Cys Gly Met Phe Pro His Leu Leu435 440 445Ser Pro Leu Leu Gln Leu Leu Arg Ala Leu Val Ser Gly Lys Ser Thr450 455 460Ala Lys Lys Val Tyr Ser Phe Leu Asp Lys Met Ser Phe Tyr Asn Glu465 470 475 480Leu Tyr Lys His Lys Pro His Asp Val Ile Ser His Glu Asp Gly Thr485 490 495Leu Trp Arg Arg Gln Thr Pro Lys Leu Leu Tyr Pro Leu Gly Gly Gln500 505 510Thr Asn Leu Arg Ile Pro Gln Gly Thr Val Gly Gln Val Met Leu Asp515 520 525Asp Arg Ala Tyr Leu Val Arg Trp Glu Tyr Ser Tyr Ser Ser Trp Thr530 535 540Leu Phe Thr Cys Glu Ile Glu Met Leu Leu His Val Val Ser Thr Ala545 550 555 560Asp Val Ile Gln His Cys Gln Arg Val Lys Pro Ile Ile Asp Leu Val565 570 575His Lys Val Ile Ser Thr Asp Leu Ser Ile Ala Asp Cys Leu Leu Pro580 585 590Ile Thr Ser Arg Ile Tyr Met Leu Leu Gln Arg Leu Thr Thr Val Ile595 600 605Ser Pro Pro Val Asp Val Ile Ala Ser Cys Val Asn Cys Leu Thr Val610 615 620Leu Ala Ala Arg Asn Pro Ala Lys Val Trp Thr Asp Leu Arg His Thr625 630 635 640Gly Phe Leu Pro Phe Val Ala His Pro Val Ser Ser Leu Ser Gln Met
645 650 655Ile Ser Ala Glu Gly Met Asn Ala Gly Gly Tyr Gly Asn Leu Leu Met660 665 670Asn Ser Glu Gln Pro Gln Gly Glu Tyr Gly Val Thr Ile Ala Phe Leu675 680 685Arg Leu Ile Thr Thr Leu Val Lys Gly Gln Leu Gly Ser Thr Gln Ser690 695 700Gln Gly Leu Val Pro Cys Val Met Phe Val Leu Lys Glu Met Leu Pro705 710 715 720Ser Tyr His Lys Trp Arg Tyr Asn Ser His Gly Val Arg Glu Gln Ile725 730 735Gly Cys Leu Ile Leu Glu Leu Ile His Ala Ile Leu Asn Leu Cys His740 745 750Glu Thr Asp Leu His Ser Ser His Thr Pro Ser Leu Gln Phe Leu Cys755 760 765Ile Cys Ser Leu Ala Tyr Thr Glu Ala Gly Gln Thr Val Ile Asn Ile770 775 780Met Gly Ile Gly Val Asp Thr Ile Asp Met Val Met Ala Ala Gln Pro785 790 795 800Arg Ser Asp Gly Ala Glu Gly Gln Gly Gln Gly Gln Leu Leu Ile Lys805 810 815Thr Val Lys Leu Ala Phe Ser Val Thr Asn Asn Val Ile Arg Leu Lys820 825 830Pro Pro Ser Asn Val Val Ser Pro Leu Glu Gln Ala Leu Ser Gln His835 840 845Gly Ala His Gly Asn Asn Leu Ile Ala Val Leu Ala Lys Tyr Ile Tyr850 855 860His Lys His Asp Pro Ala Leu Pro Arg Leu Ala Ile Gln Leu Leu Lys865 870 875 880
Arg Leu Ala Thr Val Ala Pro Met Ser Val Tyr Ala Cys Leu Gly Asn885 890 895Asp Ala Ala Ala Ile Arg Asp Ala Phe Leu Thr Arg Leu Gln Ser Lys900 905 910Ile Glu Asp Met Arg Ile Lys Val Met Ile Leu Glu Phe Leu Thr Val915 920 925Ala Val Glu Thr Gln Pro Gly Leu Ile Glu Leu Phe Leu Asn Leu Glu930 935 940Val Lys Asp Gly Ser Asp Gly Ser Lys Glu Phe Ser Leu Gly Met Trp945 950 955 960Ser Cys Leu His Ala Val Leu Glu Leu Ile Asp Ser Gln Gln Gln Asp965 970 975Arg Tyr Trp Cys Pro Pro Leu Leu His Arg Ala Ala Ile Ala Phe Leu980 985 990His Ala Leu Trp Gln Asp Arg Arg Asp Ser Ala Met Leu Val Leu Arg99510001005Thr Lys Pro Lys Phe Trp Glu Asn Leu Thr Ser Pro Leu Phe Gly Thr101010151020Leu Ser Pro Pro Ser Glu Thr Ser Glu Pro Ser Ile Leu Glu Thr Cys1025 103010351040Ala Leu Ile Met Lys Ile Ile Cys Leu Glu Ile Tyr Tyr Val Val Lys104510501055Gly Ser Leu Asp Gln Ser Leu Lys Asp Thr Leu Lys Lys Phe Ser Ile106010651070Glu Lys Arg Phe Ala Tyr Trp Ser Gly Tyr Val Arg Ser Leu Ala Val107510801085His Val Ala Glu Thr Glu Gly Ser Ser Cys Thr Ser Leu Leu Glu Tyr109010951100Gln Met Leu Val Ser Ala Trp Arg Met Leu Leu Ile Ile Ala Thr Thr1105 111011151120
His Ala Asp Ile Met His Leu Thr Asp Ser Val Val Arg Arg Gln Leu112511301135Phe Leu Asp Val Leu Asp Gly Thr Lys Ala Leu Leu Leu Val Pro Ala114011451150Ser Val Asn Cys Leu Arg Leu Gly Ser Met Lys Cys Thr Leu Leu Leu115511601165Ile Leu Leu Arg Gln Trp Lys Arg Glu Leu Gly Ser Val Asp Glu Ile117011751180Leu Gly Pro Leu Thr Glu Ile Leu Glu Gly Val Leu Gln Ala Asp Gln1185 119011951200Gln Leu Met Glu Lys Thr Lys Ala Lys Val Phe Ser Ala Phe Ile Thr120512101215Val Leu Gln Met Lys Glu Met Lys Val Ser Asp Ile Pro Gln Tyr Ser122012251230Gln Leu Val Leu Asn Val Cys Glu Thr Leu Gln Glu Glu Val Ile Ala123512401245Leu Phe Asp Gln Thr Arg His Ser Leu Ala Leu Gly Ser Ala Thr Glu125012551260Asp Lys Asp Ser Met Glu Thr Asp Asp Cys Ser Arg Ser Arg His Arg1265 127012751280Asp Gln Arg Asp Gly Val Cys Val Leu Gly Leu His Leu Ala Lys Glu128512901295Leu Cys Glu Val Asp Glu Asp Gly Asp Ser Trp Leu Gln Val Thr Arg130013051310Arg Leu Pro Ile Leu Pro Thr Leu Leu Thr Thr Leu Glu Val Ser Leu131513201325Arg Met Lys Gln Asn Leu His Phe Thr Glu Ala Thr Leu His Leu Leu133013351340Leu Thr Leu Ala Arg Thr Gln Gln Gly Ala Thr Ala Val Ala Gly Ala
1345 135013551360Gly Ile Thr Gln Ser Ile Cys Leu Pro Leu Leu Ser Val Tyr Gln Leu136513701375Ser Thr Asn Gly Thr Ala Gln Thr Pro Ser Ala Ser Arg Lys Ser Leu138013851390Asp Ala Pro Ser Trp Pro Gly Val Tyr Arg Leu Ser Met Ser Leu Met139514001405Glu Gln Leu Leu Lys Thr Leu Arg Tyr Asn Phe Leu Pro Glu Ala Leu141014151420Asp Phe Val Gly Val His Gln Glu Arg Thr Leu Gln Cys Leu Asn Ala1425 143014351440Val Arg Thr Val Gln Ser Leu Ala Cys Leu Glu Glu Ala Asp His Thr144514501455Val Gly Phe Ile Leu Gln Leu Ser Asn Phe Met Lys Glu Trp His Phe146014651470His Leu Pro Gln Leu Met Arg Asp Ile Gln Val Asn Leu Gly Tyr Leu147514801485Cys Gln Ala Cys Thr Ser Leu Leu His Ser Arg Lys Met Leu Gln His149014951500Tyr Leu Gln Asn Lys Asn Gly Asp Gly Leu Pro Ser Ala Val Ala Gln1505 151015151520Arg Val Gln Arg Pro Pro Ser Ala Ala Ser Ala Ala Pro Ser Ser Ser152515301535Lys Gln Pro Ala Ala Asp Thr Glu Ala Ser Glu Gln Gln Ala Leu His154015451550Thr Val Gln Tyr Gly Leu Leu Lys Ile Leu Ser Lys Thr Leu Ala Ala155515601565Leu Arg His Phe Thr Pro Asp ValCys Gln Ile Leu Leu Asp Gln Ser157015751580
Leu Asp Leu Ala Glu Tyr Asn Phe Leu Phe Ala Leu Ser Phe Thr Thr1585 159015951600Pro Thr Phe Asp Ser Glu Val Ala Pro Ser Phe Gly Thr Leu Leu Ala160516101615Thr Val Asn Val Ala Leu Asn Met Leu Gly Glu Leu Asp Lys Lys Lys162016251630Glu Pro Leu Thr Gln Ala Val Gly Leu Ser Thr Gln Ala Glu Gly Thr163516401645Arg Thr Leu Lys Ser Leu Leu Met Phe Thr Met Glu Asn Cys Phe Tyr165016551660Leu Leu Ile Ser Gln Ala Met Arg Tyr Leu Arg Asp Pro Ala Val His1665 167016751680Pro Arg Asp Lys Gln Arg Met Lys Gln Glu Leu Ser Ser Glu Leu Ser168516901695Thr Leu Leu Ser Ser Leu Ser Arg Tyr Phe Arg Arg Gly Ala Pro Ser170017051710Ser Pro Ala Thr Gly Val Leu Pro Ser Pro Gln Gly Lys Ser Thr Ser171517201725Leu Ser Lys Ala Ser Pro Glu Ser Gln Glu Pro Leu Ile Gln Leu Val173017351740Gln Ala Phe Val Arg His Met Gln Arg1745 1750<210>14<211>1753<212>PRT<213>人<400>14Met Ile Arg Lys Ser Lys lle Thr Ser Val Leu Ser Phe Cys Arg Ser1 5 10 15Ser Arg Glu Leu Trp Thr Ile Leu Leu Gly Arg Ser Ala Leu Arg Glu
20 25 30Leu Ser Gln Ile Glu Ala Glu Leu Asn Lys His Trp Arg Arg Leu Leu35 40 45Glu Gly Leu Ser Tyr Tyr Lys Pro Pro Ser Pro Ser Ser Ala Glu Lys50 55 60Val Lys Ala Asn Lys Asp Val Ala Ser Pro Leu Lys Glu Leu Gly Leu65 70 75 80Arg Ile Ser Lys Phe Leu Gly Leu Asp Glu Glu Gln Ser Val Gln Leu85 90 95Leu Gln Cys Tyr Leu Gln Glu Asp Tyr Arg Gly Thr Arg Asp Ser Val100 105 110Lys Thr Val Leu Gln Asp Glu Arg Gln Ser Gln Ala Leu Ile Leu Lys115 120 125Ile Ala Asp Tyr Tyr Tyr Glu Glu Arg Thr Cys Ile Leu Arg Cys Val130 135 140Leu His Leu Leu Thr Tyr Phe Gln Asp Glu Arg His Pro Tyr Arg Val145 150 155 160Glu Tyr Ala Asp Cys Val Asp Lys Leu Glu Lys Glu Leu Val Ser Lys165 170 175Tyr Arg Gln Gln Phe Glu Glu Leu Tyr Lys Thr Glu Ala Pro Thr Trp180 185 190Glu Thr His Gly Asn Leu Met Thr Glu Arg Gln Val Ser Arg Trp Phe195 200 205Val Gln Cys Leu Arg Glu Gln Ser Met Leu Leu Glu Ile Ile Phe Leu210 215 220Tyr Tyr Ala Tyr Phe Glu Met Ala Pro Ser Asp Leu Leu Val Leu Thr225 230 235 240Lys Met Phe Lys Glu Gln Gly Phe Gly Ser Arg Gln Thr Asn Arg His245 250 255
Leu Val Asp Glu Thr Met Asp Pro Phe Val Asp Arg Ile Gly Tyr Phe260 265 270Ser Ala Leu Ile Leu Val Glu Gly Met Asp Ile Glu Ser Leu His Lys275 280 285Cys Ala Leu Asp Asp Arg Arg Glu Leu His Gln Phe Ala Gln Asp Gly290 295 300Leu Ile Cys Gln Asp Met Asp Cys Leu Met Leu Thr Phe Gly Asp Ile305 310 315 320Pro His His Ala Pro Val Leu Leu Ala Trp Ala Leu Leu Arg His Thr325 330 335Leu Asn Pro Glu Glu Thr Ser Ser Val Val Arg Lys Ile Gly Gly Thr340 345 350Ala Ile Gln Leu Asn Val Phe Gln Tyr Leu Thr Arg Leu Leu Gln Ser355 360 365Leu Ala Ser Gly Gly Asn Asp Cys Thr Thr Ser Thr Ala Cys Met Cys370 375 380Val Tyr Gly Leu Leu Ser Phe Val Leu Thr Ser Leu Glu Leu His Thr385 390 395 400Leu Gly Asn Gln Gln Asp Ile Ile Asp Thr Ala Cys Glu Val Leu Ala405 410 415Asp Pro Ser Leu Pro Glu Leu Phe Trp Gly Thr Glu Pro Thr Ser Gly420 425 430Leu Gly Ile Ile Leu Asp Ser Val Cys Gly Met Phe Pro His Leu Leu435 440 445Ser Pro Leu Leu Gln Leu Leu Arg Ala Leu Val Ser Gly Lys Ser Thr450 455 460Ala Lys Lys Val Tyr Ser Phe Leu Asp Lys Met Ser Phe Tyr Asn Glu465 470 475 480Leu Tyr Lys His Lys Pro His Asp Val Ile Ser His Glu Asp Gly Thr485 490 495
Leu Trp Arg Arg Gln Thr Pro Lys Leu Leu Tyr Pro Leu Gly Gly Gln500 505 510Thr Asn Leu Arg Ile Pro Gln Gly Thr Val Gly Gln Val Met Leu Asp515 520 525Asp Arg Ala Tyr Leu Val Arg Trp Glu Tyr Ser Tyr Ser Ser Trp Thr530 535 540Leu Phe Thr Cys Glu Ile Glu Met Leu Leu His Val Val Ser Thr Ala545 550 555 560Asp Val Ile Gln His Cys Gln Arg Val Lys Pro Ile Ile Asp Leu Val565 570 575His Lys Val Ile Ser Thr Asp Leu Ser Ile Ala Asp Cys Leu Leu Pro580 585 590Ile Thr Ser Arg Ile Tyr Met Leu Leu Gln Arg Leu Thr Thr Val Ile595 600 605Ser Pro Pro Val Asp Val Ile Ala Ser Cys Val Asn Cys Leu Thr Val610 615 620Leu Ala Ala Arg Asn Pro Ala Lys Val Trp Thr Asp Leu Arg His Thr625 630 635 640Gly Phe Leu Pro Phe Val Ala His Pro Val Ser Ser Leu Ser Gln Met645 650 655Ile Ser Ala Glu Gly Met Asn Ala Gly Gly Tyr Gly Asn Leu Leu Met660 665 670Asn Ser Glu Gln Pro Gln Gly Glu Tyr Gly Val Thr Ile Ala Phe Leu675 680 685Arg Leu Ile Thr Thr Leu Val Lys Gly Gln Leu Gly Ser Thr Gln Ser690 695 700Gln Gly Leu Val Pro Cys Val Met Phe Val Leu Lys Glu Met Leu Pro705 710 715 720Ser Tyr His Lys Trp Arg Tyr Asn Ser His Gly Val Arg Glu Gln Ile
725 730 735Gly Cys Leu Ile Leu Glu Leu Ile His Ala Ile Leu Asn Leu Cys His740 745 750Glu Thr Asp Leu His Ser Ser His Thr Pro Ser Leu Gln Phe Leu Cys755 760 765Ile Cys Ser Leu Ala Tyr Thr Glu Ala Gly Gln Thr Val Ile Asn Ile770 775 780Met Gly Ile Gly Val Asp Thr Ile Asp Met Val Met Ala Ala Gln Pro785 790 795 800Arg Ser Asp Gly Ala Glu Gly Gln Gly Gln Gly Gln Leu Leu Ile Lys805 810 815Thr Val Lys Leu Ala Phe Ser Val Thr Asn Asn Val Ile Arg Leu Lys820 825 830Pro Pro Ser Asn Val Val Ser Pro Leu Glu Gln Ala Leu Ser Gln His835 840 845Gly Ala His Gly Asn Asn Leu Ile Ala Val Leu Ala Lys Tyr Ile Tyr850 855 860His Lys His Asp Pro Ala Leu Pro Arg Leu Ala Ile Gln Leu Leu Lys865 870 875 880Arg Leu Ala Thr Val Ala Pro Met Ser Val Tyr Ala Cys Leu Gly Asn885 890 895Asp Ala Ala Ala Ile Arg Asp Ala Phe Leu Thr Arg Leu Gln Ser Lys900 905 910Ile Glu Asp Met Arg Ile Lys Val Met Ile Leu Glu Phe Leu Thr Val915 920 925Ala Val Glu Thr Gln Pro Gly Leu Ile Glu Leu Phe Leu Asn Leu Glu930 935 940Val Lys Asp Gly Ser Asp Gly Ser Lys Glu Phe Ser Leu Gly Met Trp945 950 955 960
Ser Cys Leu His Ala Val Leu Glu Leu Ile Asp Ser Gln Gln Gln Asp965 970 975Arg Tyr Trp Cys Pro Pro Leu Leu His Arg Ala Ala Ile Ala Phe Leu980 985 990His Ala Leu Trp Gln Asp Arg Arg Asp Ser Ala Met Leu Val Leu Arg99510001005Thr Lys Pro Lys Phe Trp Glu Asn Leu Thr Ser Pro Leu Phe Gly Thr101010151020Leu Ser Pro Pro Ser Glu Thr Ser Glu Pro Ser Ile Leu Glu Thr Cys1025 103010351040Ala Leu Ile Met Lys Ile Ile Cys Leu Glu Ile Tyr Tyr Val Val Lys104510501055Gly Ser Leu Asp Gln Ser Leu Lys Asp Thr Leu Lys Lys Phe Ser Ile106010651070Glu Lys Arg Phe Ala Tyr Trp Ser Gly Tyr Val Lys Ser Leu Ala Val107510801085His Val Ala Glu Thr Glu Gly Ser Ser Cys Thr Ser Leu Leu Glu Tyr109010951100Gln Met Leu Val Ser Ala Trp Arg Met Leu Leu Ile Ile Ala Thr Thr1105 111011151120His Ala Asp Ile Met His Leu Thr Asp Ser Val Val Arg Arg Gln Leu112511301135Phe Leu Asp Val Leu Asp Gly Thr Lys Ala Leu Leu Leu Val Pro Ser114011451150Ser Val Asn Cys Leu Arg Leu Gly Ser Met Lys Cys Thr Leu Leu Leu115511601165Ile Leu Leu Arg Gln Trp Lys Arg Glu Leu Gly Ser Val Asp Glu Ile117011751180Leu Gly Pro Leu Thr Glu Ile Leu Glu Gly Val Leu Gln Ala Asp Gln1185 119011951200
Gln Leu Met Glu Lys Thr Lys Ala Lys Val Phe Ser Ala Phe Ile Thr120512101215Val Leu Gln Met Lys Glu Met Lys Val Ser Asp Ile Pro Gln Tyr Ser122012251230Gln Leu Val Leu Asn Val Cys Glu Thr Leu Gln Glu Glu Val Ile Ala123512401245Leu Phe Asp Gln Thr Arg His Ser Leu Ala Leu Gly Ser Ala Thr Glu125012551260Asp Lys Asp Ser Met Glu Thr Asp Asp Cys Ser Arg Ser Arg His Arg1265 127012751280Asp Gln Arg Asp Gly Val Cys Val Leu Gly Leu His Leu Ala Lys Glu128512901295Leu Cys Glu Val Asp Glu Asp Gly Asp Ser Trp Leu Gln Val Thr Arg130013051310Arg Leu Pro Ile Leu Pro Thr Leu Leu Thr Thr Leu Glu Val Ser Leu131513201325Arg Met Lys Gln Asn Leu His Phe Thr Glu Ala Thr Leu His Leu Leu133013351340Leu Thr Leu Ala Arg Thr Gln Gln Gly Ala Thr Ala Val Ala Gly Ala1345 135013551360Gly Ile Thr Gln Ser Ile Cys Leu Pro Leu Leu Ser Val Tyr Gln Leu136513701375Ser Thr Asn Gly Thr Ala Gln Thr Pro Ser Ala Ser Arg Lys Ser Leu138013851390Asp Ala Pro Ser Trp Pro Gly Val Tyr Arg Leu Ser Met Ser Leu Met139514001405Glu Gln Leu Leu Lys Thr Leu Arg Tyr Asn Phe Leu Pro Glu Ala Leu141014151420Asp Phe Val Gly Val His Gln Glu Arg Thr Leu Gln Cys Leu Asn Ala
1425 143014351440Val Arg Thr Val Gln Ser Leu Ala Cys Leu Glu Glu Ala Asp His Thr144514501455Val Gly Phe Ile Leu Gln Leu Ser Asn Phe Met Lys Glu Trp His Phe146014651470His Leu Pro Gln Leu Met Arg Asp Ile Gln Val Asn Leu Gly Tyr Leu147514801485Cys Gln Ala Cys Thr Ser Leu Leu His Ser Arg Lys Met Leu Gln His149014951500Tyr Leu Gln Asn Lys Asn Gly Asp Gly Leu Pro Ser Ala Val Ala Gln1505 151015151520Arg Val Gln Arg Pro Pro Ser Ala Ala Ser Ala Ala Pro Ser Ser Ser152515301535Lys Gln Pro Ala Ala Asp Thr Glu Ala Ser Glu Gln Gln Ala Leu His154015451550Thr Val Gln Tyr Gly Leu Leu Lys Ile Leu Ser Lys Thr Leu Ala Ala155515601565Leu Arg His Phe Thr Pro Asp Val Cys Gln Ile Leu Leu Asp Gln Ser157015751580Leu Asp Leu Ala Glu Tyr Asn Phe Leu Phe Ala Leu Ser Phe Thr Thr1585 159015951600Pro Thr Phe Asp Ser Glu Val Ala Pro Ser Phe Gly Thr Leu Leu Ala160516101615Thr Val Asn Val Ala Leu Asn Met Leu Gly Glu Leu Asp Lys Lys Lys162016251630Glu Pro Leu Thr Gln Ala Val Gly Leu Ser Thr Gln Ala Glu Gly Thr163516401645Arg Thr Leu Lys Ser Leu Leu Met Phe Thr Met Glu Asn Cys Phe Tyr165016551660
Leu Leu Ile Ser Gln Ala Met Arg Tyr Leu Arg Asp Pro Ala Val His1665 167016751680Pro Arg Asp Lys Gln Arg Met Lys Gln Glu Leu Ser Ser Glu Leu Ser168516901695Thr Leu Leu Ser Ser Leu Ser Arg Tyr Phe Arg Arg Gly Ala Pro Ser170017051710Ser Pro Ala Thr Gly Val Leu Pro Ser Pro Gln Gly Lys Ser Thr Ser171517201725Leu Ser Lys Ala Ser Pro Glu Ser Gln Glu Pro Leu Ile Gln Leu Val173017351740Gln Ala Phe Val Arg His Met Gln Arg1745 1750<210>15<211>1753<212>PRT<213>人<400>15Met Ile Arg Lys Ser Lys Ile Thr Ser Val Leu Ser Phe Cys Arg Ser1 5 10 15Ser Arg Glu Leu Trp Thr Ile Leu Leu Gly Arg Ser Ala Leu Arg Glu20 25 30Leu Ser Gln Ile Glu Ala Glu Leu Asn Lys His Trp Arg Arg Leu Leu35 40 45Glu Gly Leu Ser Tyr Tyr Lys Pro Pro Ser Pro Ser Ser Ala Glu Lys50 55 60Val Lys Ala Asn Lys Asp Val Ala Ser Pro Leu Lys Glu Leu Gly Leu65 70 75 80Arg Ile Ser Lys Phe Leu Gly Leu Asp Glu Glu Gln Ser Val Gln Leu85 90 95Leu Gln Cys Tyr Leu Gln Glu Asp Tyr Arg Gly Thr Arg Asp Ser Val
100 105 110Lys Thr Val Leu Gln Asp Glu Arg Gln Ser Gln Ala Leu Ile Leu Lys115 120 125Ile Ala Asp Tyr Tyr Tyr Glu Glu Arg Thr Cys Ile Leu Arg Cys Val130 135 140Leu His Leu Leu Thr Tyr Phe Gln Asp Glu Arg His Pro Tyr Arg Val145 150 155 160Glu Tyr Ala Asp Cys Val Asp Lys Leu Glu Lys Glu Leu Val Ser Lys165 170 175Tyr Arg Gln Gln Phe Glu Glu Leu Tyr Lys Thr Glu Ala Pro Thr Trp180 185 190Glu Thr His Gly Asn Leu Met Thr Glu Arg Gln Val Ser Arg Trp Phe195 200 205Val Gln Cys Leu Arg Glu Gln Ser Met Leu Leu Glu Ile Ile Phe Leu210 215 220Tyr Tyr Ala Tyr Phe Glu Met Ala Pro Ser Asp Leu Leu Val Leu Thr225 230 235 240Lys Met Phe Lys Glu Gln Gly Phe Gly Ser Arg Gln Thr Asn Arg His245 250 255Leu Val Asp Glu Thr Met Asp Pro Phe Val Asp Arg Ile Gly Tyr Phe260 265 270Ser Ala Leu Ile Leu Val Glu Gly Met Asp Ile Glu Ser Leu His Lys275 280 285Cys Ala Leu Asp Asp Arg Arg Glu Leu His Gln Phe Ala Gln Asp Gly290 295 300Leu Ile Cys Gln Asp Met Asp Cys Leu Met Leu Thr Phe Gly Asp Ile305 310 315 320Pro His His Ala Pro Val Leu Leu Ala Trp Ala Leu Leu Arg His Thr325 330 335
Leu Asn Pro Glu Glu Thr Ser Ser Val Val Arg Lys Ile Gly Gly Thr340 345 350Ala Ile Gln Leu Asn Val Phe Gln Tyr Leu Thr Arg Leu Leu Gln Ser355 360 365Leu Ala Ser Gly Gly Asn Asp Cys Thr Thr Ser Thr Ala Cys Met Cys370 375 380Val Tyr Gly Leu Leu Ser Phe Val Leu Thr Ser Leu Glu Leu His Thr385 390 395 400Leu Gly Asn Gln Gln Asp Ile Ile Asp Thr Ala Cys Glu Val Leu Ala405 410 415Asp Pro Ser Leu Pro Glu Leu Phe Trp Gly Thr Glu Pro Thr Ser Gly420 425 430Leu Gly Ile Ile Leu Asp Ser Val Cys Gly Met Phe Pro His Leu Leu435 440 445Ser Pro Leu Leu Gln Leu Leu Arg Ala Leu Val Ser Gly Lys Ser Thr450 455 460Ala Lys Lys Val Tyr Ser Phe Leu Asp Lys Met Ser Phe Tyr Asn Glu465 470 475 480Leu Tyr Lys His Lys Pro His Asp Val Ile Ser His Glu Asp Gly Thr485 490 495Leu Trp Arg Arg Gln Thr Pro Lys Leu Leu Tyr Pro Leu Gly Gly Gln500 505 510Thr Asn Leu Arg Ile Pro Gln Gly Thr Val Gly Gln Val Met Leu Asp515 520 525Asp Arg Ala Tyr Leu Val Arg Trp Glu Tyr Ser Tyr Ser Ser Trp Thr530 535 540Leu Phe Thr Cys Glu Ile Glu Met Leu Leu His Val Val Ser Thr Ala545 550 555 560Asp Val Ile Gln His Cys Gln Arg Val Lys Pro Ile Ile Asp Leu Val565 570 575
His Lys Val Ile Ser Thr Asp Leu Ser Ile Ala Asp Cys Leu Leu Pro580 585 590Ile Thr Ser Arg Ile Tyr Met Leu Leu Gln Arg Leu Thr Thr Val Ile595 600 605Ser Pro Pro Val Asp Val Ile Ala Ser Cys Val Asn Cys Leu Thr Val610 615 620Leu Ala Ala Arg Asn Pro Ala Lys Val Trp Thr Asp Leu Arg His Thr625 630 635 640Gly Phe Leu Pro Phe Val Ala His Pro Val Ser Ser Leu Ser Gln Met645 650 655Ile Ser Ala Glu Gly Met Asn Ala Gly Gly Tyr Gly Asn Leu Leu Met660 665 670Asn Ser Glu Gln Pro Gln Gly Glu Tyr Gly Val Thr Ile Ala Phe Leu675 680 685Arg Leu Ile Thr Thr Leu Val Lys Gly Gln Leu Gly Ser Thr Gln Ser690 695 700Gln Gly Leu Val Pro Cys Val Met Phe Val Leu Lys Glu Met Leu Pro705 710 715 720Ser Tyr His Lys Trp Arg Tyr Asn Ser His Gly Val Arg Glu Gln Ile725 730 735Gly Cys Leu Ile Leu Glu Leu Ile His Ala Ile Leu Asn Leu Cys His740 745 750Glu Thr Asp Leu His Ser Ser His Thr Pro Ser Leu Gln Phe Leu Cys755 760 765Ile Cys Ser Leu Ala Tyr Thr Glu Ala Gly Gln Thr Val Ile Asn Ile770 775 780Met Gly Ile Gly Val Asp Thr Ile Asp Met Val Met Ala Ala Gln Pro785 790 795 800Arg Ser Asp Gly Ala Glu Gly Gln Gly Gln Gly Gln Leu Leu Ile Lys
805 810 815Thr Val Lys Leu Ala Phe Ser Val Thr Asn Asn Val Ile Arg Leu Lys820 825 830Pro Pro Ser Asn Val Val Ser Pro Leu Glu Gln Ala Leu Ser Gln His835 840 845Gly Ala His Gly Asn Asn Leu Ile Ala Val Leu Ala Lys Tyr Ile Tyr850 855 860His Lys His Asp Pro Ala Leu Pro Arg Leu Ala Ile Gln Leu Leu Lys865 870 875 880Arg Leu Ala Thr Val Ala Pro Met Ser Val Tyr Ala Cys Leu Gly Asn885 890 895Asp Ala Ala Ala Ile Arg Asp Ala Phe Leu Thr Arg Leu Gln Ser Lys900 905 910Ile Glu Asp Met Arg Ile Lys Val Met Ile Leu Glu Phe Leu Thr Val915 920 925Ala Val Glu Thr Gln Pro Gly Leu Ile Glu Leu Phe Leu Asn Leu Glu930 935 940Val Lys Asp Gly Ser Asp Gly Ser Lys Glu Phe Ser Leu Gly Met Trp945 950 955 960Ser Cys Leu His Ala Val Leu Glu Leu Ile Asp Ser Gln Gln Gln Asp965 970 975Arg Tyr Trp Cys Pro Pro Leu Leu His Arg Ala Ala Ile Ala Phe Leu980 985 990His Ala Leu Trp Gln Asp Arg Arg Asp Ser Ala Met Leu Val Leu Arg99510001005Thr Lys Pro Lys Phe Trp Glu Asn Leu Thr Ser Pro Leu Phe Gly Thr101010151020Leu Ser Pro Pro Ser Glu Thr Ser Glu Pro Ser Ile Leu Glu Thr Cys1025 103010351040
Ala Leu Ile Met Lys Ile Ile Cys Leu Glu Ile Tyr Tyr Val Val Lys104510501055Gly Ser Leu Asp Gln Ser Leu Lys Asp Thr Leu Lys Lys Phe Ser Ile106010651070Glu Lys Arg Phe Ala Tyr Trp Ser Gly Tyr Val Lys Ser Leu Ala Val107510801085His Val Ala Glu Thr Glu Gly Ser Ser Cys Thr Ser Leu Leu Glu Tyr109010951100Gln Met Leu Val Ser Ala Trp Arg Met Leu Leu Ile Ile Ala Thr Thr1105 111011151120His Ala Asp Ile Met His Leu Thr Asp Ser Val Val Arg Arg Gln Leu112511301135Phe Leu Asp Val Leu Asp Gly Thr Lys Ala Leu Leu Leu Val Pro Ser114011451150Ser Val Asn Cys Leu Arg Leu Gly Ser Met Lys Cys Thr Leu Leu Leu115511601165Ile Leu Leu Arg Gln Trp Lys Arg Glu Leu Gly Ser Val Asp Glu Ile117011751180Leu Gly Pro Leu Thr Glu Ile Leu Glu Gly Val Leu Gln Ala Asp Gln1185 119011951200Gln Leu Met Glu Lys Thr Lys Ala Lys Val Phe Ser Ala Phe Ile Thr120512101215Val Leu Gln Met Lys Glu Met Lys Val Ser Asp Ile Pro Gln Tyr Ser122012251230Gln Leu Val Leu Asn Val Cys Glu Thr Leu Gln Glu Glu Val Val Ala123512401245Leu Phe Asp Gln Thr Arg His Ser Leu Ala Leu Gly Ser Ala Thr Glu125012551260Asp Lys Asp Ser Met Glu Thr Asp Asp Cys Ser Arg Ser Arg His Arg1265 127012751280
Asp Gln Arg Asp Gly Val Cys Val Leu Gly Leu His Leu Ala Lys Glu128512901295Leu Cys Glu Val Asp Glu Asp Gly Asp Ser Trp Leu Gln Val Thr Arg130013051310Arg Leu Pro Ile Leu Pro Thr Leu Leu Thr Thr Leu Glu Val Ser Leu131513201325Arg Met Lys Gln Asn Leu His Phe Thr Glu Ala Thr Leu His Leu Leu133013351340Leu Thr Leu Ala Arg Thr Gln Gln Gly Ala Thr Ala Val Ala Gly Ala1345 135013551360Gly Ile Thr Gln Ser Ile Cys Leu Pro Leu Leu Ser Val Tyr Gln Leu136513701375Ser Thr Asn Gly Thr Ala Gln Thr Pro Ser Ala Ser Arg Lys Ser Leu138013851390Asp Ala Pro Ser Trp Pro Gly Val Tyr Arg Leu Ser Met Ser Leu Met139514001405Glu Gln Leu Leu Lys Thr Leu Arg Tyr Asn Phe Leu Pro Glu Ala Leu141014151420Asp Phe Val Gly Val His Gln Glu Arg Thr Leu Gln Cys Leu Asn Ala142143014351440Val Arg Thr Val Gln Ser Leu Ala Cys Leu Glu Glu Ala Asp His Thr144514501455Val Gly Phe Ile Leu Gln Leu Ser Asn Phe Met Lys Glu Trp His Phe146014651470His Leu Pro Gln Leu Met Arg Asp Ile Gln Val Asn Leu Gly Tyr Leu147514801485Cys Gln Ala Cys Thr Ser Leu Leu His Ser Arg Lys Met Leu Gln His149014951500Tyr Leu Gln Asn Lys Asn Gly Asp Gly Leu Pro Ser Ala Val Ala Gln
1505 151015151520Arg Val Gln Arg Pro Pro Ser Ala Ala Ser Ala Ala Pro Ser Ser Ser152515301535Lys Gln Pro Ala Ala Asp Thr Glu Ala Ser Glu Gln Gln Ala Leu His154015451550Thr Val Gln Tyr Gly Leu Leu Lys Ile Leu Ser Lys Thr Leu Ala Ala155515601565Leu Arg His Phe Thr Pro Asp Val Cys Gln Ile Leu Leu Asp Gln Ser157015751580Leu Asp Leu Ala Glu Tyr Asn Phe Leu Phe Ala Leu Ser Phe Thr Thr1585 159015951600Pro Thr Phe Asp Ser Glu Val Ala Pro Ser Phe Gly Thr Leu Leu Ala160516101615Thr Val Asn Val Ala Leu Asn Met Leu Gly Glu Leu Asp Lys Lys Lys162016251630Glu Pro Leu Thr Gln Ala Val Gly Leu Ser Thr Gln Ala Glu Gly Thr163516401645Arg Thr Leu Lys Ser Leu Leu Met Phe Thr Met Glu Asn Cys Phe Tyr165016551660Leu Leu Ile Ser Gln Ala Met Arg Tyr Leu Arg Asp Pro Ala Val His1665 167016751680Pro Arg Asp Lys Gln Arg Met Lys Gln Glu Leu Ser Ser Glu Leu Ser168516901695Thr Leu Leu Ser Ser Leu Ser Arg Tyr Phe Arg Arg Gly Ala Pro Ser170017051710Ser Pro Ala Thr Gly Val Leu Pro Ser Pro Gln Gly Lys Ser Thr Ser171517201725Leu Ser Lys Ala Ser Pro Glu Ser Gln Glu Pro Leu Ile Gln Leu Val173017351740
Gln Ala Phe Val Arg His Met Gln Arg1745 1750<210>16<211>1753<212>PRT<213>人<400>16Met Ile Arg Lys Ser Lys Ile Thr Ser Val Leu Ser Phe Cys Arg Ser1 5 10 15Ser Arg Glu Leu Trp Thr Ile Leu Leu Gly Arg Ser Ala Leu Arg Glu20 25 30Leu Ser Gln Ile Glu Ala Glu Leu Asn Lys His Trp Arg Arg Leu Leu35 40 45Glu Gly Leu Ser Tyr Tyr Lys Pro Pro Ser Pro Ser Ser Ala Glu Lys50 55 60Val Lys Ala Asn Lys Asp Val Ala Ser Pro Leu Lys Glu Leu Gly Leu65 70 75 80Arg Ile Ser Lys Phe Leu Gly Leu Asp Glu Glu Gln Ser Val Gln Leu85 90 95Leu Gln Cys Tyr Leu Gln Glu Asp Tyr Arg Gly Thr Arg Asp Ser Val100 105 110Lys Thr Val Leu Gln Asp Glu Arg Gln Ser Gln Ala Leu Ile Leu Lys115 120 125Ile Ala Asp Tyr Tyr Tyr Glu Glu Arg Thr Cys Ile Leu Arg Cys Val130 135 140Leu His Leu Leu Thr Tyr Phe Gln Asp Glu Arg His Pro Tyr Arg Val145 150 155 160Glu Tyr Ala Asp Cys Val Asp Lys Leu Glu Lys Glu Leu Val Ser Lys165 170 175Tyr Arg Gln Gln Phe Glu Glu Leu Tyr Lys Thr Glu Ala Pro Thr Trp
180 185 190Glu Thr His Gly Asn Leu Met Thr Glu Arg Gln Val Ser Arg Trp Phe195 200 205Val Gln Cys Leu Arg Glu Gln Ser Met Leu Leu Glu Ile Ile Phe Leu210 215 220Tyr Tyr Ala Tyr Phe Glu Met Ala Pro Ser Asp Leu Leu Val Leu Thr225 230 235 240Lys Met Phe Lys Glu Gln Gly Phe Gly Ser Arg Gln Thr Asn Arg His245 250 255Leu Val Asp Glu Thr Met Asp Pro Phe Val Asp Arg Ile Gly Tyr Phe260 265 270Ser Ala Leu Ile Leu Val Glu Gly Met Asp Ile Glu Ser Leu His Lys275 280 285Cys Ala Leu Asp Asp Arg Arg Glu Leu His Gln Phe Ala Gln Asp Gly290 295 300Leu Ile Cys Gln Asp Met Asp Cys Leu Met Leu Thr Phe Gly Asp Ile305 310 315 320Pro His His Ala Pro Val Leu Leu Ala Trp Ala Leu Leu Arg His Thr325 330 335Leu Asn Pro Glu Glu Thr Ser Ser Val Val Arg Lys Ile Gly Gly Thr340 345 350Ala Ile Gln Leu Asn Val Phe Gln Tyr Leu Thr Arg Leu Leu Gln Ser355 360 365Leu Ala Ser Gly Gly Asn Asp Cys Thr Thr Ser Thr Ala Cys Met Cys370 375 380Val Tyr Gly Leu Leu Ser Phe Val Leu Thr Ser Leu Glu Leu His Thr385 390 395 400Leu Gly Asn Gln Gln Asp Ile Ile Asp Thr Ala Cys Glu Val Leu Ala405 410 415
Asp Pro Ser Leu Pro Glu Leu Phe Trp Gly Thr Glu Pro Thr Ser Gly420 425 430Leu Gly Ile Ile Leu Asp Ser Val Cys Gly Met Phe Pro His Leu Leu435 440 445Ser Pro Leu Leu Gln Leu Leu Arg Ala Leu Val Ser Gly Lys Ser Thr450 455 460Ala Lys Lys Val Tyr Ser Phe Leu Asp Lys Met Ser Phe Tyr Asn Glu465 470 475 480Leu Tyr Lys His Lys Pro His Asp Val Ile Ser His Glu Asp Gly Thr485 490 495Leu Trp Arg Arg Gln Thr Pro Lys Leu Leu Tyr Pro Leu Gly Gly Gln500 505 510Thr Asn Leu Arg Ile Pro Gln Gly Thr Val Gly Gln Val Met Leu Asp515 520 525Asp Arg Ala Tyr Leu Val Arg Trp Glu Tyr Ser Tyr Ser Ser Trp Thr530 535 540Leu Phe Thr Cys Glu Ile Glu Met Leu Leu His Val Val Ser Thr Ala545 550 555 560Asp Val Ile Gln His Cys Gln Arg Val Lys Pro Ile Ile Asp Leu Val565 570 575His Lys Val Ile Ser Thr Asp Leu Ser Ile Ala Asp Cys Leu Leu Pro580 585 590Ile Thr Ser Arg Ile Tyr Met Leu Leu Gln Arg Leu Thr Thr Val Ile595 600 605Ser Pro Pro Val Asp Val Ile Ala Ser Cys Val Asn Cys Leu Thr Val610 615 620Leu Ala Ala Arg Asn Pro Ala Lys Val Trp Thr Asp Leu Arg His Thr625 630 635 640Gly Phe Leu Pro Phe Val Ala His Pro Val Ser Ser Leu Ser Gln Met645 650 655
Ile Ser Ala Glu Gly Met Asn Ala Gly Gly Tyr Gly Asn Leu Leu Met660 665 670Asn Ser Glu Gln Pro Gln Gly Glu Tyr Gly Val Thr Ile Ala Phe Leu675 680 685Arg Leu Ile Thr Thr Leu Val Lys Gly Gln Leu Gly Ser Thr Gln Ser690 695 700Gln Gly Leu Val Pro Cys Val Met Phe Val Leu Lys Glu Met Leu Pro705 710 715 720Ser Tyr His Lys Trp Arg Tyr Asn Ser His Gly Val Arg Glu Gln Ile725 730 735Gly Cys Leu Ile Leu Glu Leu Ile His Ala Ile Leu Asn Leu Cys His740 745 750Glu Thr Asp Leu His Ser Ser His Thr Pro Ser Leu Gln Phe Leu Cys755 760 765Ile Cys Ser Leu Ala Tyr Thr Glu Ala Gly Gln Thr Val Ile Asn Ile770 775 780Met Gly Ile Gly Val Asp Thr Ile Asp Met Val Met Ala Ala Gln Pro785 790 795 800Arg Ser Asp Gly Ala Glu Gly Gln Gly Gln Gly Gln Leu Leu Ile Lys805 810 815Thr Val Lys Leu Ala Phe Ser Val Thr Asn Asn Val Ile Arg Leu Lys820 825 830Pro Pro Ser Asn Val Val Ser Pro Leu Glu Gln Ala Leu Ser Gln His835 840 845Gly Ala His Gly Asn Asn Leu Ile Ala Val Leu Ala Lys Tyr Ile Tyr850 855 860His Lys His Asp Pro Ala Leu Pro Arg Leu Ala Ile Gln Leu Leu Lys865 870 875 880Arg Leu Ala Thr Val Ala Pro Met Ser Val Tyr Ala Cys Leu Gly Asn
885 890 895Asp Ala Ala Ala Ile Arg Asp Ala Phe Leu Thr Arg Leu Gln Ser Lys900 905 910Ile Glu Asp Met Arg Ile Lys Val Met Ile Leu Glu Phe Leu Thr Val915 920 925Ala Val Glu Thr Gln Pro Gly Leu Ile Glu Leu Phe Leu Asn Leu Glu930 935 940Val Lys Asp Gly Ser Asp Gly Ser Lys Glu Phe Ser Leu Gly Met Trp945 950 955 960Ser Cys Leu His Ala Val Leu Glu Leu Ile Asp Ser Gln Gln Gln Asp965 970 975Arg Tyr Trp Cys Pro Pro Leu Leu His Arg Ala Ala Ile Ala Phe Leu980 985 990His Ala Leu Trp Gln Asp Arg Arg Asp Ser Ala Met Leu Val Leu Arg99510001005Thr Lys Pro Lys Phe Trp Glu Asn Leu Thr Ser Pro Leu Phe Gly Thr101010151020Leu Ser Pro Pro Ser Glu Thr Ser Glu Pro Ser Ile Leu Glu Thr Cys1025 103010351040Ala Leu Ile Met Lys Ile Ile Cys Leu Glu Ile Tyr Tyr Val Val Lys104510501055Gly Ser Leu Asp Gln Ser Leu Lys Asp Thr Leu Lys Lys Phe Ser Ile106010651070Glu Lys Arg Phe Ala Tyr Trp Ser Gly Tyr Val Lys Ser Leu Ala Val107510801085His Val Ala Glu Thr Glu Gly Ser Ser Cys Thr Ser Leu Leu Glu Tyr109010951100Gln Met Leu Val Ser Ala Trp Arg Met Leu Leu Ile Ile Ala Thr Thr1105 111011151120
His Ala Asp Ile Met His Leu Thr Asp Ser Val Val Arg Arg Gln Leu112511301135Phe Leu Asp Val Leu Asp Gly Thr Lys Ala Leu Leu Leu Val Pro Ser114011451150Ser Val Asn Cys Leu Arg Leu Gly Ser Met Lys Cys Thr Leu Leu Leu115511601165Ile Leu Leu Arg Gln Trp Lys Arg Glu Leu Gly Ser Val Asp Glu Ile117011751180Leu Gly Pro Leu Thr Glu Ile Leu Glu Gly Val Leu Gln Ala Asp Gln1185 119011951200Gln Leu Met Glu Lys Thr Lys Ala Lys Val Phe Ser Ala Phe Ile Thr120512101215Val Leu Gln Met Lys Glu Met Lys Val Ser Asp Ile Pro Gln Tyr Ser122012251230Gln Leu Val Leu Asn ValCys Glu Thr Leu Gln Glu Glu Val Ile Ala123512401245Leu Phe Asp Gln Thr Arg His Ser Leu Ala Leu Gly Ser Ala Thr Glu125012551260Asp Lys Asp Ser Met Glu Thr Asp Asp Cys Ser Arg Ser Arg His Arg1265 127012751280Asp Gln Arg Asp Gly Val Cys Val Leu Gly Leu His Leu Ala Lys Glu128512901295Leu Cys Glu Val Asp Glu Asp Gly Asp Ser Trp Leu Gln Val Thr Arg130013051310Arg Leu Pro Ile Leu Pro Thr Leu Leu Thr Thr Leu Glu Val Ser Leu131513201325Arg Met Arg Gln Asn Leu His Phe Thr Glu Ala Thr Leu His Leu Leu133013351340Leu Thr Leu Ala Arg Thr Gln Gln Gly Ala Thr Ala Val Ala Gly Ala1345 135013551360
Gly Ile Thr Gln Ser Ile Cys Leu Pro Leu Leu Ser Val Tyr Gln Leu136513701375Ser Thr Asn Gly Thr Ala Gln Thr Pro Ser Ala Ser Arg Lys Ser Leu138013851390Asp Ala Pro Ser Trp Pro Gly Val Tyr Arg Leu Ser Met Ser Leu Met139514001405Glu Gln Leu Leu Lys Thr Leu Arg Tyr Asn Phe Leu Pro Glu Ala Leu141014151420Asp Phe Val Gly Val His Gln Glu Arg Thr Leu Gln Cys Leu Asn Ala1425 143014351440Val Arg Thr Val Gln Ser Leu Ala Cys Leu Glu Glu Ala Asp His Thr144514501455Val Gly Phe Ile Leu Gln Leu Ser Asn Phe Met Lys Glu Trp His Phe146014651470His Leu Pro Gln Leu Met Arg Asp Ile Gln Val Asn Leu Gly Tyr Leu147514801485Cys Gln Ala Cys Thr Ser Leu Leu His Ser Arg Lys Met Leu Gln His149014951500Tyr Leu Gln Asn Lys Asn Gly Asp Gly Leu Pro Ser Ala Val Ala Gln1505 151015151520Arg Val Gln Arg Pro Pro Ser Ala Ala Ser Ala Ala Pro Ser Ser Ser152515301535Lys Gln Pro Ala Ala Asp Thr Glu Ala Ser Glu Gln Gln Ala Leu His154015451550Thr Val Gln Tyr Gly Leu Leu Lys Ile Leu Ser Lys Thr Leu Ala Ala155515601565Leu Arg His Phe Thr Pro Asp Val Cys Gln Ile Leu Leu Asp Gln Ser157015751580Leu Asp Leu Ala Glu Tyr Asn Phe Leu Phe Ala Leu Ser Phe Thr Thr
1585 159015951600Pro Thr Phe Asp Ser Glu Val Ala Pro Ser Phe Gly Thr Leu Leu Ala160516101615Thr Val Asn Val Ala Leu Asn Met Leu Gly Glu Leu Asp Lys Lys Lys162016251630Glu Pro Leu Thr Gln Ala Val Gly Leu Ser Thr Gln Ala Glu Gly Thr163516401645Arg Thr Leu Lys Ser Leu Leu Met Phe Thr Met Glu Asn Cys Phe Tyr165016551660Leu Leu Ile Ser Gln Ala Met Arg Tyr Leu Arg Asp Pro Ala Val His1665 167016751680Pro Arg Asp Lys Gln Arg Met Lys Gln Glu Leu Ser Ser Glu Leu Ser168516901695Thr Leu Leu Ser Ser Leu Ser Arg Tyr Phe Arg Arg Gly Ala Pro Ser170017051710Ser Pro Ala Thr Gly Val Leu Pro Ser Pro Gln Gly Lys Ser Thr Ser171517201725Leu Ser Lys Ala Ser Pro Glu Ser Gln Glu Pro Leu Ile Gln Leu Val173017351740Gln Ala Phe Val Arg His Met Gln Arg1745 1750<210>17<211>1753<212>PRT<213>人<400>17Met Ile Arg Lys Ser Lys Ile Thr Ser Val Leu Ser Phe Cys Arg Ser1 5 10 15Ser Arg Glu Leu Trp Thr Ile Leu Leu Gly Arg Ser Ala Leu Arg Glu20 25 30
Leu Ser Gln Ile Glu Ala Glu Leu Asn Lys His Trp Arg Arg Leu Leu35 40 45Glu Gly Leu Ser Tyr Tyr Lys Pro Pro Ser Pro Ser Ser Ala Glu Lys50 55 60Val Lys Ala Asn Lys Asp Val Ala Ser Pro Leu Lys Glu Leu Gly Leu65 70 75 80Arg Ile Ser Lys Phe Leu Gly Leu Asp Glu Glu Gln Ser Val Gln Leu85 90 95Leu Gln Cys Tyr Leu Gln Glu Asp Tyr Arg Gly Thr Arg Asp Ser Val100 105 110Lys Thr Val Leu Gln Asp Glu Arg Gln Ser Gln Ala Leu Ile Leu Lys115 120 125Ile Ala Asp Tyr Tyr Tyr Glu Glu Arg Thr Cys Ile Leu Arg Cys Val130 135 140Leu His Leu Leu Thr Tyr Phe Gln Asp Glu Arg His Pro Tyr Arg Val145 150 155 160Glu Tyr Ala Asp Cys Val Asp Lys Leu Glu Lys Glu Leu Val Ser Lys165 170 175Tyr Arg Gln Gln Phe Glu Glu Leu Tyr Lys Thr Glu Ala Pro Thr Trp180 185 190Glu Thr His Gly Asn Leu Met Thr Glu Arg Gln Val Ser Arg Trp Phe195 200 205Val Gln Cys Leu Arg Glu Gln Ser Met Leu Leu Glu Ile Ile Phe Leu210 215 220Tyr Tyr Ala Tyr Phe Glu Met Ala Pro Ser Asp Leu Leu Val Leu Thr225 230 235 240Lys Met Phe Lys Glu Gln Gly Phe Gly Ser Arg Gln Thr Asn Arg His245 250 255Leu Val Asp Glu Thr Met Asp Pro Phe Val Asp Arg Ile Gly Tyr Phe
260 265 270Ser Ala Leu Ile Leu Val Glu Gly Met Asp Ile Glu Ser Leu His Lys275 280 285Cys Ala Leu Asp Asp Arg Arg Glu Leu His Gln Phe Ala Gln Asp Gly290 295 300Leu Ile Cys Gln Asp Met Asp Cys Leu Met Leu Thr Phe Gly Asp Ile305 310 315 320Pro His His Ala Pro Val Leu Leu Ala Trp Ala Leu Leu Arg His Thr325 330 335Leu Asn Pro Glu Glu Thr Ser Ser Val Val Arg Lys Ile Gly Gly Thr340 345 350Ala Ile Gln Leu Asn Val Phe Gln Tyr Leu Thr Arg Leu Leu Gln Ser355 360 365Leu Ala Ser Gly Gly Asn Asp Cys Thr Thr Ser Thr Ala Cys Met Cys370 375 380Val Tyr Gly Leu Leu Ser Phe Val Leu Thr Ser Leu Glu Leu His Thr385 390 395 400Leu Gly Asn Gln Gln Asp Ile Ile Asp Thr Ala Cys Glu Val Leu Ala405 410 415Asp Pro Ser Leu Pro Glu Leu Phe Trp Gly Thr Glu Pro Thr Ser Gly420 425 430Leu Gly Ile Ile Leu Asp Ser Val Cys Gly Met Phe Pro His Leu Leu435 440 445Ser Pro Leu Leu Gln Leu Leu Arg Ala Leu Val Ser Gly Lys Ser Thr450 455 460Ala Lys Lys Val Tyr Ser Phe Leu Asp Lys Met Ser Phe Tyr Asn Glu465 470 475 480Leu Tyr Lys His Lys Pro His Asp Val Ile Ser His Glu Asp Gly Thr485 490 495
Leu Trp Arg Arg Gln Thr Pro Lys Leu Leu Tyr Pro Leu Gly Gly Gln500 505 510Thr Asn Leu Arg Ile Pro Gln Gly Thr Val Gly Gln Val Met Leu Asp515 520 525Asp Arg Ala Tyr Leu Val Arg Trp Glu Tyr Ser Tyr Ser Ser Trp Thr530 535 540Leu Phe Thr Cys Glu Ile Glu Met Leu Leu His Val Val Ser Thr Ala545 550 555 560Asp Val Ile Gln His Cys Gln Arg Val Lys Pro Ile Ile Asp Leu Val565 570 575His Lys Val Ile Ser Thr Asp Leu Ser Ile Ala Asp Cys Leu Leu Pro580 585 590Ile Thr Ser Arg Ile Tyr Met Leu Leu Gln Arg Leu Thr Thr Val Ile595 600 605Ser Pro Pro Val Asp Val Ile Ala Ser Cys Val Asn Cys Leu Thr Val610 615 620Leu Ala Ala Arg Asn Pro Ala Lys Val Trp Thr Asp Leu Arg His Thr625 630 635 640Gly Phe Leu Pro Phe Val Ala His Pro Val Ser Ser Leu Ser Gln Met645 650 655Ile Ser Ala Glu Gly Met Asn Ala Gly Gly Tyr Gly Asn Leu Leu Met660 665 670Asn Ser Glu Gln Pro Gln Gly Glu Tyr Gly Val Thr Ile Ala Phe Leu675 680 685Arg Leu Ile Thr Thr Leu Val Lys Gly Gln Leu Gly Ser Thr Gln Ser690 695 700Gln Gly Leu Val Pro Cys Val Met Phe Val Leu Lys Glu Met Leu Pro705 710 715 720Ser Tyr His Lys Trp Arg Tyr Asn Ser His Gly Val Arg Glu Gln Ile725 730 735
Gly Cys Leu Ile Leu Glu Leu Ile His Ala Ile Leu Asn Leu Cys His740 745 750Glu Thr Asp Leu His Ser Ser His Thr Pro Ser Leu Gln Phe Leu Cys755 760 765Ile Cys Ser Leu Ala Tyr Thr Glu Ala Gly Gln Thr Val Ile Asn Ile770 775 780Met Gly Ile Gly Val Asp Thr Ile Asp Met Val Met Ala Ala Gln Pro785 790 795 800Arg Ser Asp Gly Ala Glu Gly Gln Gly Gln Gly Gln Leu Leu Ile Lys805 810 815Thr Val Lys Leu Ala Phe Ser Val Thr Asn Asn Val Ile Arg Leu Lys820 825 830Pro Pro Ser Asn Val Val Ser Pro Leu Glu Gln Ala Leu Ser Gln His835 840 845Gly Ala His Gly Asn Asn Leu Ile Ala Val Leu Ala Lys Tyr Ile Tyr850 855 860His Lys His Asp Pro Ala Leu Pro Arg Leu Ala Ile Gln Leu Leu Lys865 870 875 880Arg Leu Ala Thr Val Ala Pro Met Ser Val Tyr Ala Cys Leu Gly Asn885 890 895Asp Ala Ala Ala Ile Arg Asp Ala Phe Leu Thr Arg Leu Gln Ser Lys900 905 910Ile Glu Asp Met Arg Ile Lys Val Met Ile Leu Glu Phe Leu Thr Val915 920 925Ala Val Glu Thr Gln Pro Gly Leu Ile Glu Leu Phe Leu Asn Leu Glu930 935 940Val Lys Asp Gly Ser Asp Gly Ser Lys Glu Phe Ser Leu Gly Met Trp945 950 955 960Ser Cys Leu His Ala Val Leu Glu Leu Ile Asp Ser Gln Gln Gln Asp
965 970 975Arg Tyr Trp Cys Pro Pro Leu Leu His Arg Ala Ala Ile Ala Phe Leu980 985 990His Ala Leu Trp Gln Asp Arg Arg Asp Ser Ala Met Leu Val Leu Arg99510001005Thr Lys Pro Lys Phe Trp Glu Asn Leu Thr Ser Pro Leu Phe Gly Thr101010151020Leu Ser Pro Pro Ser Glu Thr Ser Glu Pro Ser Ile Leu Glu Thr Cys1025 103010351040Ala Leu Ile Met Lys Ile Ile Cys Leu Glu Ile Tyr Tyr Val Val Lys104510501055Gly Ser Leu Asp Gln Ser Leu Lys Asp Thr Leu Lys Lys Phe Ser Ile106010651070Glu Lys Arg Phe Ala Tyr Trp Ser Gly Tyr Val Lys Ser Leu Ala Val107510801085His Val Ala Glu Thr Glu Gly Ser Ser Cys Thr Ser Leu Leu Glu Tyr109010951100Gln Met Leu Val Ser Ala Trp Arg Met Leu Leu Ile Ile Ala Thr Thr1105 111011151120His Ala Asp Ile Met His Leu Thr Asp Ser Val Val Arg Arg Gln Leu112511301135Phe Leu Asp Val Leu Asp Gly Thr Lys Ala Leu Leu Leu Val Pro Ser114011451150Ser Val Asn Cys Leu Arg Leu Gly Ser Met Lys Cys Thr Leu Leu Leu115511601165Ile Leu Leu Arg Gln Trp Lys Arg Glu Leu Gly Ser Val Asp Glu Ile117011751180Leu Gly Pro Leu Thr Glu Ile Leu Glu Gly Val Leu Gln Ala Asp Gln1185 119011951200
Gln Leu Met Glu Lys Thr Lys Ala Lys Val Phe Ser Ala Phe Ile Thr120512101215Val Leu Gln Met Lys Glu Met Lys Val Ser Asp Ile Pro Gln Tyr Ser122012251230Gln Leu Val Leu Asn Val Cys Glu Thr Leu Gln Glu Glu Val Ile Ala123512401245Leu Phe Asp Gln Thr Arg His Ser Leu Ala Leu Gly Ser Ala Thr Glu125012551260Asp Lys Asp Ser Met Glu Thr Asp Asp Cys Ser Arg Ser Arg His Arg1265 127012751280Asp Gln Arg Asp Gly Val Cys Val Leu Gly Leu His Leu Ala Lys Glu128512901295Leu Cys Glu Val Asp Glu Asp Gly Asp Ser Trp Leu Gln Val Thr Arg130013051310Arg Leu Pro Ile Leu Pro Thr Leu Leu Thr Thr Leu Glu Val Ser Leu131513201325Arg Met Lys Gln Asn Leu His Phe Thr Glu Ala Thr Leu His Leu Leu133013351340Leu Thr Leu Ala Arg Thr Gln Gln Gly Ala Thr Ala Val Ala Gly Ala1345 135013551360Gly Ile Thr Gln Ser Ile Cys Leu Pro Leu Leu Ser Val Tyr Gln Leu136513701375Ser Thr Asn Gly Thr Ala Gln Thr Pro Ser Ala Ser Arg Lys Ser Leu138013851390Asp Ala Pro Ser Trp Pro Gly Val Tyr Arg Leu Ser Met Ser Leu Met139514001405Glu Gln Leu Leu Lys Thr Leu Arg Tyr Asn Phe Leu Pro Glu Ala Leu141014151420Asp Phe Val Gly Val His Gln Glu Arg Thr Leu Gln Cys Leu Asn Ala1425 143014351440
Val Arg Thr Val Gln Ser Leu Ala Tyr Leu Glu Glu Ala Asp His Thr144514501455Val Gly Phe Ile Leu Gln Leu Ser Asn Phe Met Lys Glu Trp His Phe146014651470His Leu Pro Gln Leu Met Arg Asp Ile Gln Val Asn Leu Gly Tyr Leu147514801485Cys Gln Ala Cys Thr Ser Leu Leu His Ser Arg Lys Met Leu Gln His149014951500Tyr Leu Gln Asn Lys Asn Gly Asp Gly Leu Pro Ser Ala Val Ala Gln1505 151015151520Arg Val Gln Arg Pro Pro Ser Ala Ala Ser Ala Ala Pro Ser Ser Ser152515301535Lys Gln Pro Ala Ala Asp Thr Glu Ala Ser Glu Gln Gln Ala Leu His154015451550Thr Val Gln Tyr Gly Leu Leu Lys Ile Leu Ser Lys Thr Leu Ala Ala155515601565Leu Arg His Phe Thr Pro Asp Val Cys Gln Ile Leu Leu Asp Gln Ser157015751580Leu Asp Leu Ala Glu Tyr Asn Phe Leu Phe Ala Leu Ser Phe Thr Thr1585 159015951600Pro Thr Phe Asp Ser Glu Val Ala Pro Ser Phe Gly Thr Leu Leu Ala160516101615Thr Val Asn Val Ala Leu Asn Met Leu Gly Glu Leu Asp Lys Lys Lys162016251630Glu Pro Leu Thr Gln Ala Val Gly Leu Ser Thr Gln Ala Glu Gly Thr163516401645Arg Thr Leu Lys Ser Leu Leu Met Phe Thr Mer Glu Asn Cys Phe Tyr165016551660Leu Leu Ile Ser Gln Ala Met Arg Tyr Leu Arg Asp Pro Ala Val His
1665 167016751680Pro Arg Asp Lys Gln Arg Met Lys Gln Glu Leu Ser Ser Glu Leu Ser168516901695Thr Leu Leu Ser Ser Leu Ser Arg Tyr Phe Arg Arg Gly Ala Pro Ser170017051710Ser Pro Ala Thr Gly Val Leu Pro Ser Pro Gln Gly Lys Ser Thr Ser171517201725Leu Ser Lys Ala Ser Pro Glu Ser Gln Glu Pro Leu Ile Gln Leu Val1730 17351740Gln Ala Phe Val Arg His Met Gln Arg1745 1750<210>18<211>1753<212>PRT<213>人<400>18Met Ile Arg Lys Ser Lys Ile Thr Ser Val Leu Ser Phe Cys Arg Ser1 5 10 15Ser Arg Glu Leu Trp Thr Ile Leu Leu Gly Arg Ser Ala Leu Arg Glu20 25 30Leu Ser Gln Ile Glu Ala Glu Leu Asn Lys His Trp Arg Arg Leu Leu35 40 45Glu Gly Leu Ser Tyr Tyr Lys Pro Pro Ser Pro Ser Ser Ala Glu Lys50 55 60Val Lys Ala Asn Lys Asp Val Ala Ser Pro Leu Lys Glu Leu Gly Leu65 70 75 80Arg Ile Ser Lys Phe Leu Gly Leu Asp Glu Glu Gln Ser Val Gln Leu85 90 95Leu Gln Cys Tyr Leu Gln Glu Asp Tyr Arg Gly Thr Arg Asp Ser Val100 105 110
Lys Thr Val Leu Gln Asp Glu Arg Gln Ser Gln Ala Leu Ile Leu Lys115 120 125Ile Ala Asp Tyr Tyr Tyr Glu Glu Arg Thr Cys Ile Leu Arg Cys Val130 135 140Leu His Leu Leu Thr Tyr Phe Gln Asp Glu Arg His Pro Tyr Arg Val145 150 155 160Glu Tyr Ala Asp Cys Val Asp Lys Leu Glu Lys Glu Leu Val Ser Lys165 170 175Tyr Arg Gln Gln Phe Glu Glu Leu Tyr Lys Thr Glu Ala Pro Thr Trp180 185 190Glu Thr His Gly Asn Leu Met Thr Glu Arg Gln Val Ser Arg Trp Phe195 200 205Val Gln Cys Leu Arg Glu Gln Ser Met Leu Leu Glu Ile Ile Phe Leu210 215 220Tyr Tyr Ala Tyr Phe Glu Met Ala Pro Ser Asp Leu Leu Val Leu Thr225 230 235 240Lys Met Phe Lys Glu Gln Gly Phe Gly Ser Arg Gln Thr Asn Arg His245 250 255Leu Val Asp Glu Thr Met Asp Pro Phe Val Asp Arg Ile Gly Tyr Phe260 265 270Ser Ala Leu Ile Leu Val Glu Gly Met Asp Ile Glu Ser Leu His Lys275 280 285Cys Ala Leu Asp Asp Arg Arg Glu Leu His Gln Phe Ala Gln Asp Gly290 295 300Leu Ile Cys Gln Asp Met Asp Cys Leu Met Leu Thr Phe Gly Asp Ile305 310 315 320Pro His His Ala Pro Val Leu Leu Ala Trp Ala Leu Leu Arg His Thr325 330 335Leu Asn Pro Glu Glu Thr Ser Ser Val Val Arg Lys Ile Gly Gly Thr
340 345 350Ala Ile Gln Leu Asn Val Phe Gln Tyr Leu Thr Arg Leu Leu Gln Ser355 360 365Leu Ala Ser Gly Gly Asn Asp Cys Thr Thr Ser Thr Ala Cys Met Cys370 375 380Val Tyr Gly Leu Leu Ser Phe Val Leu Thr Ser Leu Glu Leu His Thr385 390 395 400Leu Gly Asn Gln Gln Asp Ile Ile Asp Thr Ala Cys Glu Val Leu Ala405 410 415Asp Pro Ser Leu Pro Glu Leu Phe Trp Gly Thr Glu Pro Thr Ser Gly420 425 430Leu Gly Ile Ile Leu Asp Ser Val Cys Gly Met Phe Pro His Leu Leu435 440 445Ser Pro Leu Leu Gln Leu Leu Arg Ala Leu Val Ser Gly Lys Ser Thr450 455 460Ala Lys Lys Val Tyr Ser Phe Leu Asp Lys Met Ser Phe Tyr Asn Glu465 470 475 480Leu Tyr Lys His Lys Pro His Asp Val Ile Ser His Glu Asp Gly Thr485 490 495Leu Trp Arg Arg Gln Thr Pro Lys Leu Leu Tyr Pro Leu Gly Gly Gln500 505 510Thr Asn Leu Arg Ile Pro Gln Gly Thr Val Gly Gln Val Met Leu Asp515 520 525Asp Arg Ala Tyr Leu Val Arg Trp Glu Tyr Ser Tyr Ser Ser Trp Thr530 535 540Leu Phe Thr Cys Glu Ile Glu Met Leu Leu His Val Val Ser Thr Ala545 550 555 560Asp Val Ile Gln His Cys Gln Arg Val Lys Pro Ile Ile Asp Leu Val565 570 575
His Lys Val Ile Ser Thr Asp Leu Ser Ile Ala Asp Cys Leu Leu Pro580 585 590Ile Thr Ser Arg Ile Tyr Met Leu Leu Gln Arg Leu Thr Thr Val Ile595 600 605Ser Pro Pro Val Asp Val Ile Ala Ser Cys Val Asn Cys Leu Thr Val610 615 620Leu Ala Ala Arg Asn Pro Ala Lys Val Trp Thr Asp Leu Arg His Thr625 630 635 640Gly Phe Leu Pro Phe Val Ala His Pro Val Ser Ser Leu Ser Gln Met645 650 655Ile Ser Ala Glu Gly Met Asn Ala Gly Gly Tyr Gly Asn Leu Leu Met660 665 670Asn Ser Glu Gln Pro Gln Gly Glu Tyr Gly Val Thr Ile Ala Phe Leu675 680 685Arg Leu Ile Thr Thr Leu Val Lys Gly Gln Leu Gly Ser Thr Gln Ser690 695 700Gln Gly Leu Val Pro Cys Val Met Phe Val Leu Lys Glu Met Leu Pro705 710 715 720Ser Tyr His Lys Trp Arg Tyr Asn Ser His Gly Val Arg Glu Gln Ile725 730 735Gly Cys Leu Ile Leu Glu Leu Ile His Ala Ile Leu Asn Leu Cys His740 745 750Glu Thr Asp Leu His Ser Ser His Thr Pro Ser Leu Gln Phe Leu Cys755 760 765Ile Cys Ser Leu Ala Tyr Thr Glu Ala Gly Gln Thr Val Ile Asn Ile770 775 780Met Gly Ile Gly Val Asp Thr Ile Asp Met Val Met Ala Ala Gln Pro785 790 795 800Arg Ser Asp Gly Ala Glu Gly Gln Gly Gln Gly Gln Leu Leu Ile Lys805 810 815
Thr Val Lys Leu Ala Phe Ser Val Thr Asn Asn Val Ile Arg Leu Lys820 825 830Pro Pro Ser Asn Val Val Ser Pro Leu Glu Gln Ala Leu Ser Gln His835 840 845Gly Ala His Gly Asn Asn Leu Ile Ala Val Leu Ala Lys Tyr Ile Tyr850 855 860His Lys His Asp Pro Ala Leu Pro Arg Leu Ala Ile Gln Leu Leu Lys865 870 875 880Arg Leu Ala Thr Val Ala Pro Met Ser Val Tyr Ala Cys Leu Gly Asn885 890 895Asp Ala Ala Ala Ile Arg Asp Ala Phe Leu Thr Arg Leu Gln Ser Lys900 905 910Ile Glu Asp Met Arg Ile Lys Val Met Ile Leu Glu Phe Leu Thr Val915 920 925Ala Val Glu Thr Gln Pro Gly Leu Ile Glu Leu Phe Leu Asn Leu Glu930 935 940Val Lys Asp Gly Ser Asp Gly Ser Lys Glu Phe Ser Leu Gly Met Trp945 950 955 960Ser Cys Leu His Ala Val Leu Glu Leu Ile Asp Ser Gln Gln Gln Asp965 970 975Arg Tyr Trp Cys Pro Pro Leu Leu His Arg Ala Ala Ile Ala Phe Leu980 985 990His Ala Leu Trp Gln Asp Arg Arg Asp Ser Ala Met Leu Val Leu Arg99510001005Thr Lys Pro Lys Phe Trp Glu Asn Leu Thr Ser Pro Leu Phe Gly Thr101010151020Leu Ser Pro Pro Ser Glu Thr Ser Glu Pro Ser Ile Leu Glu Thr Cys1025 103010351040Ala Leu Ile Met Lys Ile Ile Cys Leu Glu Ile Tyr Tyr Val Val Lys
104510501055Gly Ser Leu Asp Gln Ser Leu Lys Asp Thr Leu Lys Lys Phe Ser Ile106010651070Glu Lys Arg Phe Ala Tyr Trp Ser Gly Tyr Val Lys Ser Leu Ala Val107510801085His Val Ala Glu Thr Glu Gly Ser Ser Cys Thr Ser Leu Leu Glu Tyr109010951100Gln Met Leu Val Ser Ala Trp Arg Met Leu Leu Ile Ile Ala Thr Thr1105 111011151120His Ala Asp Ile Met His Leu Thr Asp Ser Val Val Arg Arg Gln Leu112511301135Phe Leu Asp Val Leu Asp Gly Thr Lys Ala Leu Leu Leu Val Pro Ser114011451150Ser Val Asn Cys Leu Arg Leu Gly Ser Met Lys Cys Thr Leu Leu Leu115511601165Ile Leu Leu Arg Gln Trp Lys Arg Glu Leu Gly Ser Val Asp Glu Ile117011751180Leu Gly Pro Leu Thr Glu Ile Leu Glu Gly Val Leu Gln Ala Asp Gln1185 119011951200Gln Leu Met Glu Lys Thr Lys Ala Lys Val Phe Ser Ala Phe Ile Thr120512101215Val Leu Gln Met Lys Glu Met Lys Val Ser Asp Ile Pro Gln Tyr Ser122012251230Gln Leu Val Leu Asn Val Cys Glu Thr Leu Gln Glu Glu Val Ile Ala123512401245Leu Phe Asp Gln Thr Arg His Ser Leu Ala Leu Gly Ser Ala Thr Glu125012551260Asp Lys Asp Ser Met Glu Thr Asp Asp Cys Ser Arg Ser Arg His Arg1265 127012751280
Asp Gln Arg Asp Gly Val Cys Val Leu Gly Leu His Leu Ala Lys Glu128512901295Leu Cys Glu Val Asp Glu Asp Gly Asp Ser Trp Leu Gln Val Thr Arg130013051310Arg Leu Pro Ile Leu Pro Thr Leu Leu Thr Thr Leu Glu Val Ser Leu131513201325Arg Met Lys Gln Asn Leu His Phe Thr Glu Ala Thr Leu His Leu Leu133013351340Leu Thr Leu Ala Arg Thr Gln Gln Gly Ala Thr Ala Val Ala Gly Ala1345 135013551360Gly Ile Thr Gln Ser Ile Cys Leu Pro Leu Leu Ser Val Tyr Gln Leu136513701375Ser Thr Asn Gly Thr Ala Gln Thr Pro Ser Ala Ser Arg Lys Ser Leu138013851390Asp Ala Pro Ser Trp Pro Gly Val Tyr Arg Leu Ser Met Ser Leu Met139514001405Glu Gln Leu Leu Lys Thr Leu Arg Tyr Asn Phe Leu Pro Glu Ala Leu141014151420Asp Phe Val Gly Val His Gln Glu Arg Thr Leu Gln Cys Leu Asn Ala1425 143014351440Val Arg Thr Val Gln Ser Leu Ala Cys Leu Glu Glu Ala Asp His Thr144514501455Val Gly Phe Ile Leu Gln Leu Ser Asn Phe Met Lys Glu Trp His Phe146014651470His Leu Pro Gln Leu Met Arg Asp Ile Gln Val Asn Leu Gly Tyr Leu147514801485Cys Gln Ala Cys Thr Ser Leu Leu His Ser Arg Lys Met Leu Gln His149014951500Tyr Leu Gln Asn Lys Asn Gly Asp Gly Leu Pro Ser Ala Val Ala Gln1505 151015151520
Arg Val Gln Arg Pro Pro Ser Ala Ala Ser Ala Ala Pro Ser Ser Ser152515301535Lys Gln Pro Ala Ala Gln Thr Glu Ala Ser Glu Gln Gln Ala Leu His154015451550Thr Val Gln Tyr Gly Leu Leu Lys Ile Leu Ser Lys Thr Leu Ala Ala155515601565Leu Arg His Phe Thr Pro Asp Val Cys Gln Ile Leu Leu Asp Gln Ser157015751580Leu Asp Leu Ala Glu Tyr Asn Phe Leu Phe Ala Leu Ser Phe Thr Thr1585 159015951600Pro Thr Phe Asp Ser Glu Val Ala Pro Ser Phe Gly Thr Leu Leu Ala160516101615Thr Val Asn Val Ala Leu Asn Met Leu Gly Glu Leu Asp Lys Lys Lys162016251630Glu Pro Leu Thr Gln Ala ValGly Leu Ser Thr Gln Ala Glu Gly Thr163516401645Arg Thr Leu Lys Ser Leu Leu Met Phe Thr Met Glu Asn Cys Phe Tyr165016551660Leu Leu Ile Ser Gln Ala Met Arg Tyr Leu Arg Asp Pro Ala Val His1665 167016751680Pro Arg Asp Lys Gln Arg Met Lys Gln Glu Leu Ser Ser Glu Leu Ser168516901695Thr Leu Leu Ser Ser Leu Ser Arg Tyr Phe Arg Arg Gly Ala Pro Ser170017051710Ser Pro Ala Thr Gly Val Leu Pro Ser Pro Gln Gly Lys Ser Thr Ser171517201725Leu Ser Lys Ala Ser Pro Glu Ser Gln Glu Pro Leu Ile Gln Leu Val1730 17351740Gln Ala Phe Val Arg His Met Gln Arg
1745 1750<210>19<211>1753<212>PRT<213>人<400>19Met Ile Arg Lys Ser Lys Ile Thr Ser Val Leu Ser Phe Cys Arg Ser1 5 10 15Ser Arg Glu Leu Trp Thr Ile Leu Leu Gly Arg Ser Ala Leu Arg Glu20 25 30Leu Ser Gln Ile Glu Ala Glu Leu Asn Lys His Trp Arg Arg Leu Leu35 40 45Glu Gly Leu Ser Tyr Tyr Lys Pro Pro Ser Pro Ser Ser Ala Glu Lys50 55 60Val Lys Ala Asn Lys Asp Val Ala Ser Pro Leu Lys Glu Leu Gly Leu65 70 75 80Arg Ile Ser Lys Phe Leu Gly Leu Asp Glu Glu Gln Ser Val Gln Leu85 90 95Leu Gln Cys Tyr Leu Gln Glu Asp Tyr Arg Gly Thr Arg Asp Ser Val100 105 110Lys Thr Val Leu Gln Asp Glu Arg Gln Ser Gln Ala Leu Ile Leu Lys115 120 125Ile Ala Asp Tyr Tyr Tyr Glu Glu Arg Thr Cys Ile Leu Arg Cys Val130 135 140Leu His Leu Leu Thr Tyr Phe Gln Asp Glu Arg His Pro Tyr Arg Val145 150 155 160Glu Tyr Ala Asp Cys Val Asp Lys Leu Glu Lys Glu Leu Val Ser Lys165 170 175Tyr Arg Gln Gln Phe Glu Glu Leu Tyr Lys Thr Glu Ala Pro Thr Trp180 185 190
Glu Thr His Gly Asn Leu Met Thr Glu Arg Gln Val Ser Arg Trp Phe195 200 205Val Gln Cys Leu Arg Glu Gln Ser Met Leu Leu Glu Ile Ile Phe Leu210 215 220Tyr Tyr Ala Tyr Phe Glu Met Ala Pro Ser Asp Leu Leu Val Leu Thr225 230 235 240Lys Met Phe Lys Glu Gln Gly Phe Gly Ser Arg Gln Thr Asn Arg His245 250 255Leu Val Asp Glu Thr Met Asp Pro Phe Val Asp Arg Ile Gly Tyr Phe260 265 270Ser Ala Leu Ile Leu Val Glu Gly Met Asp Ile Glu Ser Leu His Lys275 280 285Cys Ala Leu Asp Asp Arg Arg Glu Leu His Gln Phe Ala Gln Asp Gly290 295 300Leu Ile Cys Gln Asp Met Asp Cys Leu Met Leu Thr Phe Gly Asp Ile305 310 315 320Pro His His Ala Pro Val Leu Leu Ala Trp Ala Leu Leu Arg His Thr325 330 335Leu Asn Pro Glu Glu Thr Ser Ser Val Val Arg Lys Ile Gly Gly Thr340 345 350Ala Ile Gln Leu Asn Val Phe Gln Tyr Leu Thr Arg Leu Leu Gln Ser355 360 365Leu Ala Ser Gly Gly Asn Asp Cys Thr Thr Ser Thr Ala Cys Met Cys370 375 380Val Tyr Gly Leu Leu Ser Phe Val Leu Thr Ser Leu Glu Leu His Thr385 390 395 400Leu Gly Asn Gln Gln Asp Ile Ile Asp Thr Ala Cys Glu Val Leu Ala405 410 415Asp Pro Ser Leu Pro Glu Leu Phe Trp Gly Thr Glu Pro Thr Ser Gly
420 425 430Leu Gly Ile Ile Leu Asp Ser Val Cys Gly Met Phe Pro His Leu Leu435 440 445Ser Pro Leu Leu Gln Leu Leu Arg Ala Leu Val Ser Gly Lys Ser Thr450 455 460Ala Lys Lys Val Tyr Ser Phe Leu Asp Lys Met Ser Phe Tyr Asn Glu465 470 475 480Leu Tyr Lys His Lys Pro His Asp Val Ile Ser His Glu Asp Gly Thr485 490 495Leu Trp Arg Arg Gln Thr Pro Lys Leu Leu Tyr Pro Leu Gly Gly Gln500 505 510Thr Asn Leu Arg Ile Pro Gln Gly Thr ValGly Gln Val Met Leu Asp515 520 525Asp Arg Ala Tyr Leu ValArg Trp Glu Tyr Ser Tyr Ser Ser Trp Thr530 535 540Leu Phe Thr Cys Glu Ile Glu Met Leu Leu His Val Val Ser Thr Ala545 550 555 560Asp Val Ile Gln His Cys Gln Arg Val Lys Pro Ile Ile Asp Leu Val565 570 575His Lys Val Ile Ser Thr Asp Leu Ser Ile Ala Asp Cys Leu Leu Pro580 585 590Ile Thr Ser Arg Ile Tyr Met Leu Leu Gln Arg Leu Thr Thr Val Ile595 600 605Ser Pro Pro Val Asp Val Ile Ala Ser Cys Val Asn Cys Leu Thr Val610 615 620Leu Ala Ala Arg Asn Pro Ala Lys Val Trp Thr Asp Leu Arg His Thr625 630 635 640Gly Phe Leu Pro Phe Val Ala His Pro Val Ser Ser Leu Ser Gln Met645 650 655
Ile Ser Ala Glu Gly Met Asn Ala Gly Gly Tyr Gly Asn Leu Leu Met660 665 670Asn Ser Glu Gln Pro Gln Gly Glu Tyr Gly Val Thr Ile Ala Phe Leu675 680 685Arg Leu Ile Thr Thr Leu Val Lys Gly Gln Leu Gly Ser Thr Gln Ser690 695 700Gln Gly Leu Val Pro Cys Val Met Phe Val Leu Lys Glu Met Leu Pro705 710 715 720Ser Tyr His Lys Trp Arg Tyr Asn Ser His Gly Val Arg Glu Gln Ile725 730 735Gly Cys Leu Ile Leu Glu Leu Ile His Ala Ile Leu Asn Leu Cys His740 745 750Glu Thr Asp Leu His Ser Ser His Thr Pro Ser Leu Gln Phe Leu Cys755 760 765Ile Cys Ser Leu Ala Tyr Thr Glu Ala Gly Gln Thr Val Ile Asn Ile770 775 780Met Gly Ile Gly Val Asp Thr Ile Asp Met Val Met Ala Ala Gln Pro785 790 795 800Arg Ser Asp Gly Ala Glu Gly Gln Gly Gln Gly Gln Leu Leu Ile Lys805 810 815Thr Val Lys Leu Ala Phe Ser Val Thr Asn Asn Val Ile Arg Leu Lys820 825 830Pro Pro Ser Asn Val Val Ser Pro Leu Glu Gln Ala Leu Ser Gln His835 840 845Gly Ala His Gly Asn Asn Leu Ile Ala Val Leu Ala Lys Tyr Ile Tyr850 855 860His Lys His Asp Pro Ala Leu Pro Arg Leu Ala Ile Gln Leu Leu Lys865 870 875 880Arg Leu Ala Thr Val Ala Pro Met Ser Val Tyr Ala Cys Leu Gly Asn885 890 895
Asp Ala Ala Ala Ile Arg Asp Ala Phe Leu Thr Arg Leu Gln Ser Lys900 905 910Ile Glu Asp Met Arg Ile Lys Val Met Ile Leu Glu Phe Leu Thr Val915 920 925Ala Val Glu Thr Gln Pro Gly Leu Ile Glu Leu Phe Leu Asn Leu Glu930 935 940Val Lys Asp Gly Ser Asp Gly Ser Lys Glu Phe Ser Leu Gly Met Trp945 950 955 960Ser Cys Leu His Ala Val Leu Glu Leu Ile Asp Ser Gln Gln Gln Asp965 970 975Arg Tyr Trp Cys Pro Pro Leu Leu His Arg Ala Ala Ile Ala Phe Leu980 985 990His Ala Leu Trp Gln Asp Arg Arg Asp Ser Ala Met Leu Val Leu Arg99510001005Thr Lys Pro Lys Phe Trp Glu Asn Leu Thr Ser Pro Leu Phe Gly Thr101010151020Leu Ser Pro Pro Ser Glu Thr Ser Glu Pro Ser Ile Leu Glu Thr Cys1025 103010351040Ala Leu Ile Met Lys Ile Ile Cys Leu Glu Ile Tyr Tyr Val Val Lys104510501055Gly Ser Leu Asp Gln Ser Leu Lys Asp Thr Leu Lys Lys Phe Ser Ile106010651070Glu Lys Arg Phe Ala Tyr Trp Ser Gly Tyr Val Lys Ser Leu Ala Val107510801085His Val Ala Glu Thr Glu Gly Ser Ser Cys Thr Ser Leu Leu Glu Tyr109010951100Gln Met Leu Val Ser Ala Trp Arg Met Leu Leu Ile Ile Ala Thr Thr1105 111011151120His Ala Asp Ile Met His Leu Thr Asp Ser Val Val Arg Arg Gln Leu
112511301135Phe Leu Asp Val Leu Asp Gly Thr Lys Ala Leu Leu Leu Val Pro Ser114011451150Ser Val Asn Cys Leu Arg Leu Gly Ser Met Lys Cys Thr Leu Leu Leu115511601165Ile Leu Leu Arg Gln Trp Lys Arg Glu Leu Gly Ser Val Asp Glu Ile117011751180Leu Gly Pro Leu Thr Glu Ile Leu Glu Gly Val Leu Gln Ala Asp Gln1185 119011951200Gln Leu Met Glu Lys Thr Lys Ala Lys Val Phe Ser Ala Phe Ile Thr120512101215Val Leu Gln Met Lys Glu Met Lys Val Ser Asp Ile Pro Gln Tyr Ser122012251230Gln Leu Val Leu Asn Val Cys Glu Thr Leu Gln Glu Glu Val Ile Ala123512401245Leu Phe Asp Gln Thr Arg His Ser Leu Ala Leu Gly Ser Ala Thr Glu125012551260Asp Lys Asp Ser Met Glu Thr Asp Asp Cys Ser Arg Ser Arg His Arg1265 127012751280Asp Gln Arg Asp Gly Val Cys Val Leu Gly Leu His Leu Ala Lys Glu128512901295Leu Cys Glu Val Asp Glu Asp Gly Asp Ser Trp Leu Gln Val Thr Arg130013051310Arg Leu Pro Ile Leu Pro Thr Leu Leu Thr Thr Leu Glu Val Ser Leu131513201325Arg Met Lys Gln Asn Leu His Phe Thr Glu Ala Thr Leu His Leu Leu133013351340Leu Thr Leu Ala Arg Thr Gln Gln Gly Ala Thr Ala Val Ala Gly Ala1345 135013551360
Gly Ile Thr Gln Ser Ile Cys Leu Pro Leu Leu Ser Val Tyr Gln Leu136513701375Ser Thr Asn Gly Thr Ala Gln Thr Pro Ser Ala Ser Arg Lys Ser Leu138013851390Asp Ala Pro Ser Trp Pro Gly Val Tyr Arg Leu Ser Met Ser Leu Met139514001405Glu Gln Leu Leu Lys Thr Leu Arg Tyr Asn Phe Leu Pro Glu Ala Leu141014151420Asp Phe Val Gly Val His Gln Glu Arg Thr Leu Gln Cys Leu Asn Ala1425 143014351440Val Arg Thr Val Gln Ser Leu Ala Cys Leu Glu Glu Ala Asp His Thr144514501455ValGly Phe Ile Leu Gln Leu Ser Asn Phe Met Lys Glu Trp His Phe146014651470His Leu Pro Gln Leu Met Arg Asp Ile Gln Val Asn Leu Gly Tyr Leu147514801485Cys Gln Ala Cys Thr Ser Leu Leu His Ser Arg Lys Met Leu Gln His149014951500Tyr Leu Gln Asn Lys Asn Gly Asp Gly Leu Pro Ser Ala Val Ala Gln1505 151015151520Arg Val Gln Arg Pro Pro Ser Ala Ala Ser Ala Ala Pro Ser Ser Ser152515301535Lys Gln Pro Ala Ala Gln Thr Glu Ala Ser Glu Gln Gln Ala Leu His154015451550Thr Val Gln Tyr Gly Leu Leu Lys Ile Leu Ser Lys Thr Leu Ala Ala155515601565Leu Arg His Phe Thr Pro Asp Val Cys Gln Ile Leu Leu Asp Gln Ser157015751580Leu Asp Leu Ala Glu Tyr Asn Phe Leu Phe Ala Leu Ser Phe Thr Thr1585 159015951600
Pro Thr Phe Asp Ser Glu Val Ala Pro Ser Phe Gly Thr Leu Leu Ala1605 1610 1615Thr Val Asn Val Ala Leu Asn Met Leu Gly Glu Leu Asp Lys Lys Lys1620 1625 1630Glu Pro Leu Thr Gln Ala ValGly Leu Ser Thr Gln Ala Glu Gly Thr1635 1640 1645Arg Thr Leu Lys Ser Leu Leu Met Phe Thr Met Glu Asn Cys Phe Tyr1650 1655 1660Leu Leu Ile Ser Gln Ala Met Arg Tyr Leu Arg Asp Pro Ala Val His1665 1670 1675 1680Pro Arg Asp Lys Gln Arg Met Lys Gln Glu Leu Ser Ser Glu Leu Ser1685 1690 1695Thr Leu Leu Ser Ser Leu Ser Arg Tyr His Arg Arg Gly Ala Pro Ser1700 1705 1710Ser Pro Ala Thr Gly Val Leu Pro Ser Pro Gln Gly Lys Ser Thr Ser1715 1720 1725Leu Ser Lys Ala Ser Pro Glu Ser Gln Glu Pro Leu Ile Gln Leu Val1730 1735 1740Gln Ala Phe Val Arg His Met Gln Arg1745 1750<210>20<211>14<212>PRT<213>人<400>20Met Ile Arg Lys Ser Lys Ile Thr Ser Val Leu Ser Phe Cys1 5 10<210>21<211>1745
<212>PRT<213>人<400>21Ala Gly Gly Pro Cys Val Arg Ser Ser Arg Glu Leu Trp Thr Ile Leu1 5 10 15Leu Gly Arg Ser Ala Leu Arg Glu Leu Ser Gln Ile Glu Ala Glu Leu20 25 30Asn Lys His Trp Arg Arg Leu Leu Glu Gly Leu Ser Tyr Tyr Lys Pro35 40 45Pro Ser Pro Ser Ser Ala Glu Lys Val Lys Ala Asn Lys Asp Val Ala50 55 60Ser Pro Leu Lys Glu Leu Gly Leu Arg Ile Ser Lys Phe Leu Gly Leu65 70 75 80Asp Glu Glu Gln Ser Val Gln Leu Leu Gln Cys Tyr Leu Gln Glu Asp85 90 95Tyr Arg Gly Thr Arg Asp Ser Val Lys Thr Val Leu Gln Asp Glu Arg100 105 110Gln Ser Gln Ala Leu Ile Leu Lys Ile Ala Asp Tyr Tyr Tyr Glu Glu115 120 125Arg Thr Cys Ile Leu Arg Cys Val Leu His Leu Leu Thr Tyr Phe Gln130 135 140Asp Glu Arg His Pro Tyr Arg Val Glu Tyr Ala Asp Cys Val Asp Lys145 150 155 160Leu Glu Lys Glu Leu Val Ser Lys Tyr Arg Gln Gln Phe Glu Glu Leu165 170 175Tyr Lys Thr Glu Ala Pro Thr Trp Glu Thr His Gly Asn Leu Met Thr180 185 190Glu Arg Gln Val Ser Arg Trp Phe Val Gln Cys Leu Arg Glu Gln Ser195 200 205Met Leu Leu Glu Ile Ile Phe Leu Tyr Tyr Ala Tyr Phe Glu Met Ala
210 215 220Pro Ser Asp Leu Leu Val Leu Thr Lys Met Phe Lys Glu Gln Gly Phe225 230 235 240Gly Ser Arg Gln Thr Asn Arg His Leu Val Asp Glu Thr Met Asp Pro245 250 255Phe Val Asp Arg Ile Gly Tyr Phe Ser Ala Leu Ile Leu Val Glu Gly260 265 270Met Asp Ile Glu Ser Leu His Lys Cys Ala Leu Asp Asp Arg Arg Glu275 280 285Leu His Gln Phe Ala Gln Asp Gly Leu Ile Cys Gln Asp Met Asp Cys290 295 300Leu Met Leu Thr Phe Gly Asp Ile Pro His His Ala Pro Val Leu Leu305 310 315 320Ala Trp Ala Leu Leu Arg His Thr Leu Asn Pro Glu Glu Thr Ser Ser325 330 335Val Val Arg Lys Ile Gly Gly Thr Ala Ile Gln Leu Asn Val Phe Gln340 345 350Tyr Leu Thr Arg Leu Leu Gln Ser Leu Ala Ser Gly Gly Asn Asp Cys355 360 365Thr Thr Ser Thr Ala Cys Met Cys Val Tyr Gly Leu Leu Ser Phe Val370 375 380Leu Thr Ser Leu Glu Leu His Thr Leu Gly Asn Gln Gln Asp Ile Ile385 390 395 400Asp Thr Ala Cys Glu Val Leu Ala Asp Pro Ser Leu Pro Glu Leu Phe405 410 415Trp Gly Thr Glu Pro Thr Ser Gly Leu Gly Ile Ile Leu Asp Ser Val420 425 430Cys Gly Met Phe Pro His Leu Leu Ser Pro Leu Leu Gln Leu Leu Arg435 440 445
Ala Leu Val Ser Gly Lys Ser Thr Ala Lys Lys Val Tyr Ser Phe Leu450 455 460Asp Lys Met Ser Phe Tyr Asn Glu Leu Tyr Lys His Lys Pro His Asp465 470 475 480Val Ile Ser His Glu Asp Gly Thr Leu Trp Arg Arg Gln Thr Pro Lys485 490 495Leu Leu Tyr Pro Leu Gly Gly Gln Thr Asn Leu Arg Ile Pro Gln Gly500 505 510Thr Val Gly Gln Val Met Leu Asp Asp Arg Ala Tyr Leu Val Arg Trp515 520 525Glu Tyr Ser Tyr Ser Ser Trp Thr Leu Phe Thr Cys Glu Ile Glu Met530 535 540Leu Leu His Val Val Ser Thr Ala Asp Val Ile Gln His Cys Gln Arg545 550 555 560Val Lys Pro Ile Ile Asp Leu Val His Lys Val Ile Ser Thr Asp Leu565 570 575Ser Ile Ala Asp Cys Leu Leu Pro Ile Thr Ser Arg Ile Tyr Met Leu580 585 590Leu Gln Arg Leu Thr Thr Val Ile Ser Pro Pro Val Asp Val Ile Ala595 600 605Ser Cys Val Asn Cys Leu Thr Val Leu Ala Ala Arg Asn Pro Ala Lys610 615 620Val Trp Thr Asp Leu Arg His Thr Gly Phe Leu Pro Phe Val Ala His625 630 635 640Pro Val Ser Ser Leu Ser Gln Met Ile Ser Ala Glu Gly Met Asn Ala645 650 655Gly Gly Tyr Gly Asn Leu Leu Met Asn Ser Glu Gln Pro Gln Gly Glu660 665 670Tyr Gly Val Thr Ile Ala Phe Leu Arg Leu Ile Thr Thr Leu Val Lys675 680 685
Gly Gln Leu Gly Ser Thr Gln Ser Gln Gly Leu Val Pro Cys Val Met690 695 700Phe Val Leu Lys Glu Met Leu Pro Ser Tyr His Lys Trp Arg Tyr Asn705 710 715 720Ser His Gly Val Arg Glu Gln Ile Gly Cys Leu Ile Leu Glu Leu Ile725 730 735His Ala Ile Leu Asn Leu Cys His Glu Thr Asp Leu His Ser Ser His740 745 750Thr Pro Ser Leu Gln Phe Leu Cys Ile Cys Ser Leu Ala Tyr Thr Glu755 760 765Ala Gly Gln Thr Val Ile Asn Ile Met Gly Ile Gly Val Asp Thr Ile770 775 780Asp Met Val Met Ala Ala Gln Pro Arg Ser Asp Gly Ala Glu Gly Gln785 790 795 800Gly Gln Gly Gln Leu Leu Ile Lys Thr Val Lys Leu Ala Phe Ser Val805 810 815Thr Asn Asn Val Ile Arg Leu Lys Pro Pro Ser Asn Val Val Ser Pro820 825 830Leu Glu Gln Ala Leu Ser Gln His Gly Ala His Gly Asn Asn Leu Ile835 840 845Ala Val Leu Ala Lys Tyr Ile Tyr His Lys His Asp Pro Ala Leu Pro850 855 860Arg Leu Ala Ile Gln Leu Leu Lys Arg Leu Ala Thr Val Ala Pro Met865 870 875 880Ser Val Tyr Ala Cys Leu Gly Asn Asp Ala Ala Ala Ile Arg Asp Ala885 890 895Phe Leu Thr Arg Leu Gln Ser Lys Ile Glu Asp Met Arg Ile Lys Val900 905 910Met Ile Leu Glu Phe Leu Thr Val Ala Val Glu Thr Gln Pro Gly Leu
915 920 925Ile Glu Leu Phe Leu Asn Leu Glu Val Lys Asp Gly Ser Asp Gly Ser930 935 940Lys Glu Phe Ser Leu Gly Met Trp Ser Cys Leu His Ala Val Leu Glu945 950 955 960Leu Ile Asp Ser Gln Gln Gln Asp Arg Tyr Trp Cys Pro Pro Leu Leu965 970 975His Arg Ala Ala Ile Ala Phe Leu His Ala Leu Trp Gln Asp Arg Arg980 985 990Asp Ser Ala Met Leu Val Leu Arg Thr Lys Pro Lys Phe Trp Glu Asn99510001005Leu Thr Ser Pro Leu Phe Gly Thr Leu Ser Pro Pro Ser Glu Thr Ser101010151020Glu Pro Ser Ile Leu Glu Thr Cys Ala Leu Ile Met Lys Ile Ile Cys1025 103010351040Leu Glu Ile Tyr Tyr Val Val Lys Gly Ser Leu Asp Gln Ser Leu Lys104510501055Asp Thr Leu Lys Lys Phe Ser Ile Glu Lys Arg Phe Ala Tyr Trp Ser106010651070Gly Tyr Val Lys Ser Leu Ala Val His Val Ala Glu Thr Glu Gly Ser107510801085Ser Cys Thr Ser Leu Leu Glu Tyr Gln Met Leu Val Ser Ala Trp Arg109010951100Met Leu Leu Ile Ile Ala Thr Thr His Ala Asp Ile Met His Leu Thr1105 111011151120Asp Ser Val Val Arg Arg Gln Leu Phe Leu Asp Val Leu Asp Gly Thr112511301135Lys Ala Leu Leu Leu Val Pro Ala Ser Val Asn Cys Leu Arg Leu Gly114011451150
Ser Met Lys Cys Thr Leu Leu Leu Ile Leu Leu Arg Gln Trp Lys Arg115511601165Glu Leu Gly Ser Val Asp Glu Ile Leu Gly Pro Leu Thr Glu Ile Leu117011751180Glu Gly Val Leu Gln Ala Asp Gln Gln Leu Met Glu Lys Thr Lys Ala1185 119011951200Lys Val Phe Ser Ala Phe Ile Thr Val Leu Gln Met Lys Glu Met Lys120512101215Val Ser Asp Ile Pro Gln Tyr Ser Gln Leu Val Leu Asn Val Cys Glu122012251230Thr Leu Gln Glu Glu Val Ile Ala Leu Phe Asp Gln Thr Arg His Ser123512401245Leu Ala Leu Gly Ser Ala Thr Glu Asp Lys Asp Ser Met Glu Thr Asp125012551260Asp Cys Ser Arg Ser Arg His Arg Asp Gln Arg Asp Gly Val Cys Val1265 127012751280Leu Gly Leu His Leu Ala Lys Glu Leu Cys Glu Val Asp Glu Asp Gly128512901295Asp Ser Trp Leu Gln Val Thr Arg Arg Leu Pro Ile Leu Pro Thr Leu130013051310Leu Thr Thr Leu Glu Val Ser Leu Arg Met Lys Gln Asn Leu His Phe131513201325Thr Glu Ala Thr Leu His Leu Leu Leu Thr Leu Ala Arg Thr Gln Gln133013351340Gly Ala Thr Ala Val Ala Gly Ala Gly Ile Thr Gln Ser Ile Cys Leu1345 135013551360Pro Leu Leu Ser Val Tyr Gln Leu Ser Thr Asn Gly Thr Ala Gln Thr136513701375Pro Ser Ala Ser Arg Lys Ser Leu Asp Ala Pro Ser Trp Pro Gly Val138013851390
Tyr Arg Leu Ser Met Ser Leu Met Glu Gln Leu Leu Lys Thr Leu Arg139514001405Tyr Asn Phe Leu Pro Glu Ala Leu Asp Phe Val Gly Val His Gln Glu141014151420Arg Thr Leu Gln Cys Leu Asn Ala Val Arg Thr Val Gln Ser Leu Ala1425 143014351440Cys Leu Glu Glu Ala Asp His Thr Val Gly Phe Ile Leu Gln Leu Ser144514501455Asn Phe Met Lys Glu Trp His Phe His Leu Pro Gln Leu Met Arg Asp146014651470Ile Gln Val Asn Leu Gly Tyr Leu Cys Gln Ala Cys Thr Ser Leu Leu147514801485His Ser Arg Lys Met Leu Gln His Tyr Leu Gln Asn Lys Asn Gly Asp149014951500Gly Leu Pro Ser Ala Val Ala Gln Arg Val Gln Arg Pro Pro Ser Ala1505 151015151520Ala Ser Ala Ala Pro Ser Ser Ser Lys Gln Pro Ala Ala Asp Thr Glu152515301535Ala Ser Glu Gln Gln Ala Leu His Thr Val Gln Tyr Gly Leu Leu Lys154015451550Ile Leu Ser Lys Thr Leu Ala Ala Leu Arg His Phe Thr Pro Asp Val155515601565Cys Gln Ile Leu Leu Asp Gln Ser Leu Asp Leu Ala Glu Tyr Asn Phe157015751580Leu Phe Ala Leu Ser Phe Thr Thr Pro Thr Phe Asp Ser Glu ValAla1585 159015951600Pro Ser Phe Gly Thr Leu Leu Ala Thr Val Asn Val Ala Leu Asn Met160516101615Leu Gly Glu Leu Asp Lys Lys Lys Glu Pro Leu Thr Gln Ala Val Gly
162016251630Leu Ser Thr Gln Ala Glu Gly Thr Arg Thr Leu Lys Ser Leu Leu Met163516401645Phe Thr Met Glu Asn Cys Phe Tyr Leu Leu Ile Ser Gln Ala Met Arg165016551660Tyr Leu Arg Asp Pro Ala Val His Pro Arg Asp Lys Gln Arg Met Lys1665 167016751680Gln Glu Leu Ser Ser Glu Leu Ser Thr Leu Leu Ser Ser Leu Ser Arg168516901695Tyr Phe Arg Arg Gly Ala Pro Ser Ser Pro Ala Thr Gly Val Leu Pro170017051710Ser Pro Gln Gly Lys Ser Thr Ser Leu Ser Lys Ala Ser Pro Glu Ser171517201725Gln Glu Pro Leu Ile Gln Leu Val Gln Ala Phe Val Arg His Met Gln173017351740Arg1745<210>22<211>3534<212>PRT<213>人<400>22Met Ala Ser Gly Gly Gly Val Arg Ala Ser Gly Arg Ala Lys Met Ala1 5 10 15Ala Ala Ala Gly Gly Pro Cys Val Arg Ser Ser Arg Glu Leu Trp Thr20 25 30Ile Leu Leu Gly Arg Ser Ala Leu Arg Glu Leu Ser Gln Ile Glu Ala35 40 45Glu Leu Asn Lys His Trp Arg Arg Leu Leu Glu Gly Leu Ser Tyr Tyr50 55 60
Lys Pro Pro Ser Pro Ser Ser Ala Glu Lys Val Lys Ala Asn Lys Asp65 70 75 80Val Ala Ser Pro Leu Lys Glu Leu Gly Leu Arg Ile Ser Lys Phe Leu85 90 95Gly Leu Asp Glu Glu Gln Ser Val Gln Leu Leu Gln Cys Tyr Leu Gln100 105 110Glu Asp Tyr Arg Gly Thr Arg Asp Ser Val Lys Thr Val Leu Gln Asp115 120 125Glu Arg Gln Ser Gln Ala Leu Ile Leu Lys Ile Ala Asp Tyr Tyr Tyr130 135 140Glu Glu Arg Thr Cys Ile Leu Arg Cys Val Leu His Leu Leu Thr Tyr145 150 155 160Phe Gln Asp Glu Arg His Pro Tyr Arg Val Glu Tyr Ala Asp Cys Val165 170 175Asp Lys Leu Glu Lys Glu Leu Val Ser Lys Tyr Arg Gln Gln Phe Glu180 185 190Glu Leu Tyr Lys Thr Glu Ala Pro Thr Trp Glu Thr His Gly Asn Leu195 200 205Met Thr Glu Arg Gln Val Ser Arg Trp Phe Val Gln Cys Leu Arg Glu210 215 220Gln Ser Met Leu Leu Glu Ile Ile Phe Leu Tyr Tyr Ala Tyr Phe Glu225 230 235 240Met Ala Pro Ser Asp Leu Leu Val Leu Thr Lys Met Phe Lys Glu Gln245 250 255Gly Phe Gly Ser Arg Gln Thr Asn Arg His Leu Val Asp Glu Thr Met260 265 270Asp Pro Phe Val Asp Arg Ile Gly Tyr Phe Ser Ala Leu Ile Leu Val275 280 285Glu Gly Met Asp Ile Glu Ser Leu His Lys Cys Ala Leu Asp Asp Arg
290 295 300Arg Glu Leu His Gln Phe Ala Gln Asp Gly Leu Ile Cys Gln Asp Met305 310 315 320Asp Cys Leu Met Leu Thr Phe Gly Asp Ile Pro His His Ala Pro Val325 330 335Leu Leu Ala Trp Ala Leu Leu Arg His Thr Leu Asn Pro Glu Glu Thr340 345 350Ser Ser Val Val Arg Lys Ile Gly Gly Thr Ala Ile Gln Leu Asn Val355 360 365Phe Gln Tyr Leu Thr Arg Leu Leu Gln Ser Leu Ala Ser Gly Gly Asn370 375 380Asp Cys Thr Thr Ser Thr Ala Cys Met Cys Val Tyr Gly Leu Leu Ser385 390 395 400Phe Val Leu Thr Ser Leu Glu Leu His Thr Leu Gly Asn Gln Gln Asp405 410 415Ile Ile Asp Thr Ala Cys Glu Val Leu Ala Asp Pro Ser Leu Pro Glu420 425 430Leu Phe Trp Gly Thr Glu Pro Thr Ser Gly Leu Gly Ile Ile Leu Asp435 440 445Ser Val Cys Gly Met Phe Pro His Leu Leu Ser Pro Leu Leu Gln Leu450 455 460Leu Arg Ala Leu Val Ser Gly Lys Ser Thr Ala Lys Lys Val Tyr Ser465 470 475 480Phe Leu Asp Lys Met Ser Phe Tyr Asn Glu Leu Tyr Lys His Lys Pro485 490 495His Asp Val Ile Ser His Glu Asp Gly Thr Leu Trp Arg Arg Gln Thr500 505 510Pro Lys Leu Leu Tyr Pro Leu Gly Gly Gln Thr Asn Leu Arg Ile Pro515 520 525
Gln Gly Thr Val Gly Gln Val Met Leu Asp Asp Arg Ala Tyr Leu Val530 535 540Arg Trp Glu Tyr Ser Tyr Ser Ser Trp Thr Leu Phe Thr Cys Glu Ile545 550 555 560Glu Met Leu Leu His Val Val Ser Thr Ala Asp Val Ile Gln His Cys565 570 575Gln Arg Val Lys Pro Ile Ile Asp Leu Val His Lys Val Ile Ser Thr580 585 590Asp Leu Ser Ile Ala Asp Cys Leu Leu Pro Ile Thr Ser Arg Ile Tyr595 600 605Met Leu Leu Gln Arg Leu Thr Thr Val Ile Ser Pro Pro Val Asp Val610 615 620Ile Ala Ser Cys Val Asn Cys Leu Thr Val Leu Ala Ala Arg Asn Pro625 630 635 640Ala Lys Val Trp Thr Asp Leu Arg His Thr Gly Phe Leu Pro Phe Val645 650 655Ala His Pro Val Ser Ser Leu Ser Gln Met Ile Ser Ala Glu Gly Met660 665 670Asn Ala Gly Gly Tyr Gly Asn Leu Leu Met Asn Ser Glu Gln Pro Gln675 680 685Gly Glu Tyr Gly Val Thr Ile Ala Phe Leu Arg Leu Ile Thr Thr Leu690 695 700Val Lys Gly Gln Leu Gly Ser Thr Gln Ser Gln Gly Leu Val Pro Cys705 710 715 720Val Met Phe Val Leu Lys Glu Met Leu Pro Ser Tyr His Lys Trp Arg725 730 735Tyr Asn Ser His Gly Val Arg Glu Gln Ile Gly Cys Leu Ile Leu Glu740 745 750Leu Ile His Ala Ile Leu Asn Leu Cys His Glu Thr Asp Leu His Ser755 760 765
Ser His Thr Pro Ser Leu Gln Phe Leu Cys Ile Cys Ser Leu Ala Tyr770 775 780Thr Glu Ala Gly Gln Thr Val Ile Asn Ile Met Gly Ile Gly Val Asp785 790 795 800Thr Ile Asp Met Val Met Ala Ala Gln Pro Arg Ser Asp Gly Ala Glu805 810 815Gly Gln Gly Gln Gly Gln Leu Leu Ile Lys Thr Val Lys Leu Ala Phe820 825 830Ser Val Thr Asn Asn Val Ile Arg Leu Lys Pro Pro Ser Asn Val Val835 840 845Ser Pro Leu Glu Gln Ala Leu Ser Gln His Gly Ala His Gly Asn Asn850 855 860Leu Ile Ala Val Leu Ala Lys Tyr Ile Tyr His Lys His Asp Pro Ala865 870 875 880Leu Pro Arg Leu Ala Ile Gln Leu Leu Lys Arg Leu Ala Thr Val Ala885 890 895Pro Met Ser Val Tyr Ala Cys Leu Gly Asn Asp Ala Ala Ala Ile Arg900 905 910Asp Ala Phe Leu Thr Arg Leu Gln Ser Lys Ile Glu Asp Met Arg Ile915 920 925Lys Val Met Ile Leu Glu Phe Leu Thr Val Ala Val Glu Thr Gln Pro930 935 940Gly Leu Ile Glu Leu Phe Leu Asn Leu Glu Val Lys Asp Gly Ser Asp945 950 955 960Gly Ser Lys Glu Phe Ser Leu Gly Met Trp Ser Cys Leu His Ala Val965 970 975Leu Glu Leu Ile Asp Ser Gln Gln Gln Asp Arg Tyr Trp Cys Pro Pro980 985 990Leu Leu His Arg Ala Ala Ile Ala Phe Leu His Ala Leu Trp Gln Asp
99510001005Arg Arg Asp Ser Ala Met Leu Val Leu Arg Thr Lys Pro Lys Phe Trp101010151020Glu Asn Leu Thr Ser Pro Leu Phe Gly Thr Leu Ser Pro Pro Ser Glu1025 103010351040Thr Ser Glu Pro Ser Ile Leu Glu Thr Cys Ala Leu Ile Met Lys Ile104510501055Ile Cys Leu Glu Ile Tyr Tyr Val Val Lys Gly Ser Leu Asp Gln Ser106010651070Leu Lys Asp Thr Leu Lys Lys Phe Ser Ile Glu Lys Arg Phe Ala Tyr107510801085Trp Ser Gly Tyr Val Lys Ser Leu Ala Val His Val Ala Glu Thr Glu109010951100Gly Ser Ser Cys Thr Ser Leu Leu Glu Tyr Gln Met Leu Val Ser Ala1105 111011151120Trp Arg Met Leu Leu Ile Ile Ala Thr Thr His Ala Asp Ile Met His112511301135Leu Thr Asp Ser Val Val Arg Arg Gln Leu Phe Leu Asp Val Leu Asp114011451150Gly Thr Lys Ala Leu Leu Leu Val Pro Ala Ser Val Asn Cys Leu Arg115511601165Leu Gly Ser Met Lys Cys Thr Leu Leu Leu Ile Leu Leu Arg Gln Trp117011751180Lys Ser Ile Leu Ser Arg Glu Leu Gly Ser Val Asp Glu Ile Leu Gly1185 119011951200Pro Leu Thr Glu Ile Leu Glu Gly Val Leu Gln Ala Asp Gln Gln Leu120512101215Met Glu Lys Thr Lys Ala Lys Val Phe Ser Ala Phe Ile Thr Val Leu122012251230
Gln Met Lys Glu Met Lys Val Ser Asp Ile Pro Gln Tyr Ser Gln Leu123512401245Val Leu Asn Val Cys Glu Thr Leu Gln Glu Glu Val Ile Ala Leu Phe125012551260Asp Gln Thr Arg His Ser Leu Ala Leu Gly Ser Ala Thr Glu Asp Lys1265 127012751280Asp Ser Met Glu Thr Asp Asp Cys Ser Arg Ser Arg His Arg Asp Gln128512901295Arg Asp Gly Val Cys Val Leu Gly Leu His Leu Ala Lys Glu Leu Cys130013051310Glu Val Asp Glu Asp Gly Asp Ser Trp Leu Gln Val Thr Arg Arg Leu131513201325Pro Ile Leu Pro Thr Leu Leu Thr Thr Leu Glu Val Ser Leu Arg Met133013351340Lys Gln Asn Leu His Phe Thr Glu Ala Thr Leu His Leu Leu Leu Thr1345 135013551360Leu Ala Arg Thr Gln Gln Gly Ala Thr Ala Val Ala Gly Ala Gly Ile136513701375Thr Gln Ser Ile Cys Leu Pro Leu Leu Ser Val Tyr Gln Leu Ser Thr138013851390Asn Gly Thr Ala Gln Thr Pro Ser Ala Ser Arg Lys Ser Leu Asp Ala139514001405Pro Ser Trp Pro Gly Val Tyr Arg Leu Ser Met Ser Leu Met Glu Gln141014151420Leu Leu Lys Thr Leu Arg Tyr Asn Phe Leu Pro Glu Ala Leu Asp Phe1425 143014351440Val Gly Val His Gln Glu Arg Thr Leu Gln Cys Leu Asn Ala Val Arg144514501455Thr Val Gln Ser Leu Ala Cys Leu Glu Glu Ala Asp His Thr Val Gly146014651470
Phe Ile Leu Gln Leu Ser Asn Phe Met Lys Glu Trp His Phe His Leu147514801485Pro Gln Leu Met Arg Asp Ile Gln Val Asn Leu Gly Tyr Leu Cys Gln149014951500Ala Cys Thr Ser Leu Leu His Ser Arg Lys Met Leu Gln His Tyr Leu1505 151015151520Gln Asn Lys Asn Gly Asp Gly Leu Pro Ser Ala Val Ala Gln Arg Val152515301535Gln Arg Pro Pro Ser Ala Ala Ser Ala Ala Pro Ser Ser Ser Lys Gln154015451550Pro Ala Ala Asp Thr Glu Ala Ser Glu Gln Gln Ala Leu His Thr Val155515601565Gln Tyr Gly Leu Leu Lys Ile Leu Ser Lys Thr Leu Ala Ala Leu Arg157015751580His Phe Thr Pro Asp Val Cys Gln Ile Leu Leu Asp Gln Ser Leu Asp1585159015951600Leu Ala Glu Tyr Asn Phe Leu Phe Ala Leu Ser Phe Thr Thr Pro Thr160516101615Phe Asp Ser Glu Val Ala Pro Ser Phe Gly Thr Leu Leu Ala Thr Val162016251630Asn Val Ala Leu Asn Met Leu Gly Glu Leu Asp Lys Lys Lys Glu Pro163516401645Leu Thr Gln Ala Val Gly Leu Ser Thr Gln Ala Glu Gly Thr Arg Thr165016551660Leu Lys Ser Leu Leu Met Phe Thr Met Glu Asn Cys Phe Tyr Leu Leu1665 167016751680Ile Ser Gln Ala Met Arg Tyr Leu Arg Asp Pro Ala Val His Pro Arg168516901695Asp Lys Gln Arg Met Lys Gln Glu Leu Ser Ser Glu Leu Ser Thr Leu
170017051710Leu Ser Ser Leu Ser Arg Tyr Phe Arg Arg Gly Ala Pro Ser Ser Pro171517201725Ala Thr Gly Val Leu Pro Ser Pro Gln Gly Lys Ser Thr Ser Leu Ser173017351740Lys Ala Ser Pro Glu Ser Gln Glu Pro Leu Ile Gln Leu Val Gln Ala1745 175017551760Phe Val Arg His Met Gln Arg Met Ala Ser Gly Gly Gly Val Arg Ala176517701775Ser Gly Arg Ala Lys Met Ala Ala Ala Ala Gly Gly Pro Cys Val Arg178017851790Ser Ser Arg Glu Leu Trp Thr Ile Leu Leu Gly Arg Ser Ala Leu Arg179518001805Glu Leu Ser Gln Ile Glu Ala Glu Leu Asn Lys His Trp Arg Arg Leu181018151820Leu Glu Gly Leu Ser Tyr Tyr Lys Pro Pro Ser Pro Ser Ser Ala Glu1825 183018351840Lys Val Lys Ala Asn Lys Asp Val Ala Ser Pro Leu Lys Glu Leu Gly184518501855Leu Arg Ile Ser Lys Phe Leu Gly Leu Asp Glu Glu Gln Ser Val Gln186018651870Leu Leu Gln Cys Tyr Leu Gln Glu Asp Tyr Arg Gly Thr Arg Asp Ser187518801885Val Lys Thr Val Leu Gln Asp Glu Arg Gln Ser Gln Ala Leu Ile Leu189018951900Lys Ile Ala Asp Tyr Tyr Tyr Glu Glu Arg Thr Cys Ile Leu Arg Cys1905 191019151920Val Leu His Leu Leu Thr Tyr Phe Gln Asp Glu Arg His Pro Tyr Arg192519301935
Val Glu Tyr Ala Asp Cys Val Asp Lys Leu Glu Lys Glu Leu Val Ser194019451950Lys Tyr Arg Gln Gln Phe Glu Glu Leu Tyr Lys Thr Glu Ala Pro Thr195519601965Trp Glu Thr His Gly Asn Leu Met Thr Glu Arg Gln Val Ser Arg Trp197019751980Phe Val Gln Cys Leu Arg Glu Gln Ser Met Leu Leu Glu Ile Ile Phe1985 199019952000Leu Tyr Tyr Ala Tyr Phe Glu Met Ala Pro Ser Asp Leu Leu Val Leu200520102015Thr Lys Met Phe Lys Glu Gln Gly Phe Gly Ser Arg Gln Thr Asn Arg202020252030His Leu Val Asp Glu Thr Met Asp Pro Phe Val Asp Arg Ile Gly Tyr203520402045Phe Ser Ala Leu Ile Leu Val Glu Gly Met Asp Ile Glu Ser Leu His205020552060Lys Cys Ala Leu Asp Asp Arg Arg Glu Leu His Gln Phe Ala Gln Asp2065 207020752080Gly Leu Ile Cys Gln Asp Met Asp Cys Leu Met Leu Thr Phe Gly Asp208520902095Ile Pro His His Ala Pro Val Leu Leu Ala Trp Ala Leu Leu Arg His210021052110Thr Leu Asn Pro Glu Glu Thr Ser Ser Val Val Arg Lys Ile Gly Gly211521202125Thr Ala Ile Gln Leu Asn Val Phe Gln Tyr Leu Thr Arg Leu Leu Gln213021352140Ser Leu Ala Ser Gly Gly Asn Asp Cys Thr Thr Ser Thr Ala Cys Met2145 215021552160Cys ValTyr Gly Leu Leu Ser Phe Val Leu Thr Ser Leu Glu Leu His216521702175
Thr Leu Gly Asn Gln Gln Asp Ile Ile Asp Thr Ala Cys Glu Val Leu218021852190Ala Asp Pro Ser Leu Pro Glu Leu Phe Trp Gly Thr Glu Pro Thr Ser219522002205Gly Leu Gly Ile Ile Leu Asp Ser Val Cys Gly Met Phe Pro His Leu221022152220Leu Ser Pro Leu Leu Gln Leu Leu Arg Ala Leu Val Ser Gly Lys Ser2225 223022352240Thr Ala Lys Lys Val Tyr Ser Phe Leu Asp Lys Met Ser Phe Tyr Asn224522502255Glu Leu Tyr Lys His Lys Pro His Asp Val Ile Ser His Glu Asp Gly226022652270Thr Leu Trp Arg Arg Gln Thr Pro Lys Leu Leu Tyr Pro Leu Gly Gly227522802285Gln Thr Asn Leu Arg Ile Pro Gln Gly Thr Val Gly Gln Val Met Leu229022952300Asp Asp Arg Ala Tyr Leu Val Arg Trp Glu Tyr Ser Tyr Ser Ser Trp2305 231023152320Thr Leu Phe Thr Cys Glu Ile Glu Met Leu Leu His Val Val Ser Thr232523302335Ala Asp Val Ile Gln His Cys Gln Arg Val Lys Pro Ile Ile Asp Leu234023452350Val His Lys Val Ile Ser Thr Asp Leu Ser Ile Ala Asp Cys Leu Leu235523602365Pro Ile Thr Ser Arg Ile Tyr Met Leu Leu Gln Arg Leu Thr Thr Val237023752380Ile Ser Pro Pro Val Asp Val Ile Ala Ser Cys Val Asn Cys Leu Thr2385 239023952400Val Leu Ala Ala Arg Asn Pro Ala Lys Val Trp Thr Asp Leu Arg His
240524102415Thr Gly Phe Leu Pro Phe Val Ala His Pro Val Ser Ser Leu Ser Gln242024252430Met Ile Ser Ala Glu Gly Met Asn Ala Gly Gly Tyr Gly Asn Leu Leu243524402445Met Asn Ser Glu Gln Pro Gln Gly Glu Tyr Gly Val Thr Ile Ala Phe245024552460Leu Arg Leu Ile Thr Thr Leu Val Lys Gly Gln Leu Gly Ser Thr Gln2465 247024752480Ser Gln Gly Leu Val Pro Cys Val Met Phe Val Leu Lys Glu Met Leu248524902495Pro Ser Tyr His Lys Trp Arg Tyr Asn Ser His Gly Val Arg Glu Gln250025052510Ile Gly Cys Leu Ile Leu Glu Leu Ile His Ala Ile Leu Asn Leu Cys251525202525His Glu Thr Asp Leu His Ser Ser His Thr Pro Ser Leu Gln Phe Leu253025352540Cys Ile Cys Ser Leu Ala Tyr Thr Glu Ala Gly Gln Thr Val Ile Asn2545 255025552560Ile Met Gly Ile Gly Val Asp Thr Ile Asp Met Val Met Ala Ala Gln256525702575Pro Arg Ser Asp Gly Ala Glu Gly Gln Gly Gln Gly Gln Leu Leu Ile258025852590Lys Thr Val Lys Leu Ala Phe Ser Val Thr Asn Asn Val Ile Arg Leu259526002605Lys Pro Pro Ser Asn Val Val Ser Pro Leu Glu Gln Ala Leu Ser Gln261026152620His Gly Ala His Gly Asn Asn Leu Ile Ala Val Leu Ala Lys Tyr Ile2625 263026352640
Tyr His Lys His Asp Pro Ala Leu Pro Arg Leu Ala Ile Gln Leu Leu264526502655Lys Arg Leu Ala Thr Val Ala Pro Met Ser Val Tyr Ala Cys Leu Gly266026652670Asn Asp Ala Ala Ala Ile Arg Asp Ala Phe Leu Thr Arg Leu Gln Ser267526802685Lys Ile Glu Asp Met Arg Ile Lys Val Met Ile Leu Glu Phe Leu Thr269026952700Val Ala Val Glu Thr Gln Pro Gly Leu Ile Glu Leu Phe Leu Asn Leu2705 271027152720Glu Val Lys Asp Gly Ser Asp Gly Ser Lys Glu Phe Ser Leu Gly Met272527302735Trp Ser Cys Leu His Ala Val Leu Glu Leu Ile Asp Ser Gln Gln Gln274027452750Asp Arg Tyr Trp Cys Pro Pro Leu Leu His Arg Ala Ala Ile Ala Phe275527602765Leu His Ala Leu Trp Gln Asp Arg Arg Asp Ser Ala Met Leu Val Leu277027752780Arg Thr Lys Pro Lys Phe Trp Glu Asn Leu Thr Ser Pro Leu Phe Gly2785 279027952800Thr Leu Ser Pro Pro Ser Glu Thr Ser Glu Pro Ser Ile Leu Glu Thr280528102815Cys Ala Leu Ile Met Lys Ile Ile Cys Leu Glu Ile Tyr Tyr Val Val282028252830Lys Gly Ser Leu Asp Gln Ser Leu Lys Asp Thr Leu Lys Lys Phe Ser283528402845Ile Glu Lys Arg Phe Ala Tyr Trp Ser Gly Tyr Val Lys Ser Leu Ala285028552860Val His Val Ala Glu Thr Glu Gly Ser Ser Cys Thr Ser Leu Leu Glu2865 287028752880
Tyr Gln Met Leu Val Ser Ala Trp Arg Met Leu Leu Ile Ile Ala Thr288528902895Thr His Ala Asp Ile Met His Leu Thr Asp Ser Val Val Arg Arg Gln290029052910Leu Phe Leu Asp Val Leu Asp Gly Thr Lys Ala Leu Leu Leu Val Pro291529202925Ala Ser ValAsn Cys Leu Arg Leu Gly Ser Met Lys Cys Thr Leu Leu293029352940Leu Ile Leu Leu Arg Gln Trp Lys Ser Ile Leu Ser Arg Glu Leu Gly2945 295029552960Ser Val Asp Glu Ile Leu Gly Pro Leu Thr Glu Ile Leu Glu Gly Val296529702975Leu Gln Ala Asp Gln Gln Leu Met Glu Lys Thr Lys Ala Lys Val Phe298029852990Ser Ala Phe Ile Thr Val Leu Gln Met Lys Glu Met Lys Val Ser Asp299530003005Ile Pro Gln Tyr Ser Gln Leu Val Leu Asn Val Cys Glu Thr Leu Gln301030153020Glu Glu Val Ile Ala Leu Phe Asp Gln Thr Arg His Ser Leu Ala Leu3025 303030353040Gly Ser Ala Thr Glu Asp Lys Asp Ser Met Glu Thr Asp Asp Cys Ser304530503055Arg Ser Arg His Arg Asp Gln Arg Asp Gly Val Cys Val Leu Gly Leu306030653070His Leu Ala Lys Glu Leu Cys Glu Val Asp Glu Asp Gly Asp Ser Trp307530803085Leu Gln ValThr Arg Arg Leu Pro Ile Leu Pro Thr Leu Leu Thr Thr309030953100Leu Glu Val Ser Leu Arg Met Lys Gln Asn Leu His Phe Thr Glu Ala
3105 311031153120Thr Leu His Leu Leu Leu Thr Leu Ala Arg Thr Gln Gln Gly Ala Thr312531303135Ala Val Ala Gly Ala Gly Ile Thr Gln Ser Ile Cys Leu Pro Leu Leu314031453150Ser Val Tyr Gln Leu Ser Thr Asn Gly Thr Ala Gln Thr Pro Ser Ala315531603165Ser Arg Lys Ser Leu Asp Ala Pro Ser Trp Pro Gly Val Tyr Arg Leu317031753180Ser Met Ser Leu Met Glu Gln Leu Leu Lys Thr Leu Arg Tyr Asn Phe3185 319031953200Leu Pro Glu Ala Leu Asp Phe Val Gly Val His Gln Glu Arg Thr Leu320532103215Gln Cys Leu Asn Ala Val Arg Thr Val Gln Ser Leu Ala Cys Leu Glu322032253230Glu Ala Asp His Thr Val Gly Phe Ile Leu Gln Leu Ser Asn Phe Met323532403245Lys Glu Trp His Phe His Leu Pro Gln Leu Met Arg Asp Ile Gln Val325032553260Asn Leu Gly Tyr Leu Cys Gln Ala Cys Thr Ser Leu Leu His Ser Arg3265 327032753280Lys Met Leu Gln His Tyr Leu Gln Asn Lys Asn Gly Asp Gly Leu Pro328532903295Ser Ala Val Ala Gln Arg Val Gln Arg Pro Pro Ser Ala Ala Ser Ala330033053310Ala Pro Ser Ser Ser Lys Gln Pro Ala Ala Asp Thr Glu Ala Ser Glu331533203325Gln Gln Ala Leu His Thr Val Gln Tyr Gly Leu Leu Lys Ile Leu Ser333033353340
Lys Thr Leu Ala Ala Leu Arg His Phe Thr Pro Asp Val Cys Gln Ile3345 335033553360Leu Leu Asp Gln Ser Leu Asp Leu Ala Glu Tyr Asn Phe Leu Phe Ala336533703375Leu Ser Phe Thr Thr Pro Thr Phe Asp Ser Glu Val Ala Pro Ser Phe338033853390Gly Thr Leu Leu Ala Thr Val Asn Val Ala Leu Asn Met Leu Gly Glu339534003405Leu Asp Lys Lys Lys Glu Pro Leu Thr Gln Ala Val Gly Leu Ser Thr341034153420Gln Ala Glu Gly Thr Arg Thr Leu Lys Ser Leu Leu Met Phe Thr Met3425 343034353440Glu Asn Cys Phe Tyr Leu Leu Ile Ser Gln Ala Met Arg Tyr Leu Arg344534503455Asp Pro Ala Val His Pro Arg Asp Lys Gln Arg Met Lys Gln Glu Leu346034653470Ser Ser Glu Leu Ser Thr Leu Leu Ser Ser Leu Ser Arg Tyr Phe Arg347534803485Arg Gly Ala Pro Ser Ser Pro Ala Thr Gly Val Leu Pro Ser Pro Gln349034953500Gly Lys Ser Thr Ser Leu Ser Lys Ala Ser Pro Glu Ser Gln Glu Pro3505 351035153520Leu Ile Gln Leu Val Gln Ala Phe Val Arg His Met Gln Arg35253530<210>23<211>1111<212>PRT<213>人<400>23Met Thr Gln Met Ile Ser Ala Glu Gly Met Asn Ala Gly Gly Tyr Gly
1 5 10 15Ser Leu Leu Met Asn Ser Glu Gln Pro Gln Gly Glu Tyr Gly Val Thr20 25 30Ile Ala Phe Leu Arg Leu Val Thr Thr Leu Val Lys Gly Gln Leu Gly35 40 45Ser Thr Gln Ser Gln Gly Leu Val Pro Cys Val Met Phe Val Leu Lys50 55 60Glu Met Leu Pro Ser Tyr His Lys Trp Arg Tyr Asn Ser His Gly Val65 70 75 80Arg Glu Leu Ile Gly Cys Leu Ile Leu Glu Leu Ile His Ala Ile Leu85 90 95Asn Leu Cys Gln Glu Thr Glu Leu His Ser Ser His Thr Pro Ser Leu100 105 110Pro Ser Leu Cys Ile Cys Ser Leu Ala Tyr Thr Glu Ala Gly Gln Thr115 120 125Val Ile Ser Ile Met Gly Ile Gly Val Asp Thr Ile Asp Met Val Met130 135 140Ala Ala Gln Pro Arg Ser Asp Gly Pro Glu Gly Gln Gly Gln Gly Gln145 150 155 160Leu Leu Ile Lys Thr Val Lys Leu Ala Phe Ser Val Thr Asn Asn Val165 170 175Ile Arg Leu Lys Pro Pro Ser Asn Val Val Ser Pro Leu Glu Gln Ala180 185 190Leu Thr Gln His Gly Ala His Gly Asn Asn Leu Ile Ala Val Leu Ala195 200 205Lys Tyr Ile Tyr His Arg His Asp Pro Ala Leu Pro Arg Leu Ala Ile210 215 220Gln Leu Leu Lys Arg Leu Ala Thr Val Ala Pro Met Ser Val Tyr Ala225 230 235 240
Cys Leu Gly Ser Asp Ala Ala Ala Ile Arg Asp Ala Phe Leu Thr Arg245 250 255Leu Gln Ser Lys Ile Glu Asp Met Arg Ile Lys Val Met Ile Leu Glu260 265 270Phe Leu Thr Val Ala Val Glu Thr Gln Pro Gly Leu Ile Glu Leu Phe275 280 285Leu Asn Leu Glu Val Lys Asp Gly Ser Asn Gly Ser Lys Glu Phe Ser290 295 300Leu Gly Val Trp Ser Cys Leu His Val Val Leu Glu Leu Ile Asp Ser305 310 315 320Gln Gln Gln Asp Arg Tyr Trp Cys Pro Pro Leu Leu His Arg Ala Ala325 330 335Ile Ala Phe Leu His Ala Leu Trp Gln Asp Arg Arg Asp Ser Ala Met340 345 350Leu Val Leu Arg Thr Lys Pro Lys Phe Trp Glu Asn Leu Thr Ser Pro355 360 365Leu Phe Gly Thr Leu Ser Pro Pro Ser Glu Thr Ser Glu Pro Ser Val370 375 380Leu Glu Thr Cys Ala Leu Ile Met Lys Ile Ile Cys Leu Glu Ile Tyr385 390 395 400Tyr Val Val Lys Gly Ser Leu Asp Gln Ser Leu Lys Asp Thr Leu Lys405 410 415Lys Phe Ser Ser Glu Lys Arg Phe Ala Tyr Trp Ser Gly Tyr Val Lys420 425 430Ser Leu Ala Val Tyr Met Ala Asp Thr Glu Gly Ser Ser Cys Thr Ser435 440 445Leu Leu Glu Tyr Gln Met Leu Val Ser Ala Trp Arg Ile Leu Leu Ile450 455 460Ile Ala Ala Ser His Ala Asp Val Met His Leu Thr Asp Met Ala Val465 470 475 480
Arg Arg Gln Leu Phe Leu Asp Val Leu Asp Gly Thr Lys Ala Leu Leu485 490 495Leu Val Ala Ala Ser Val Asn Cys Leu Arg Leu Gly Ser Met Met Cys500 505 510Thr Leu Leu Leu Ile Leu Leu Arg Gln Trp Lys Arg Glu Leu Gly Ala515 520 525Val Glu Lys Ile Leu Gly Pro Leu Thr Glu Ile Leu Glu Gly Val Leu530 535 540Gln Ala Asp Gln Gln Leu Met Glu Lys Thr Lys Ala Lys Val Phe Ser545 550 555 560Ala Phe Ile Thr Val Leu Gln Met Lys Glu Leu Arg Val Gly Asp Ile565 570 575Pro Gln Tyr Ser Gln Leu Val Leu Asn ValCys Glu Thr Leu Gln Glu580 585 590Glu Val Ile Ala Leu Phe Asp Gln Thr Arg His Ser Leu Ala Ser Asp595 600 605Ser Ala Ala Glu Asp Lys Asp Ser Met Glu Thr Asp Asp Cys Pro Arg610 615 620Pro Arg His Lys Asp Gln Arg Asp Gly Val Cys Val Leu Gly Leu His625 630 635 640Leu Ala Lys Glu Leu Cys Glu Val Asp Glu Asp Gly Asp Ser Trp Leu645 650 655Gln Val Thr Arg Arg Leu Pro Ile Leu Pro Thr Leu Leu Thr Thr Leu660 665 670Glu Val Ser Leu Arg Met Lys Gln Asn Leu His Phe Thr Glu Ala Ala675 680 685Leu His Leu Leu Leu Thr Leu Ala Arg Thr Gln Gln Gly Ala Thr Ala690 695 700Val Ala Gly Ala Gly Ile Thr Gln Ser Ile Cys Leu Pro Leu Leu Ser
705 710 715 720Val Tyr Gln Leu Ser Ser Asn Gly Thr Gly Gln Thr Pro Ser Thr Ser725 730 735Arg Lys Ser Leu Asp Ala Pro Ser Trp Pro Gly Val Tyr Arg Leu Ser740 745 750Met Ser Leu Met Glu Arg Leu Leu Lys Thr Leu Arg Tyr Asn Phe Leu755 760 765Thr Glu Ala Leu Asp Phe Val Gly Val His Gln Glu Arg Thr Leu Gln770 775 780Cys Leu Asn Ala Val Lys Thr Val Gln Ser Leu Ala Cys Leu Glu Glu785 790 795 800Ala Asp His Thr Val Gly Phe Ile Leu Gln Leu Ser His Phe Arg Lys805 810 815Glu Trp His Phe His Leu Pro Gln Leu Met Arg Asp Val Gln Val Asn820 825 830Leu Gly Tyr Leu Cys Gln Ala Cys Thr Ser Leu Leu His Ser Arg Lys835 840 845Met Leu Gln His Tyr Leu Gln Asn Lys Asn Gly Asp Gly Leu Pro Ser850 855 860Ala Val Thr Pro Arg Ala Gln Arg Pro Ser Thr Thr Thr Thr Thr Thr865 870 875 880Thr Thr Thr Thr Ala Leu Ala Thr Pro Ala Gly Cys Ser Ser Lys Gln885 890 895Pro Thr Ala Asp Thr Glu Ala Ser Glu Gln Arg Ala Leu His Thr Val900 905 910Gln Tyr Gly Leu Leu Lys Ile Leu Ser Arg Thr Leu Ala Ala Leu Arg915 920 925His Phe Thr Pro Asp Val Cys Gln Ile Leu Leu Asp Gln Ser Leu Asp930 935 940
Leu Ala Glu Tyr Asn Phe Leu Phe Ala Leu Ser Phe Thr Thr Pro Thr945 950 955 960Phe Asp Ser Glu Val Ala Pro Ser Phe Gly Thr Leu Leu Ala Thr Val965 970 975Asn Val Ala Leu Asn Met Leu Gly Glu Leu Asp Lys Lys Lys Glu Ser980 985 990Leu Thr Gln Ala Val Gly Leu Ser Thr Gln Ala Glu Gly Thr Arg Thr99510001005Leu Lys Ser Leu Leu Met Phe Thr Met Glu Asn Cys Phe Tyr Leu Leu101010151020Ile Ser Gln Ala Val Arg Tyr Leu Arg Asp Pro Ala Val His Pro Arg1025 103010351040Asp Lys Gln Arg Met Lys Gln Glu Leu Ser Ser Glu Leu Ser Thr Leu104510501055Leu Ser Ser Leu Ser Arg Tyr Phe Arg Arg Gly Ala Pro Ser Ser Pro106010651070Ala Ala Gly Val Leu Pro Ser Pro Gln Gly Lys Ala Thr Ser Leu Ser107510801085Lys Ala Ser Pro Glu Ser Gln Glu Pro Leu Ile Gln Leu Val Gln Ala109010951100Phe Val Arg His Val Gln Arg1105 1110<210>24<211>853<212>PRT<213>人<400>24Val Thr Ile Ala Phe Leu Arg Leu Ile Thr Thr Leu Val Lys Gly Gln1 5 10 15Leu Gly Ser Thr Gln Ser Gln Gly Leu Val Pro Cys Val Met Phe Val
20 25 30Leu Lys Glu Met Leu Pro Ser Tyr His Lys Trp Arg Tyr Asn Ser His35 40 45Gly Val Arg Glu Gln Ile Gly Cys Leu Ile Leu Glu Leu Ile His Ala50 55 60Ile Leu Asn Leu Cys His Glu Thr Asp Leu His Ser Ser His Thr Pro65 70 75 80Ser Leu Gln Phe Leu Cys Ile Cys Ser Leu Ala Tyr Thr Glu Ala Gly85 90 95Gln Thr Val Ile Asn Ile Met Gly Ile Gly Val Asp Thr Ile Asp Met100 105 110Val Met Ala Ala Gln Pro Arg Ser Asp Gly Ala Glu Gly Gln Gly Gln115 120 125Gly Gln Leu Leu Ile Lys Thr Val Lys Leu Ala Phe Ser Val Thr Asn130 135 140Asn Val Ile Arg Leu Lys Pro Pro Ser Asn Val Val Ser Pro Leu Glu145 150 155 160Gln Ala Leu Ser Gln His Gly Ala His Gly Asn Asn Leu Ile Ala Val165 170 175Leu Ala Lys Tyr Ile Tyr His Lys His Asp Pro Ala Leu Pro Arg Leu180 185 190Ala Ile Gln Leu Leu Lys Arg Leu Ala Thr Val Ala Pro Met Ser Val195 200 205Tyr Ala Cys Leu Gly Asn Asp Ala Ala Ala Ile Arg Asp Ala Phe Leu210 215 220Thr Arg Leu Gln Ser Lys Ile Glu Asp Met Arg Ile Lys Val Met Ile225 230 235 240Leu Glu Phe Leu Thr Val Ala Val Glu Thr Gln Pro Gly Leu Ile Glu245 250 255
Leu Phe Leu Asn Leu Glu Val Lys Asp Gly Ser Asp Gly Ser Lys Glu260 265 270Phe Ser Leu Gly Met Trp Ser Cys Leu His Ala Val Leu Glu Leu Ile275 280 285Asp Ser Gln Gln Gln Asp Arg Tyr Trp Cys Pro Pro Leu Leu His Arg290 295 300Ala Ala Ile Ala Phe Leu His Ala Leu Trp Gln Asp Arg Arg Asp Ser305 310 315 320Ala Met Leu Val Leu Arg Thr Lys Pro Lys Phe Trp Glu Asn Leu Thr325 330 335Ser Pro Leu Phe Gly Thr Leu Ser Pro Pro Ser Glu Thr Ser Glu Pro340 345 350Ser Ile Leu Glu Thr Cys Ala Leu Ile Met Lys Ile Ile Cys Leu Glu355 360 365Ile Tyr Tyr Val Val Lys Gly Ser Leu Asp Gln Ser Leu Lys Asp Thr370 375 380Leu Lys Lys Phe Ser Ile Glu Lys Arg Phe Ala Tyr Trp Ser Gly Tyr385 390 395 400Val Lys Ser Leu Ala Val His Val Ala Glu Thr Glu Gly Ser Ser Cys405 410 415Thr Ser Leu Leu Glu Tyr Gln Met Leu Val Ser Ala Trp Arg Met Leu420 425 430Leu Ile Ile Ala Thr Thr His Ala Asp Ile Met His Leu Thr Asp Ser435 440 445Val Val Arg Arg Gln Leu Phe Leu Asp Val Leu Asp Gly Thr Lys Ala450 455 460Leu Leu Leu Val Pro Ala Ser Val Asn Cys Leu Arg Leu Gly Ser Met465 470 475 480Lys Cys Thr Leu Leu Leu Ile Leu Leu Arg Gln Trp Lys Arg Glu Leu485 490 495
Gly Ser Val Asp Glu Ile Leu Gly Pro Leu Thr Glu Ile Leu Glu Gly500 505 510Val Leu Gln Ala Asp Gln Gln Leu Met Glu Lys Thr Lys Ala Lys Val515 520 525Phe Ser Ala Phe Ile Thr Val Leu Gln Met Lys Glu Met Lys Val Ser530 535 540Asp Ile Pro Gln Tyr Ser Gln Leu Val Leu Asn Val Cys Glu Thr Leu545 550 555 560Gln Glu Glu Val Ile Ala Leu Phe Asp Gln Thr Arg His Ser Leu Ala565 570 575Leu Gly Ser Ala Thr Glu Asp Lys Asp Ser Met Glu Thr Asp Asp Cys580 585 590Ser Arg Ser Arg His Arg Asp Gln Arg Asp Gly Val Cys Val Leu Gly595 600 605Leu His Leu Ala Lys Glu Leu Cys Glu Val Asp Glu Asp Gly Asp Ser610 615 620Trp Leu Gln Val Thr Arg Arg Leu Pro Ile Leu Pro Thr Leu Leu Thr625 630 635 640Thr Leu Glu Val Ser Leu Arg Met Lys Gln Asn Leu His Phe Thr Glu645 650 655Ala Thr Leu His Leu Leu Leu Thr Leu Ala Arg Thr Gln Gln Gly Ala660 665 670Thr Ala Val Ala Gly Ala Gly Ile Thr Gln Ser Ile Cys Leu Pro Leu675 680 685Leu Ser Val Tyr Gln Leu Ser Thr Asn Gly Thr Ala Gln Thr Pro Ser690 695 700Ala Ser Arg Lys Ser Leu Asp Ala Pro Ser Trp Pro Gly Val Tyr Arg705 710 715 720Leu Ser Met Ser Leu Met Glu Gln Leu Leu Lys Thr Leu Arg Tyr Asn
725 730 735Phe Leu Pro Glu Ala Leu Asp Phe Val Gly Val His Gln Glu Arg Thr740 745 750Leu Gln Cys Leu Asn Ala Val Arg Thr Val Gln Ser Leu Ala Cys Leu755 760 765Glu Glu Ala Asp His Thr Val Gly Phe Ile Leu Gln Leu Ser Asn Phe770 775 780Met Lys Glu Trp His Phe His Leu Pro Gln Leu Met Arg Asp Ile Gln785 790 795 800Val Gly Ala Gln Asp Gly Val Leu Glu Ser Gly Val Met Leu Gly Asp805 810 815Arg Glu Ala Val Arg Ser His Trp Gly Thr Pro Ser Glu Leu Gln Asp820 825 830Val Pro Glu Arg Gly Leu Phe Pro Trp Gly Ala Gln Gly Leu Leu Ser835 840 845Cys Ala Tyr Ser Gly850<210>25<211>525<212>PRT<213>鼠肌<400>25Thr Arg Pro Leu Gln Glu Glu Val Ile Ala Leu Phe Asp Gln Thr Arg1 5 10 15His Ser Leu Ala Ser Asp Ser Ala Ala Glu Asp Lys Asp Ser Met Glu20 25 30Thr Asp Asp Cys Pro Arg Pro Arg His Lys Asp Gln Arg Asp Gly Val35 40 45Cys Val Leu Gly Leu His Leu Ala Lys Glu Leu Cys Glu Val Asp Glu50 55 60
Asp Gly Asp Ser Trp Leu Gln Val Thr Arg Arg Leu Pro Ile Leu Pro65 70 75 80Thr Leu Leu Thr Thr Leu Glu Val Ser Leu Arg Met Lys Gln Asn Leu85 90 95His Phe Thr Glu Ala Ala Leu His Leu Leu Leu Thr Leu Ala Arg Thr100 105 110Gln Gln Gly Ala Thr Ala Val Ala Gly Ala Gly Ile Thr Gln Ser Ile115 120 125Cys Leu Pro Leu Leu Ser Val Tyr Gln Leu Ser Ser Asn Gly Thr Gly130 135 140Gln Thr Pro Ser Thr Ser Arg Lys Ser Leu Asp Ala Pro Ser Trp Pro145 150 155 160Gly Val Tyr Arg Leu Ser Met Ser Leu Met Glu Arg Leu Leu Lys Thr165 170 175Leu Arg Tyr Asn Phe Leu Thr Glu Ala Leu Asp Phe Val Gly Val His180 185 190Gln Glu Arg Thr Leu Gln Cys Leu Asn Ala Val Lys Thr Val Gln Ser195 200 205Leu Ala Cys Leu Glu Glu Ala Asp His Thr Val Gly Phe Ile Leu Gln210 215 220Leu Ser His Phe Arg Lys Glu Trp His Phe His Leu Pro Gln Leu Met225 230 235 240Arg Asp Val Gln Val Asn Leu Gly Tyr Leu Cys Gln Ala Cys Thr Ser245 250 255Leu Leu His Ser Arg Lys Met Leu Gln His Tyr Leu Gln Asn Lys Asn260 265 270Gly Asp Gly Leu Pro Ser Ala Val Thr Pro Arg Ala Gln Arg Pro Ser275 280 285Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Ala Leu Ala Thr Pro Ala
290 295 300Gly Cys Ser Ser Lys Gln Pro Thr Ala Asp Thr Glu Ala Ser Glu Gln305 310 315 320Arg Ala Leu His Thr Val Gln Tyr Gly Leu Leu Lys Ile Leu Ser Arg325 330 335Thr Leu Ala Ala Leu Arg His Phe Thr Pro Asp Val Cys Gln Ile Leu340 345 350Leu Asp Gln Ser Leu Asp Leu Ala Glu Tyr Asn Phe Leu Phe Ala Leu355 360 365Ser Phe Thr Thr Pro Thr Phe Asp Ser Glu Val Ala Pro Ser Phe Gly370 375 380Thr Leu Leu Ala Thr Val Asn Val Ala Leu Asn Met Leu Gly Glu Leu385 390 395 400Asp Lys Lys Lys Glu Ser Leu Thr Gln Ala Val Gly Leu Ser Thr Gln405 410 415Ala Glu Gly Thr Arg Thr Leu Lys Ser Leu Leu Met Phe Thr Met Glu420 425 430Asn Cys Phe Tyr Leu Leu Ile Ser Gln Ala Val Arg Tyr Leu Arg Asp435 440 445Pro Ala Val His Pro Arg Asp Lys Gln Arg Met Lys Gln Glu Leu Ser450 455 460Ser Glu Leu Ser Thr Leu Leu Ser Ser Leu Ser Arg Tyr Phe Arg Arg465 470 475 480Gly Ala Pro Ser Ser Pro Ala Ala Gly Val Leu Pro Ser Pro Gln Gly485 490 495Lys Ala Thr Ser Leu Ser Lys Ala Ser Pro Glu Ser Gln Glu Pro Leu500 505 510Ile Gln Leu Val Gln Ala Phe Val Arg His Val Gln Arg515 520 525
<210>26<211>6<212>PRT<213>人<400>26Ala Gly Gly Pro Cys Val1 權利要求
1.一種編碼多肽的分離核酸分子，所述多肽包括與SEQ ID NO2的氨基酸序列至少95％同一的氨基酸序列。
2.權利要求1的分離核酸分子，其中所述的核酸分子編碼結合雷帕霉素的多肽。
3.權利要求1的分離核酸分子，其中所述的核酸分子編碼與SEQ IDNO2的氨基酸序列至少98％同一的多肽。
4.權利要求1的核酸分子，其中所述的分子在嚴謹條件下與互補于包括SEQ ID NO1的第1-1811位核苷酸的核酸分子的核酸序列雜交。
5.權利要求1的分離核酸分子，其中所述的核酸分子編碼包括SEQID NO2的氨基酸序列的多肽。
6.權利要求1的分離核酸分子，其中所述的核酸分子包括SEQ IDNO1的第1-1811位核苷酸。
7.包括權利要求1的核酸分子的載體。
8.包括權利要求7的載體的細胞。
9.一種基本上純化的多肽，其包括與SEQ ID NO2的氨基酸序列至少95％同一的氨基酸序列。
10.權利要求9的多肽，其中所述的多肽結合雷帕霉素。
11.權利要求9的多肽，其中所述多肽的氨基酸序列與SEQ ID NO2的氨基酸序列至少98％同一。
12.權利要求9的多肽，其中所述多肽的氨基酸序列與SEQ ID NO2的氨基酸序列至少99％同一。
13.權利要求9的多肽，其中所述多肽的氨基酸序列包括SEQ IDNO2的氨基酸序列。
14.權利要求9的多肽，其中所述多肽的氨基酸序列由SEQ ID NO2的氨基酸序列組成。
15.一種融合多肽，其包括與非BFLP0169多肽可操作連接的權利要求9的多肽。
16.權利要求9的融合多肽，其中所述的非BFLP0169多肽包括選自免疫球蛋白分子的Fc區域或FLAG表位、HIS標記，和MYC標記的至少一個成員。
17.一種多肽，其包括SEQ ID NO2的氨基酸序列的雷帕霉素結合結構域。
18.一種長度為至少1740個氨基酸的多肽，其包括SEQ ID NO2的至少5個連續的氨基酸，只要所述的多肽包括除了SEQ ID NO26外的氨基酸序列。
19.權利要求18的多肽，其中所述的多肽包括雷帕霉素結合結構域。
20.一種多肽，其包括SEQ ID NO20的至少5個連續的氨基酸。
21.權利要求20的多肽，其中所述的多肽包括雷帕霉素結合結構域。
22.權利要求20的多肽，其中所述多肽的長度為至少50個氨基酸。
23.權利要求20的多肽，其中所述多肽的長度為至少100個氨基酸。
24.權利要求20的多肽，其中所述多肽的長度為至少220個氨基酸。
25.一種藥物組合物，其包括權利要求17的多肽和藥物學上可接受的載體。
26.一種融合多肽，其包括與非BFLP0169多肽可操作連接的BFLP0169多肽的雷帕霉素結合結構域。
27.權利要求26的融合多肽，其中所述的非BFLP01626多肽包括選自免疫球蛋白分子的Fc區域或FLAG表位、HIS標記，和MYC標記的至少一個成員。
28.一種藥物組合物，其包括權利要求26的融合多肽和藥物學上可接受的載體。
29.選擇性地結合權利要求9的多肽的抗體。
30.權利要求29的抗體，其中所述的抗體抑制BFLP0169多肽與雷帕霉素的結合。
31.權利要求29的抗體，其中所述的抗體是多克隆抗體。
32.權利要求29的抗體，其中所述的抗體是單克隆抗體。
33.權利要求32的單克隆抗體，其中所述的單克隆抗體選自鼠單克隆抗體和人源化的單克隆抗體。
34.一種生產BFLP0169多肽的方法，所述的方法包括在容許所述核酸分子編碼的BFLP0169多肽表達的條件下培養包括權利要求1的核酸分子的細胞。
35.一種檢測在生物樣品中存在BFLP0169核酸分子的方法，該方法包括將樣品與特異結合BFLP0169核酸的核酸探針接觸；以及鑒定結合的探針，如果存在，由此檢測在所述的樣品中BFLP0169核酸分子的存在。
36.一種檢測在樣品中存在BFLP0169多肽的方法，該方法包括將樣品與選擇性地結合所述多肽的化合物在容許在所述多肽與所述化合物之間形成復合物的條件下接觸；以及檢測所述的復合物，如果存在，由此鑒定在所述的樣品中所述的多肽的存在。
37.權利要求36的方法，其中所述的化合物是雷帕霉素。
38.權利要求36的方法，其中所述的化合物是抗-BFLP0169的抗體。
39.一種用于確定在受試個體中存在狼瘡腎炎或是易患狼瘡腎炎的體質的方法，該方法包括a)測量來自所述受試個體的樣品中BFLP0169核酸分子的數量；以及b)將上述步驟中所述核酸的數量與存在于來自沒有狼瘡腎炎的受試個體的對照樣品中的核酸數量進行比較，其中步驟(a)中所述BFLP0169的核酸水平與對照樣品中的核酸水平相比有增加，就表明在所述的受試個體中存在狼瘡腎炎或是易患狼瘡腎炎的體質。
40.權利要求39的方法，其中所述的受試個體是人。
41.一種用于確定在受試個體中存在狼瘡腎炎或是易患狼瘡腎炎的體質的方法，該方法包括a)測量來自所述受試個體的樣品中BFLP0169多肽的數量；以及b)將所述多肽的數量與來自存在于沒有狼瘡腎炎的受試個體對照樣品中的核酸數量進行比較，其中所述BFLP0169的多肽水平與對照樣品中的多肽水平相比有增加，就表明在所述的受試個體中存在狼瘡腎炎或是易患狼瘡腎炎的體質。
42.權利要求41的方法，其中所述的受試個體是人。
43.一種篩選用于治療自身免疫病癥的治療劑的方法，該方法包括將測試化合物與BFLP0169多肽接觸；以及確定所述的測試化合物是否結合所述的BFLP0169多肽，其中所述測試化合物與所述多肽的結合表明該測試化合物是用于自身免疫病癥的治療劑。
44.權利要求43的方法，其中所述的免疫病癥是自身免疫病癥。
45.權利要求44的方法，其中所述的自身免疫病癥是狼瘡。
46.權利要求44的方法，其中所述的自身免疫病癥是狼瘡腎炎。
47.權利要求43的方法，其中所述的BFLP0169是在無細胞抽提物中提供的。
48.權利要求43的方法，其中所述的BFLP1069是在細胞中提供的。
49.一種在受試個體中治療狼瘡腎炎的方法，該方法包括對所述的受試個體施用在所述的受試個體中抑制BFLP0169多肽活性的治療有效量的試劑。
50.權利要求49的方法，其中所述的受試個體是人。
51.權利要求49的方法，其中所述的試劑是抗-BFLP0169的抗體。
52.一種藥物組合物，其包括在受試個體中抑制BFLP0169多肽活性的試劑和藥物學上可接受的載體。
53.權利要求52的藥物組合物，其中所述的試劑是抗-BFLP0169的抗體。
全文摘要
本發明提供新的分離的BFLP0169多核苷酸和由該BFLP0169多核苷酸編碼的多肽。也提供特異性免疫結合BFLP0169多肽或BFLP0169多肽、多核苷酸或抗體的任何衍生物(包括融合衍生物)、變體、突變體或片段的抗體。另外本發明提供利用BFLP0169多肽、多核苷酸和抗體檢測和治療大量病理狀態的方法，及其它用途。
文檔編號C12P21/08GK1741741SQ200380109087
公開日2006年3月1日 申請日期2003年11月21日 優先權日2002年11月21日
發明者M·奧托爾, W·M·穆恩茨, N·肖耶 申請人:惠氏公司