TWI748306B - 包含人類Lefty A蛋白變體的融合蛋白及其用途 - Google Patents

包含人類Lefty A蛋白變體的融合蛋白及其用途 Download PDF

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TWI748306B
TWI748306B TW108146308A TW108146308A TWI748306B TW I748306 B TWI748306 B TW I748306B TW 108146308 A TW108146308 A TW 108146308A TW 108146308 A TW108146308 A TW 108146308A TW I748306 B TWI748306 B TW I748306B
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鄭善英
李璟雨
文昇基
姜聲俊
崔炳玉
郭建
蔣鍾旭
金宗顯
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南韓商鍾根堂股份有限公司
社會福祉法人三星生命公益財團
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Abstract

本發明係關於具有改善之生產性及穩定性的人類Lefty A蛋白變體、包含蛋白變體的融合蛋白，以及用以預防及/或治療神經肌肉疾病的組成物，所述組成物包含蛋白變體或融合蛋白。根據本發明，建構一種人類Lefty A蛋白變體及包含此變體之融合蛋白，相較於天然產生之人類Lefty A蛋白具有較佳的穩定性，因此在動物細胞中以高程度表現並以高產量生產。此外，給予所建構之人類Lefty A蛋白變體或融合蛋白可恢復周邊神經病變之動物模型的神經及運動功能。因此，使用人類Lefty A蛋白變體或融合蛋白可有效預防或治療多種神經疾病及肌肉疾病。

Description

包含人類Lefty　A蛋白變體的融合蛋白及其用途
本發明係關於具有改善之生產性及穩定性的人類Lefty A蛋白變體、包含蛋白變體的融合蛋白，以及用以預防及/或治療神經肌肉疾病的組成物，所述組成物包含蛋白變體或融合蛋白。
Lefty(左右決定因子，left-right determination factor)是屬於轉形生長因子-β(transforming growth factor-beta，TGF-β)超家族的一種型態分化因子，並藉由結合其他TGF-β配體在胚細胞的分化和發展扮演關鍵的角色(Shiratori H et al., Semin Cell Dev Biol. 2014; 32:80-4)。
人類LEFTY 基因包含由獨立複製所產生的兩種基因(編碼Lefty A蛋白的LEFTY2 和編碼Lefty B蛋白質的LEFTY1 ) (Gharib WH, Robinson-Rechavi M, Brief Bioinform. 2011; 12(5):436-41)。推導之Lefty A及Lefty B的胺基酸序列顯示96%的同一性。
人類LEFTY基因轉譯出由366個胺基酸組成的多肽，由21個胺基酸組成的胺基端訊息肽在轉位(translocation)到內質網(endoplasmic reticulum，ER)的過程中被切斷，最後細胞外釋放為42千道耳頓(kDa)的原蛋白質(pro-protein)。釋放的42 kDaLefty蛋白質可透過在其胺基端切割位點(RXXR)之蛋白酶切割移除原胜肽(propeptide)來修飾。不像其他TGF-β家族的成員，Lefty具有兩個而不是一個假定的切割位點(RXXRs)，並且不具有用於同源二聚體之形成所需的保留的半胱胺酸(Juan et al., Genes to Cells. 2001; 6:923-30)。
Lefty多肽可藉由原蛋白轉化酶(proprotein convertase)在各切割位點之第二個精胺酸的羧基端被切斷，並加工成34 kDa及28 kDa的多肽。可藉由將第一切割位點(RGKR)的兩個精胺酸殘基突變成甘胺酸或將第二切割位點(RHGR)的第一個精胺酸突變成甘胺酸來阻止Lefty多肽的蛋白水解修飾(Ulloa L et al., J Biol Chem. 2001; 276:217387-96)。
已有報告指出42 kDa的Lefty原蛋白質以及28 kDa的成熟蛋白質可誘導MAPK活化(MAPK activation) (Ulloa L et al., J Biol Chem. 2001; 276:217387-96)。
Lefty作為Nodal(一種TGF-β家族蛋白)的內源抑制物(endogenous inhibitor)，在脊椎動物發育之早期胚胎發育中扮演重要的角色，例如誘導中胚層(mesoderm)及內胚層(endoderm)分化、控制左右不對稱(Schier AF, Annu Rev Cell Biol. 2003; 19:589-621)。Lefty抑制Nodal的確切作用機制仍不清楚，但可知Lefty可與Nodal結合，從而阻止Nodal結合到促進素受體(Activin receptor) (例如ActRI或ActRII)及輔受體EGF-CFC (co-receptor EGF-CFC)(Branford et al., Current Biol. 2004; 14:341-3 and Chen et al. Current Biol. 2004; 14:618-24)。此外，已報導Lefty會抑制TGF-β或BMP傳訊(Ulloa L et al., J Biol Chem. 2001; 276(24): 21397-404)。
有許多TGF-β超家族配體，例如BMP、GDF、Nodal、促進素及TGF-β。它們在調節胚胎發育以及出生後之許多細胞和器官的功能中扮演重要的角色。舉例來說，TGF-β家族成員參與神經分化，並從早期胚胎到成人之整個發育過程中調節中樞神經系統的多個部分(Myers EA and Kessler JA, Cold Spring Harb Perspect Biol. 2017; 9(8))。TGF-β在神經分化的過程中抑制許旺細胞(Schwann cell)的存活(Parkinson et al., J Neurosci. 2001; 21:8572-85)。BMP7藉由活化周邊神經的p38來抑制許旺細胞髓鞘化過程(myelination process) (Liu X et al., Sci Rep. 2016; 6:31049)。GDF8 (肌肉生長抑制素，Myostatin)抑制骨骼肌生長，且GDF8的表現誘導骨骼肌萎縮(skeletal muscle atrophy) (Elkina Y et al., J Cachexia Sarcopenia Muscle. 2001; 2:143-51)。
夏馬杜三氏病(Charcot-Marie-Tooth disease，CMT)為最常見的遺傳性周邊神經病變之一，具有2500分之1的患病率。已確定有超過80種基因會造成CMT。CMT患者從下肢開始發生緩慢的漸進性肌肉萎縮症(progressive muscular atrophy)和感覺喪失。
CMT為一種表現型且遺傳型的異質性疾病(heterogeneous disease)，並根據上肢運動神經傳導速度(motor nerve conduction velocities，MCV)分成脫髓鞘型(demyelinating type，CMT1)和軸索病(axonal type，CMT2)。在這些類型之中，脫髓鞘型(CMT1)佔所有CMT患者約70%，脫髓鞘型(CMT1)是由諸如PMP22和MPZ之髓鞘蛋白(myelin protein)的突變或過度表現而造成。雖然病理上的機制尚未闡明，但已提出蛋白質脂過度表現或突變會誘導內質網壓力並伴隨許旺細胞的凋亡為機制之一。由於沒有藥物被批准用於CMT的治療，對於開發對CMT之有效療法的興趣日益增加。
在此技術背景下，本發明人藉由將突變引入人類Lefty A蛋白來建構具有提高之生產性及穩定性的變體，以使Lefty A蛋白可被溶解以用於治療神經病變或肌肉疾病，進而完成本發明。
在先前技術中所揭露的資訊僅用以加強對本發明之背景的理解，因此可能不包含形成本領域具有通常知識者已知之先前技術的資訊。
本發明一目的在於提供具有提升之生產性及穩定性的人類Lefty A蛋白變體。
本發明另一目的在於提供包含人類Lefty A蛋白變體的融合蛋白。
本發明又一目的在於提供編碼融合蛋白的核酸分子、包含核酸分子的表現載體、導入有表現載體的重組細胞，以及使用重組細胞製造融合蛋白的方法。
本發明還有一目的在於提供預防及/或治療神經肌肉疾病的組成物，包含蛋白變體或融合蛋白。
本發明更有一目的在於提供預防及/或治療神經肌肉疾病的方法，包含將蛋白變體或融合蛋白給予受試者。
本發明更有另一目的在於提供蛋白變體或融合蛋白的用途，用於神經肌肉疾病的預防及/或治療。
本發明還更有一目的在於提供蛋白變體或融合蛋白的用途，用以製造用於治療神經肌肉疾病的藥物。
為了達成上述目的，本發明提供一種人類Lefty A蛋白變體，包含人類Lefty A蛋白的L22至P366之胺基酸序列，人類Lefty A蛋白具有SEQ ID NO: 131之胺基酸序列，其中人類Lefty A蛋白變體包含：(1)在修飾位點(processing site) (R74至R77及R132至R135)之一個或多個胺基酸殘基的取代；以及(2)在原胜肽域(propeptide domain) (L22至S73)之一個或多個胺基酸殘基的取代。
本發明亦提供一種融合蛋白，包含人類Lefty A蛋白變體。
本發明亦提供編碼有包含人類Lefty A蛋白變體之融合蛋白的核酸分子、包含核酸分子的表現載體、導入有表現載體的重組細胞，以及使用重組細胞製造包含人類Lefty A蛋白變體之融合蛋白的方法。
本發明亦提供一種用以預防及/或治療神經肌肉疾病的組成物，包含人類Lefty A蛋白變體或包含人類Lefty A蛋白變體的融合蛋白。
本發明亦提供一種用以防止及/或治療神經肌肉疾病的方法，包含將人類Lefty A蛋白變體或包含人類Lefty A蛋白變體之融合蛋白給予受試者。
本發明亦提供一種人類Lefty A蛋白變體或包含人類Lefty A蛋白變體之融合蛋白的用途，用於神經肌肉疾病的預防及/或治療。
本發明亦提供一種人類Lefty A蛋白變體或包含人類Lefty A蛋白變體之融合蛋白的用途，用以製造用於治療神經肌肉疾病的藥物。
除非另有定義，否則本文所使用之所有技術及科學術語具有與本發明所屬技術領域中具有通常知識者通常理解之含義相同的含意。通常，本文所使用之命名法和如下所述之實驗方法為本領域中眾所周知且常採用者。
在本發明中，一種融合蛋白相較於野生型(wild-type，WT)蛋白質及先前報導之人類Lefty A變體，改善了中國倉鼠卵巢細胞(Chinese hamster ovary cell，CHO cell)中的生產性及穩定性，亦可結合人類Nodal並抑制Nodal媒介的傳訊，有助於改善周邊神經病變(peripheral neuropathy)的症狀，所述融合蛋白包含具有提升之生產性及穩定性的人類Lefty A(Uniprot No.000292；NCBI DB NM_003240)蛋白變體。因此，融合蛋白可有效地單獨使用或與習知之藥學上可接受的載體(carrier)、神經病變治療試劑、肌肉疾病治療試劑等結合作為組成物，用以預防或治療神經及肌肉疾病。
因此，在一方面，本發明係針對一種人類Lefty A蛋白變體，包含人類Lefty A蛋白的L22至P366之胺基酸序列，人類Lefty A蛋白具有SEQ ID NO: 131之胺基酸序列，其中人類Lefty A蛋白變體包含：(1)在修飾位點(processing site) (R74至R77及R132至R135)之一個或多個胺基酸殘基的取代；以及(2)在原胜肽域(propeptide domain) (L22至S73)之一個或多個胺基酸殘基的取代。
具有SEQ ID NO: 131之胺基酸序列的人類Lefty A蛋白中之M1至A21對應訊息肽(signal peptide)。
根據本發明之人類Lefty A蛋白變體亦指包含在特定胺基酸殘基位置的胺基酸殘基經保留取代(conservatively substituted)的變體。
於此所使用之術語「保留取代」係指Lefty A蛋白變體的修飾，所述Lefty A蛋白變體的修飾涉及以具有相似生化性質之胺基酸取代一個或多個胺基酸，所述具有相似生化性質之胺基酸不會導致Lefty A蛋白變體之生物或生化功能的喪失。
「保留胺基酸取代」是某胺基酸殘基替換成具有相似側鏈之胺基酸殘基。具有相似側鏈之胺基酸殘基家族已被定義，並且在本發明所屬領域中為眾所周知。這些家族包含具有鹼性側鏈的胺基酸(例如離胺酸、精胺酸及組胺酸)、具有酸性側鏈的胺基酸(例如天門冬胺酸及麩胺酸)、具有不帶電之極性側鏈的胺基酸(例如甘胺酸、天門冬醯胺酸、麩醯胺酸、絲胺酸、蘇胺酸、酪胺酸及半胱胺酸)、具有非極性側鏈的胺基酸(例如丙胺酸、纈胺酸、白胺酸、異白胺酸、脯胺酸、苯丙胺酸、甲硫胺酸及色胺酸)、具有β支鏈側鏈的胺基酸(例如蘇胺酸、纈胺酸及異白胺酸)，以及具有芳香側鏈的胺基酸(例如酪胺酸、苯丙胺酸、色胺酸及組胺酸)。
可想見儘管本發明之Lefty A蛋白變體具有保留性(conservative)胺基酸取代，但仍可保留活性。
此外，本發明之人類Lefty A蛋白變體被解釋為包含具有與本發明之Lefty A蛋白變體之功能及/或功效實質上相同之功能及/或功效的Lefty A蛋白變體，並具有與根據本發明之Lefty A蛋白變體至少80%或85%的胺基酸序列同源性，以至少90%為佳，以至少95%為較佳，以至少99%為最佳。
較佳地，根據本發明之人類Lefty A蛋白變體可包含選自由SEQ ID NO: 86至SEQ ID NO: 111所組成之群組之任一者的L22至P366之胺基酸序列，或者選自由SEQ ID NOS: 112至129及133所組成之群組之任一者的L23至P367之胺基酸序列，但不限於此。
應理解根據本發明之Lefty A蛋白變體亦包含實質上具有與根據本發明之Lefty A蛋白變體相同之功效者，即使在胺基端、羧基端或其內部胺基酸序列被切割或取代。
在野生型Lefty A中沒有突變，亦即在位置R74至R77中沒有胺基酸殘基的取代，因此當對應區域之蛋白酶誘導之切割發生時，會獲得34 kDa Lefty A蛋白片段。此外，在位置R132至R135中沒有突變，因此當對應區域之蛋白酶誘導之切割發生時，會獲得28 kDa Lefty A蛋白片段。
因此，本發明之人類Lefty A蛋白變體較佳地包含在修飾位點之一個或多個胺基酸的取代，修飾位點由R74至R77及R132至R135組成。
在本發明中，在原胜肽域(L22至S73)之胺基酸殘基的取代可為選自由E24、L27、R33、S38、V40、V42、R45、M48、K50、A55、V63、R66、R67、G70和D71組成之群組之一個或多個位置之胺基酸殘基的取代，但不限於此。
較佳地，在原胜肽域(L22至S73)之胺基酸殘基的取代可為選自由E24G、S38K、V42T、K50E、A55T、V63A和 R66Q組成之群組之一個或多個胺基酸殘基的取代。
最佳地，在原胜肽域(L22至S73)之胺基酸殘基的取代可包含V63A，可更包含選自由E24G、S38K、V42T、K50E、A55T和R66Q組成之群組之一個或多個胺基酸殘基取代。
在本發明中，在修飾位點(R74至R77及R132至R135)之一個或多個胺基酸殘基的取代可為選自由R74G、R77G、R77V、R132G及R135G組成之群組之一個或多個胺基酸殘基取代。
位置R74至R77的胺基酸序列可為RGKR、GGKG、RGKA、RGKV或RHGG，位置R132至R135的胺基酸序列可為RHGR、GHGR、RHGG、RHER、GHGG、RHGA或RHGV，其源自於在修飾位點(R74至R77及R132至R135)之一個或多個胺基酸殘基的取代。
在本發明中，人類Lefty A蛋白變體可更包含在凝血酶切割位點(thrombin cleavage site) (L311、P313、R314、L359、P361或R362)之一個或多個胺基酸殘基的取代，但不限於此。
較佳地，在選自由凝血酶切割位點L311、P313、R314、L359、P361及R362組成之群組之一個或多個位置的胺基酸殘基可以被選自由天門冬胺酸(D)、麩胺酸(E)、絲胺酸(S)、離胺酸(K)和麩醯胺酸(Q)組成之群組之胺基酸殘基取代。
在本發明中，人類Lefty A蛋白變體可更包含在斷裂位點(fragmentation site) (S202或S223)之一個或多個胺基酸殘基以除了絲胺酸(S)和半胱胺酸(C)以外之胺基酸殘基的取代。
在本發明中，人類Lefty A蛋白變體可更包含訊息肽(signal peptide)於胺基端。
在本發明揭露的內容中，訊息肽與訊息序列(signal sequence)為相同之意義，訊息肽為短的胺基酸序列，所述短的胺基酸序列在使新表現之多肽派送至內質網並進入分泌路徑中扮演重要的角色。當蛋白質在細胞中被合成並離開細胞時，訊息序列會被切斷，而Lefty A蛋白變體的胺基端從L22開始。本發明所使用之訊息序列可為源自於Lefty A蛋白的訊息序列(M1至A21)，但不限於此。亦可使用源自於除了Lefty A蛋白以外之蛋白質的訊息序列，舉例而言，可為抗體衍生序列(antibody-derived sequence)，如MDMRVPAQLLGLLLLWFPGSRC (UniProt: A0A0C4DH73；SEQ ID NO: 132)，但不限於此。
在另一方面，本發明係針對包含人類Lefty A蛋白變體的融合蛋白。
在本發明中，「包含人類Lefty A蛋白變體的融合蛋白」與「Lefty A融合蛋白變體」為相同之意義。
在本發明中，可藉由將人類Lefty A蛋白變體與Fc或白蛋白(albumin)融合來製造融合蛋白，但不限於此。
較佳地，可藉由將Fc或白蛋白融合至人類Lefty A蛋白變體的胺基端或羧基端來製造本發明之融合蛋白，以羧基端為佳。此外，可藉由將人類Lefty A蛋白變體透過連接鏈(linker)與Fc或白蛋白融合來製造本發明之融合蛋白。
本發明之Fc係指抗體的Fc(可結晶片段，fragment crystallizable)區域，Fc可為選自由IgG、IgA、IgM及IgE組成之群組之抗體的Fc。較佳地，Fc可為選自由人類IgG、IgA、IgM及IgE組成之群組之抗體的Fc，但不限於此。
更佳地，Fc可為選自源自於人類IgG之IgG1、IgG2、IgG3及IgG4之中之一者，最佳地，Fc可為人類IgG1衍生Fc(human IgG1-derived Fc)，但不限於此。此外，本發明之Fc可為野生型Fc或其胺基酸序列變體。
此外，本發明之白蛋白係指包含所有動物衍生白蛋白。較佳地，可使用人類白蛋白，但本發明的範圍不限於此。
在本發明中，融合蛋白可具有選自由SEQ ID NOS: 134至178所記載之胺基酸序列組成之群組之任一胺基酸序列，但不限於此。
在本發明中，SEQ ID NOS: 134至159所記載之胺基酸序列分別指SEQ ID NO: 86至SEQ ID NO: 111所記載之胺基酸序列中除了訊息序列以外之L22至K614的胺基酸序列。SEQ ID NOS: 160至178所記載之胺基酸序列分別指SEQ ID NOS: 112至129及SEQ ID NO: 133所記載之胺基酸序列中除了訊息序列以外之L23至K615的胺基酸序列(圖22a至圖22j及圖23a至圖23m)。
根據本發明之融合蛋白可更包含位於胺基端的訊息肽。能夠結合融合蛋白之胺基端的訊息肽可為源自於Lefty A蛋白的訊息序列(M1至A21)，相似於人類Lefty A蛋白變體的訊息序列，但不限於此。本發明所使用之訊息肽可為源自於除了Lefty A蛋白以外之蛋白質的訊息序列，舉例而言，可為抗體衍生序列，如MDMRVPAQLLGLLLLWFPGSRC (UniProt: A0A0C4DH73；SEQ ID NO: 132)，但不限於此。
又另一方面，本發明係針對編碼融合蛋白的核酸分子、包含核酸分子的表現載體、導入有表現載體的重組細胞，以及使用重組細胞製造包含人類Lefty A蛋白變體之融合蛋白的方法。
於此所使用之術語「核酸分子」係指全面包含DNA(gDNA及cDNA)及RNA分子，而核苷酸為核酸分子的基本單元，核苷酸亦包含糖或鹼基修飾的類似物以及天然核苷酸(Scheit, Nucleotide Analogs, John Wiley, New York(1980)；Uhlman and Peyman, Chemical Reviews. 1990; 90:543-84)。核酸分子可以編碼本發明之人類Lefty A融合蛋白變體，且此核酸分子的序列可被修飾。修飾包含核苷酸的插入、刪除或者非保留取代或保留取代。
於此所使用之術語「載體」包含質體載體(plasmid vector)、黏接質體載體(cosmid vector)、噬菌體載體(bacteriophage vector)，以及病毒載體(viral vector)，病毒載體例如腺病毒載體(adenovirus vector)、反轉錄病毒載體(retroviral vector)及腺相關之病毒載體(adeno-associated viral vector)，以作為在宿主細胞中表現目標基因的手段。較佳地，載體可包含質體載體，但不限於此。
在本發明之載體中，編碼包含人類Lefty A蛋白變體之融合蛋白的核酸分子可與啟動子(promoter)可操作地連接。
於此所使用之術語「可操作地連接」係指在核酸表現控制序列(例如一列啟動子、訊息序列或轉錄調控因子結合位點)與另一核酸序列之間的功能性連鎖(functional linkage)，因此控制序列控制另一核酸序列的轉錄及/或轉譯。
可藉由在相關技術領域中已知的多種方法來建構本發明之重組載體系統，詳細的方法揭露於Sambrook et al., Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory Press (2001)，透過引用併入於此。
載體通常可建構為用於選殖(cloning)的載體或用於表現的載體。載體可建構為應用原核細胞或真核細胞為宿主的載體。
舉例而言，當本發明之載體為表現載體，且使用原核細胞作為宿主細胞時，通常包含能夠啟動轉錄的強啟動子(例如tac啟動子、lac啟動子、lacUV5啟動子、lpp啟動子、pLλ啟動子、pRλ啟動子、rac5啟動子、amp啟動子、recA啟動子、SP6啟動子、trp啟動子、T7啟動子等)、用於轉譯起始的核糖體結合位點(ribosome-binding site)及轉錄/轉譯終止序列。作為宿主細胞，當使用大腸桿菌E. coli 如HB101、BL21、DH5α等時，可使用用於大腸桿菌色胺酸生合成的操作子和啟動子(Yanofsky, C., J. Bacteriol., (1984) 158:1018-1024)以及噬菌體λ左啟動子(pLλ promoter, Herskowitz, I. and Hagen, D., Ann. Rev. Genet., (1980) 14:399-445)作為調控序列。當使用桿菌(bacilli)作為宿主細胞時，可使用用於源自蘇力菌(bacillus thuringiensis)之毒素(蛋白質)基因(toxin (protein) gene)的啟動子或可在桿菌中表現的任何啟動子作為調控序列。
同時，可藉由操縱在本領域中常用之質體(例如pCL、pSC101、pGV1106、pACYC177、ColE1、pKT230、pME290、pBR322、pUC8/9、pUC6、pBD9、pHC79、pIJ61、pLAFR1、pHV14、pGEX系列、pET系列、pUC19等)、噬菌體(例如λgt·4λB、λ-Charon、λΔz1、M13等)或病毒(例如SV40等)來建構本發明之表現載體。舉例而言，可藉由操縱pCL表現載體來建構本發明之表現載體，具體上為pCLS05(韓國專利註冊第10-1420274號)表現載體，但不限於此。
此外，當本發明之載體為表現載體，且使用真核細胞作為宿主細胞時，可使用源自於哺乳動物細胞基因體的啟動子，例如金屬硫蛋白啟動子(metallothionein promoter)、β-肌動蛋白啟動子(β-actin promoter)、人類血紅蛋白啟動子(human hemoglobin promoter)及人類肌肉肌酸酐啟動子(human muscle creatinine promoter))或源自於哺乳動物病毒(例如腺病毒晚期啟動子(adenovirus late promoter)、牛痘病毒7.5K啟動子(vaccinia virus 7.5K promoter)、SV40啟動子、巨細胞病毒(cytomegalovirus，CMV)啟動子、HSV之tk啟動子、小鼠乳腺腫瘤病毒(mouse mammary tumor virus，MMTV)之啟動子、HIV之LTR啟動子、莫洛尼氏病毒(moloney virus)之啟動子、Epstein-Barr二氏病毒(Epstein Barr Virus，EBV)之啟動子及勞斯肉瘤(Rous Sarcoma Virus，RSV)之啟動子。並且，載體通常包含聚腺苷酸化序列作為轉錄終止序列。具體而言，本發明之重組載體包含CMV啟動子。
本發明之重組載體可與其他序列融合以幫助純化由重組載體所表現之重組蛋白。融合序列包含例如麩胺基硫S-轉移酶(glutathione S-transferase，Pharmacia, USA)、麥芽糖結合蛋白(maltose-binding protein，NEB, USA)、FLAG標籤(IBI, USA)、6xHis(hexahistidine)標籤(Quiagen, USA)等。此外，由於Fc融合於本發明之載體所表現的蛋白質，所表現的蛋白質可藉由蛋白A管柱(protein A column)等被輕易純化，而不需要用於純化的額外序列。
同時，本發明之重組載體包含本領域中常用之抗生素抗藥性基因作為選擇標記(selective marker)，本發明之重組載體可包含例如具有抵抗胺苄青黴素(ampicillin)、建它黴素(gentamicin)、卡本西林(carbenicillin)、氯黴素(chloramphenicol)、鏈黴素(streptomycin)、卡那黴素(kanamycin)、遺傳黴素(geneticin)、新黴素(neomycin)及四環黴素(tetracycline)的基因。
可使用能夠穩定且連續選殖並表達本發明之載體的重組細胞作為本領域已知的任何宿主細胞。宿主細胞包含原核宿主細胞，舉例而言，屬於Bacillus屬(例如大腸桿菌(Escherichia coli )、枯草桿菌(Bacillus subtilis )及蘇力菌(Bacillus thuringiensis ))、鏈黴菌屬(Streptomyces )、假單胞菌屬(Pseudomonas )(例如戀臭假單孢菌(Pseudomonas putida ))、奇異變形桿菌屬(Proteus mirabilis )及葡萄球菌屬(Staphylococcus )(例如葡萄球菌(Staphylococcus carnosus ))之菌株，但不限於此。
適合與此載體使用的真核宿主細胞包含真菌(例如麴菌(Aspergillus sp. ))及酵母菌(例如畢赤酵母菌(Pichia pastoris )、釀酒酵母菌(Saccharomyces cerevisia e)、裂殖酵母菌(Schizosaccharomyces )及紅麵包黴菌(Neurospora crassa ))及其他低等真核細胞，以及高等真核細胞，例如源自昆蟲的細胞及源自植物和哺乳動物的細胞。
具體而言，宿主細胞可為猴子腎臟細胞(monkey kidney cells，COS7)、NSO細胞、SP2/0、中國倉鼠卵巢(Chinese hamster ovary，CHO)細胞、W138、小倉鼠腎臟(baby hamster kidney，BHK)細胞、MDCK、骨髓瘤(myeloma)細胞、HuT 78細胞或HEK293細胞。
相較於動物細胞等，使用諸如大腸桿菌之微生物具有較高的生產性，但由於諸如形成雙硫鍵或醣化(glycosylation)之問題，對蛋白質的生產不是較佳的。然而，微生物可藉由聚乙二醇化(pegylation)等而被使用於以提高藥物之體內穩定性為目的之生產。
在本發明中，轉染(transfection)或轉形(transformation)至宿主細胞包含可將核酸導入生物體、細胞、組織或器官的任何方法，轉染或轉形至宿主細胞可如本領域中已知般，依據宿主細胞的種類選擇適合的標準技術來進行。這些方法包含電穿孔(electroporation)、原生質體融合(protoplast fusion)、磷酸鈣沉澱(calcium phosphate precipitation)、氯化鈣沉澱(calcium chloride precipitation)、與碳化矽纖維攪拌(agitation with silicon carbide fiber)，以及農桿菌(agrobacterium)媒介、PEG媒介、硫酸聚葡萄糖(dextran sulfate)媒介、脂質轉染胺(lipofectamine)媒介及乾燥/抑制(desiccation/inhibition)媒介的轉形，但不限於此。
本發明提供使用重組細胞製造重組蛋白的方法。具體而言，此方法可為製造人類Lefty A融合蛋白變體的方法，包含下述步驟：(a)培養使用本發明之重組載體轉形的重組細胞；以及(b)在重組細胞中表現重組蛋白。
產生重組蛋白之培養步驟可使用本領域中已知之適合的培養基及培養條件來進行。本領域中具有通常知識者能夠毫無困難地依據所選之特定菌株調整培養條件。這些培養方法揭露於多份文件(例如James M. Lee, Biochemical Engineering，Prentice-Hall International Editions, 138-176)。用於培養細胞的方法基於細胞生長模式可分成懸浮培養(suspension culture)和貼壁培養(adherent culture)，依據培養模式可分成分批法(batch method)、饋料批式法(fed-batch method)和連續方法(continuous method)。用於培養之培養基應選適當選擇以符合所使用之特定菌株所需的條件。
在動物細胞中，培養基包含碳源、氮源及微量元素成分。可使用於本發明之碳源之例包含碳水化合物、脂肪、脂肪酸、醇類及有機酸；碳水化合物，例如葡萄糖、蔗糖、乳糖、果糖、麥芽糖、澱粉和纖維素；脂肪，例如大豆油、葵花籽油、蓖麻油和椰子油；脂肪酸，例如棕櫚酸、硬脂酸和亞麻油酸；醇類，例如甘油和乙醇；有機酸，例如乙酸。這些碳源可單獨使用或者結合兩種或更多來使用。
可使用於本發明之氮源包含例如有機氮源及無機氮源；有機氮源，例如蛋白腖(peptone)、酵母萃取物、肉汁(gravy)、麥芽萃取物、玉米浸液(corn steep liquor，CSL)和豆粕粉(soybean meal powder)；無機氮源，例如尿素、硫化銨、氯化銨、磷酸銨、碳酸銨和硝酸銨，這些氮源可單獨使用或者結合兩種或更多來使用。培養基可包含磷酸二氫鉀、磷酸氫二鉀及其對應之含鈉鹽類作為磷源(phosphate source)。此外，在培養基中可包含金屬鹽類，例如硫酸鎂或硫酸鐵作為硫源(sulfate source)。此外，培養基中可包含胺基酸、維生素及適當的前驅物。
在培養細胞的過程中，可以適合的方式將諸如氫氧化銨、氫氧化鉀、氨、磷酸及硫酸之化合物添加至培養基來調整細胞培養基的pH。此外，在培養過程中，可使用諸如脂肪酸聚乙二醇酯(antifoaming agent)之消泡劑(fatty acid polyglycol ester)以抑制氣泡產生。再者，氧氣或含氧氣體(例如空氣)被注入至培養基以保持培養物含有氧。培養溫度通常為20°C至45°C，以25°C至40°C為佳。
藉由培養轉形之重組細胞所獲得之重組蛋白可不純化即使用，或可藉由多種習知方法在純化至高純度後使用，習知方法例如透析、鹽沉澱及層析。在這些方法之中，基於層析之方法最常被使用，層析的種類及順序可依據重組蛋白的性質、培養方法等選自離子交換層析法、粒徑篩析層析法或親和性層析法等。
還有一方面，本發明係針對用以預防及/或治療神經肌肉疾病的組成物，包含人類Lefty A蛋白變體或融合蛋白。
更有一方面，本發明係針對用以預防及/或治療神經肌肉疾病的方法，包含將人類Lefty A蛋白變體或包含人類Lefty A蛋白變體之融合蛋白給予受試者。
更有另一方面，本發明係針對人類Lefty A蛋白變體或包含人類Lefty A蛋白變體之融合蛋白的用途，用於神經肌肉疾病的預防及/或治療。
還更有一方面，本發明係針對人類Lefty A蛋白變體或包含人類Lefty A蛋白變體之融合蛋白的用途，用以製造用於治療神經肌肉疾病的藥物。
於此所使用之術語「預防」係指藉由給予根據本發明之組成物來抑制或延遲諸如神經肌肉疾病等之疾病的進展的任何動作，「治療」係指抑制發展、緩解或消除諸如神經肌肉疾病等之疾病。
在本發明一實施例中，證實包含根據本發明之人類Lefty A蛋白變體的融合蛋白可結合人類Nodal並抑制Nodal誘導之傳訊，因此改善周邊神經病變相關之參數。此外，在本發明一實施例中，證實人類Lefty A融合蛋白變體可劑量依賴地抑制肌肉生長抑制素傳訊。再者，發現人類Lefty A融合蛋白變體可阻擋p38傳訊，p38為一種髓鞘化之負調控子(negative regulator of myelination)，因此可用作為治療周邊神經病變的試劑，尤其是由脫髓鞘(demyelination)引起之神經病變。
因此，在本發明中，神經肌肉疾病可為發生於周邊神經或肌肉的疾病，以關於Nodal及/或肌肉生長抑制素傳訊的疾病為佳，但不限於此。Nodal及/或肌肉生長抑制素傳訊相關之疾病可為肌病(myopathy)、周邊神經病變(peripheral neuropathy)或僵直性脊椎症候群(rigid spine syndrome)。
肌病可為選自由肌少症(sarcopenia)、肌肉失養症(muscular dystrophy)、重症肌無力(myasthenia gravis)、肌肉萎縮性脊髓側索硬化症(amyotrophic lateral sclerosis)(或魯—蓋瑞氏症，Lou Gehrig's disease)、原發性脊髓側索硬化症(primary lateral sclerosis)、漸進性肌肉萎縮症(progressive muscular atrophy)、甘迺迪氏症(Kennedy's disease)(或脊髓延髓性肌肉萎縮症，spinobulbar muscular atrophy)脊髓性肌肉萎縮症(spinal muscular atrophy)和遠端肌病(distal myopathy)組成之群組。
周邊神經病變可為選自由夏馬杜三氏病(Charcot-Marie-Tooth disease)、慢性脫髓鞘性神經炎(chronic inflammatory demyelinating polyneuropathy)、腕隧道症候群(carpal tunnel syndrome)、糖尿病周邊神經病變(diabetic peripheral neuropathy)和格巴二氏症候群(Guillain-Barre syndrome)組成之群組。
此組成物可以為藥學組成物、準藥物組成物或保健功能食品組成物。
本發明之用於預防或治療疾病之組成物可包含藥學上可接受的載體(carrier)。
於此所使用之術語「藥學上可接受的載體」係指不損害所給予之化合物之生物活性及特性而不刺激有機體的載體或稀釋劑(diluent)。作為組成物中之藥學上可接受的載體可製備成液體溶液，使用無菌且生物相容的載體。藥學上可接受的載體可為生理食鹽水、無菌水、緩衝食鹽水、白蛋白注射溶液、葡萄糖溶液、麥芽糖糊精溶液、甘油或者其兩種或多種的混合物。此外，如果需要，本發明之組成物可包含其他已知添加劑，包含抗氧化劑、緩衝液及抑菌劑。再者，本發明之組成物可在稀釋劑、分散劑、界面活性劑、黏合劑及潤滑劑的幫助下製備成可注射的形式，例如水溶液、懸浮液或乳液。此外，根據本發明之組成物可製備成丸劑、膠囊劑、顆粒劑或片劑。
根據本發明之藥學上組成物可製備成口服(oral)或非經口(parenteral)劑型。根據本發明之藥學上組成物可使用常用之稀釋劑或賦形劑(excipient)來製備，常用之稀釋劑或賦形劑例如填充劑、增量劑、黏合劑、濕潤劑、崩散劑或界面活性劑。用於口服給藥的固體製劑包含片劑、丸劑、粉劑、顆粒劑、膠囊劑等。此固體製劑藉由將一或多個化合物與至少一賦形劑混合來製備，賦形劑例如澱粉、碳酸鈣、蔗糖、乳糖、明膠等。除了簡單的方法之外，亦可添加諸如硬脂酸鎂、滑石等之潤滑劑。用於口服給藥的液體製劑，例如懸浮液、內部溶液、乳液、糖漿等，可包含簡單稀釋劑及多種賦形劑，稀釋劑例如水及液態石蠟，賦形劑例如濕潤劑、甜味劑、芳香劑、防腐劑等。用於非經口給藥的製劑包含無菌水溶液、非水溶劑、懸浮液、乳液、凍乾劑和栓劑。非水溶劑及懸浮液可使用丙二醇、聚乙二醇、諸如橄欖油之植物油或諸如油酸乙酯之可注射的酯類。作為栓劑的基底可使用Witepsol、Macrogol、Tween 61、可可脂(cacao fat)、月桂脂(laurin fat)、甘油明膠(glycerogelatin)等。
藥學上可接受的載體及製劑詳細揭露於Remington's Pharmaceutical Sciences (19th ed., 1995)。
本發明之藥學上組成物可口服給藥或非經口給藥。非經口給藥藉由靜脈注射(intravenous injection)、皮下注射(subcutaneous injection)、肌內注射(intramuscular injection)、腹膜內注射(intraperitoneal injection)、內皮給藥(endothelial administration)、局部給藥(topical administration)、鼻內給藥(intranasal administration)、肺內給藥(intrapulmonary administration)、直腸給藥(rectal administration)等。對於口服給藥，考量到胜肽和蛋白質在胃中會被消化，組成物中的活性成分需要製成包衣劑型(coated dosage form)，或者在胃中可保護活性成分免於被消化的劑型。或者，本發明之組成物可透過可使活性成分移至送目標細胞的任何裝置來給藥。
根據本發明之用以預防或治療疾病之組成物的適當劑型可依不同因素而改變，因素例如製劑方法、給藥方法、病患年齡、體重、性別、病理狀態、食物、給藥時間、給藥路徑、排泄率及反應靈敏性。因此，具有通常知識之醫者可輕易判斷並配出對所欲治療或預防之目標疾病有效的劑量。
根據本發明一實施例，根據本發明之藥學上組成物的每日劑量可為0.001毫克/公斤(mg/kg)至100 mg/kg。使用於此之術語「藥學上有效量」係指足以預防、治療及診斷諸如神經肌肉疾病等之疾病的量。
本發明之用以預防或治療的組成物可依據本發明所屬領域中具有通常知識者可輕易實現的方法，使用藥學上可接受的載體及/或賦形劑來製劑，以提供為單位劑型或裝於多劑量小瓶。於此，製劑可為在油或水介質中之溶液、懸浮液或乳液的形式，或者為萃取物、顆粒(grain)、栓劑、粉劑、顆粒劑、片劑或膠囊劑的形式，製劑可額外包含分散劑或穩定劑。
較佳地，本發明之組成物可製成可注射型式，在此情況下，可注射製劑可為重組凍乾製劑(reconstituted lyophilized formulation)或以準備注射(ready-to-inject，RTI)型式提供的液體製劑，但不限於此。
本發明之組成物可作為單獨治療試劑或與其他治療試劑之組合來給藥，本發明之組成物可與習知之治療試劑依序或同時給藥。
在下文中將參考實施例更詳細描述本發明。對本領域中具有通常知識者顯而易見，這些實施例僅用於示例目的，不解釋為限制本發明的範圍。
實施例1：人類Lefty A融合蛋白的建構
實施例1-1：人類Lefty A蛋白變體的建構
野生型人類Lefty A蛋白的胺基酸序列如下：MWPLWLCWAL WVLPLAGPGA A LTEEQLLGS LLRQLQLSEV PVLDRADMEK LVIPAHVRAQ YVV LLRR SHG DRSRGKR FSQ SFREVAGRFL ASEASTHLLV FGMEQRLPPN SELVQAVLRL FQEPVPKAAL HRHGR LSPRS AQARVTVEWL RVRDDGSNRT SLIDSRLVSV HESGWKAFDV TEAVNFWQQL SRPRQPLLLQ VS VQREHLGP LASGAHKLVR FAS QGAPAGL GEPQLELHTL DLRDYGAQGD CDPEAPMTEG TRCCRQEMYI DLQGMKWAKN WVLEPPGFLA YECVGTCQQP PEALAFNWPFL GPRQCIASE TASLPMIVSI KEGGRTRPQV VSLPNMRVQK CSCASDGAL V PRRLQP (SEQ ID NO: 131)
在此胺基酸序列中，M1至A21對應訊息肽序列，L22至S73對應原胜肽域，R74至R77及R132至R135對應修飾位點。
在加工前之野生型人類Lefty A蛋白為42 kDa之型態，但當包含原胜肽域的區域被原蛋白質轉化酶(proprotein convertase)移除時會被加工成34 kDa或28 kDa之型態。為了闡明這三種型態之蛋白質片段的功能，而建構42 kDa、34 kDa及28 kDa蛋白質的表現載體。
對於42 kDa及34 kDa型態的蛋白質，在建構過程中導入修飾位點突變(42：R74G/R77G/R132G，34：R132G)以防止額外的切割(THE JOURNAL OF BIOLOGICAL CHEMISTRY, Vol. 276, No. 24, Issue of June 15, pp. 21387–21396, 2001)。人類Lefty A之42片段(L22至P366，R74G/R77G/R132G)、34片段(F78至P366，R132G)及28片段(L136至P366)的基因由Bioneer Co., Ltd.(Korea)合成並使用作為PCR模板。使用L1_F(SEQ ID NO: 13)與L2_R(SEQ ID NO: 14)之引子對(primer pair)及ProFlex系統(Applied Biosystems, USA)，依據製造商之手冊在下述條件下，使用Ex標籤(Ex taq，Takara, Japan)進行擴增過程(amplification process)，進而獲得人類Lefty A蛋白的42、34及28片段。條件：22個循環，每個循環由95°C變性(denaturation)60秒鐘、58°C引子貼合(primer annealing)60秒鐘及72°C延伸60秒鐘組成。
實施例1-2：羧基端Fc融合蛋白的建構
藉由將人類IgG1 Fc連結於實施例1之人類Lefty A蛋白變體，建構羧基端Fc融合蛋白(42 Fc(SEQ ID NO: 1)、34 Fc(SEQ ID NO: 2)及28 Fc(SEQ ID NO: 3))之三種表現載體。28 Fc、34 Fc及42 Fc係指Fc融合於各個28 kDa、34 kDa及42 kDa之Lefty A蛋白的羧基端。
使用編碼人類IgG1序列(Uniprot: P01857)的DNA作為模板以及L3_F(SEQ ID NO: 15)與L4_R(SEQ ID NO: 16)之引子對，在與人類Lefty A片段之PCR擴增條件相同的條件下進行擴增，進而獲得人類IgG1片段。所獲得之PCR產物藉由1.5%之瓊脂糖凝膠電泳(agarose gel electrophoresis)來分離，然後在相同的條件下進行組裝PCR反應(assembly PCR reaction)。所獲得之反應產物藉由1.5%之瓊脂糖凝膠電泳分離並純化，然後使用限制酶(restriction enzyme) Hind III與Xho I (NEB，USA)切割。各切割產物與經限制酶Hind III與Xho I切割之pCLS05載體(韓國專利申請第2011-0056685號)在25°C接合60分鐘，然後將接合產物轉形至大腸桿菌DH5α。將轉形之細胞培養於包含100微克/毫升(μg/ml)之胺苄青黴素的LB培養基過夜，並從產生之菌落萃取出質體，然後由Cosmo Genetech Co., Ltd. (Korea)之服務定序，進而確定建構了三種羧基端Fc融合蛋白表現載體。
實施例1-3：羧基端連接鏈Fc融合蛋白的建構
藉由將人類IgG1 Fc透過SGGGGSGGGGSGGGGS連接鏈(SEQ ID NO: 130)連結於人類Lefty A，建構羧基端連接鏈 Fc融合蛋白(42 LFc (SEQ ID NO: 4)、34 LFc (SEQ ID NO: 5)及28 LFc (SEQ ID NO: 6))的三種表現載體。28 LFc、34 LFc及42 LFc係指Fc透過連接鏈融合於各個28 kDa、34 kDa及42 kDa之Lefty A蛋白的羧基端。
人類Lefty A蛋白的42、34及28之片段的獲得方法可與建構羧基端Fc融合蛋白表現載體所述之方法相同。對於連接鏈Fc片段，使用編碼人類IgG1序列(Uniprot: P01857)的DNA作為模板以及L5_F (SEQ ID NO: 17)與L4_R (SEQ ID NO: 16)之引子對，在相同條件下進行PCR擴增，進而獲得人類連接鏈IgG1片段。後續程序與如上所述之關於羧基端Fc融合蛋白之建構相同。
實施例1-4：胺基端Fc融合蛋白的建構
建構胺基端Fc融合蛋白(Fc 42 (SEQ ID NO: 7)、Fc 34 (SEQ ID NO: 8)及Fc 28 (SEQ ID NO: 9))的三種表現載體。Fc 28、Fc 34及Fc 42係指Fc融合於各個28 kDa、34 kDa及42 kDa之Lefty A蛋白的胺基端。
使用L6_F (SEQ ID NO: 18)、L7_F (SEQ ID NO: 19)、L8_F (SEQ ID NO: 20)及L9_R (SEQ ID NO: 21)之引子對，獲得人類Lefty A蛋白的42、34及28片段。各個所獲得之反應產物藉由1.5%之瓊脂糖凝膠電泳分離並純化，然後使用In-Fusion® HD Cloning Kit (Clontech, 639650)在50°C反應15分鐘，將各個所獲得之反應產物與經限制酶Xho I裁切之編碼人類IgG1 Fc之pCLS05載體接合。後續程序與如上所述之關於羧基端Fc融合蛋白之建構相同。
實施例1-5：羧基端HSA融合蛋白的建構
當在動物細胞中表現時，人類IgG1 Fc融合蛋白形成同源二聚體(homodimer)。為此，為了建構單體之融合蛋白，而建構了融合人類血清白蛋白(human serum albumin，HSA)之蛋白質。建構羧基端HSA融合蛋白(42 HSA (SEQ ID NO: 10)、34 HSA (SEQ ID NO: 11)及28 HSA(SEQ ID NO: 12))之三種表現載體。28 HSA、34 HSA及42 HSA係指HSA融合於各個28 kDa、34 kDa及42 kDa之Lefty A蛋白的羧基端。
使用L1_F (SEQ ID NO: 13)與L9_R (SEQ ID NO: 21)之引子對，以相同於實施例1之方法獲得Lefty A蛋白的42、34及28片段。使用限制酶Hind III與Xho I將各片段切割，並將其與經限制酶Hind III與Xho I裁切之pCLS05載體在25°C接合60分鐘。將接合產物轉形至大腸桿菌DH5α。將轉形之細胞培養於包含100微克/毫升(μg/ml)之胺苄青黴素的LB培養基過夜，並從產生之菌落萃取出質體，然後定序，進而確定第一步選殖。
在第二步選殖中，使用由Bioneer合成之人類血清白蛋白基因作為模板以及L10_F (SEQ ID NO: 22)與L11_R (SEQ ID NO: 23)之引子對，在如同實施例1中所使用之PCR條件下，獲得包含人類血清白蛋白的片段。所獲得之PCR產物藉由1.5%之瓊脂糖凝膠電泳分離並純化，然後使用In-Fusion® HD Cloning Kit (Clontech, 639650)在50°C反應15分鐘，將所獲得之PCR產物與經限制酶Xho I裁切之DNA(編碼在第一步選殖中所獲得之人類Lefty A蛋白的42、34及28片段)接合。後續程序與如上所述之關於羧基端Fc融合蛋白之建構相同。
在實施例1-1至實施例1-5中所建構之表現載體的示意圖繪示於圖1，其胺基酸序列揭示於下表1，融合蛋白之建構所使用的引子揭示於下表2。
〔表1〕人類Lefty A融合蛋白的胺基酸序列
  胺基酸序列 SEQ ID NOS:
42 Fc MWPLWLCWALWVLPLAGPGAA LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVVLLRRSHGDRSGGKGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHGHGRLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 1
34 Fc MWPLWLCWALWVLPLAGPGAA FSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHGHGRLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 2
28 Fc MWPLWLCWALWVLPLAGPGAA LSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 3
42 LFc MWPLWLCWALWVLPLAGPGAA LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVVLLRRSHGDRSGGKGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHGHGRLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 4
34 LFc MWPLWLCWALWVLPLAGPGAA FSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHGHGRLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 5
28 LFc MWPLWLCWALWVLPLAGPGAA LSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 6
Fc 42 MGWSCIILFLVATATGVHS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKLTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVVLLRRSHGDRSRGKRFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHRHGRLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQP 7
Fc 34 MGWSCIILFLVATATGVHS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHRHGRLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQP 8
Fc 28 MGWSCIILFLVATATGVHS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQP 9
42 HSA MWPLWLCWALWVLPLAGPGAA LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVVLLRRSHGDRSGGKGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHGHGRLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPDAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAKTCVADESAENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADDRADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPCAEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPKEFNAETFTFHADICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGKKLVAASQAALGL 10
34 HSA MWPLWLCWALWVLPLAGPGAA FSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHGHGRLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPDAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAKTCVADESAENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADDRADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPCAEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPKEFNAETFTFHADICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGKKLVAASQAALGL 11
28 HSA MWPLWLCWALWVLPLAGPGAA LSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPDAHKSEVAHRFKDLGEENFKALVLIAFAQYLQQCPFEDHVKLVNEVTEFAKTCVADESAENCDKSLHTLFGDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRLVRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFYAPELLFFAKRYKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKCASLQKFGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDLLECADDRADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVENDEMPADLPSLAADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPDYSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEPQNLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNLGKVGSKCCKHPEAKRMPCAEDYLSVVLNQLCVLHEKTPVSDRVTKCCTESLVNRRPCFSALEVDETYVPKEFNAETFTFHADICTLSEKERQIKKQTALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKETCFAEEGKKLVAASQAALGL 12
〔表2〕人類Lefty A融合蛋白之建構所使用的引子
引子名稱 序列(5’->3’) SEQ ID NOS:
L1_F AATTAAGCTTGCCACCATGTGGCCTCTGTGGCTCTG 13
L2_R AGGTTGCAATCGTCTTGGGACAAG 14
L3_F CTTGTCCCAAGACGATTGCAACCTGAGCCCAAATCTTGTGACAAA 15
L4_R AATTCTCGAGTCATTTACCCGGAGACAGGGA 16
L5_F GTCCCAAGACGATTGCAACCTAGCGGCGGTGGCGGTTCTGGCGGTGGTGGAAGTGGCGGTGGCGGGTCTGAGCCCAAATCTTGTGAC 17
L6_F CTCTCCCTGTCTCCGGGTAAACTCACCGAAGAGCAGTTGTTG 18
L7_F CTCTCCCTGTCTCCGGGTAAATTCAGCCAATCATTCCGTGAG 19
L8_F CTCTCCCTGTCTCCGGGTAAACTCTCCCCCCGAAGCGCCCAG 20
L9_R GAAGGCACAGCTCGAGTCAAGGTTGCAATCGTCTTGGGACAAG 21
L10_F GTCCCAAGACGATTGCAACCTGACGCTCACAAGTCTGAAGTTGCT 22
L11_R AGATCCACGCGGAACCAGCTCGAGTCACAGCCCCAAAGCGGCCTGTGA 23
實施例1-6：人類Lefty A融合蛋白的暫時表現(Transient Expression)、純化及分析
使用FreestyleTM MAX CHO Expression system表現人類Lefty A及其變體蛋白質。具體而言，使用如上所述之表現載體轉染FreestyleTM CHO-S細胞(Invitrogen，USA)，並使細胞於CHO無血清培養基(CHO serum-free medium，Invitrogen，USA)生長5天。將培養基離心，將上清液回收並過濾，然後稍後用於培養基中Lefty A之蛋白質表現程度分析與純化。
使用MabSelect蛋白A樹脂(MabSelect Protein A resin，GE Healthcare，USA)藉由基於蛋白A之親和性層析法(Protein A-based affinity chromatography)純化來自培養物的融合蛋白。填裝有蛋白A樹脂的管柱以磷酸鹽緩衝液(phosphate-buffered saline，PBS，pH 7.4)平衡，然後將過濾的細胞培養上清液裝入管柱。以10管柱體積(column volume，CV)之PBS沖洗後，再以5管柱體積之沖堤緩衝液(0.1M檸檬酸鈉，Sodium Citrate)沖堤蛋白質，並藉由添加200微升(μl)之1M Tris-HCl(pH 8.0)中和洗出液。為了以PBS(pH 7.4)緩衝液交換經沖堤之重組蛋白分液，而使用Amicon Ultra-15離心過濾器(Amicon Ultra-15 Centrifugal filter) (MWCO: 30000) (Millipore, Cat. No. UFC903096)。混有樣品之純化的蛋白質分液被放置，以4,000 rpm與4°C離心10分鐘，稀釋10倍，然後再離心三次，使得緩衝液交換1,000倍或更多。在乾淨的工作台透過25毫米(mm)之PES針筒過濾器(PES syringe filter，0.22µm；Nalgene, Cat. No. NAL-194-2520)過濾純化之重組蛋白，同時最小化樣品的損失，然後密封並儲存於4°C而不暴露於外界。
使用CaptureSelectTM HSA親合基質(CaptureSelectTM HSA affinity matrix) (ThermoFisher Scientific, USA)或特異性結合HSA之HiTrap Blue HP樹脂(HiTrap Blue HP resin)純化HSA融合蛋白。將過濾之培養上清液通過PBS填充之CaptureSelect親和性管柱，以包含1M氯化鈉之20mM Tris-Cl沖洗，然後使用包含1M精胺酸及1M氯化鈉之20mM Tris-Cl沖堤。或者，將準備之培養上清液通過以20mM磷酸鈉(pH 7.0)作為結合緩衝液填充之HiTrap Blue HP管柱，使得僅所欲之蛋白質結合到樹脂，然後使用20mM磷酸鈉(pH 7.0)、使用2M氯化鈉沖堤蛋白質。完成純化之後，使用NANODROP 2000 分光光譜儀(NANODROP 2000 spectrophotometer，Thermo Scientific, Cat. No. ND-2000)在波長280奈米(nm)量測各分液之蛋白質濃度。為了量測各分液是否包含所欲之蛋白質，使用1200系列HPLC(1200 series HPLC) (Agilent Technologies)與SWxl保護管柱(SWxl Guard column) (TOSOH, Cat. No. 08543)及TSKgel G3000SWxl (TOSOH, Cat. No. 08541)作為粒徑篩析HPLC (size exclusion HPLC)。
各純化之融合蛋白由十二烷基硫酸鈉聚丙烯醯胺凝膠電泳(SDS-PAGE)、粒徑篩析層析法(SEC)分析。SDS-PAGE於Tris/甘胺酸之4-12% 聚丙烯醯胺凝膠(Tris/glycine 4-12% acrylamide gel) (Invitrogen, USA)進行。用於分析之凝膠使用考馬斯亮藍(Coomassie blue)染色並透過數位掃描成像。使用以包含0.02%疊氮化鈉(NaN3 )之磷酸鹽緩衝液平衡的TSK-GEL G300 SWXL管柱(7.8 x 300 mm, Tosohaas, USA)，以0.5毫升/分鐘(ml/min)之流速，藉由粒徑篩析層析法(SEC)分析各純化之蛋白質，進而確定蛋白質的表現程度及純度。結果揭示於下表3。
〔表3〕人類Lefty A融合蛋白的純化產率及純度
蛋白質名稱 產率 (微克/公升) (μg/L) 純度 SEC (%)
42 Fc 63.8 45.9
34 Fc 未表現 -
28 Fc 未表現 -
42 LFc 125 46.2
34 LFc 未表現 -
28 LFc 未表現 -
Fc 42 7.2 -
Fc 34 未表現 -
Fc 28 未表現 -
不論Fc融合位點如何，皆未表現34或28 Fc融合蛋白。在「42」片段的情形中，羧基端融合(「42 Fc」)相較於胺基端融合(「Fc 42」)有更加顯著提升的蛋白質表現效率，尤其在連接鏈Fc融合(「42 LFc」)的情形中，蛋白質表現效率會大大提升。同樣，在HSA融合蛋白的情形中，僅表現42 HSA，而未表現34 HSA或28 HSA。此由培養物之西方墨點法分析(Western blot analysis)證實(圖2)。
依據如上所述之表現數據以及實施例6中所述之體內效能，稍後將使用42 Fc或42 LFc作為變體建構的模板。
實施例2：具有改善之生產性及穩定性之人類Lefty A融合蛋白變體的建構
依據如實施例1所述之表現載體，建構出相較於42 LFc在動物細胞中具有改善之蛋白質穩定性及之表現的Lefty A 融合蛋白變體。
實施例2-1：人類Lefty A融合蛋白變體表現載體的建構
實施例1中所建構之移除原胜肽的融合蛋白大多不被表現。甚至連42 LFc蛋白在宿主細胞內亦表現不佳，純化出之蛋白質純度差且產率低。如圖3所示，在42 LFc蛋白經親和性純化之後，額外較小之條帶(band)出現於SDS-PAGE凝膠上，這可能是由於蛋白質不穩定而在修飾位點的切割或非專一性切割所造成(圖3)。此外，使用ExPASy PeptideCutter DB (https://web.expasy.org/peptide_cutter/)預測由多種酵素及化學物質切割之可能的切割位點，結果預測出在位置311及359的白胺酸殘基可能被凝血酶切割。因此，為了增加人類Lefty A融合蛋白變體的表現程度、穩定性及純化純度，在原胜肽域、修飾位點及位置L311、P313、R314、L359、P361及R362導入突變。使用42 LFc基因作為模板與下表4所示之引子對，在與實施例1中所述之條件相同的條件下藉由PCR獲得各個片段，然後將各個片段進行組裝PCR反應。各個所獲得之反應產物藉由1.5%之瓊脂糖凝膠電泳分離並純化，然後使用In-Fusion® HD Cloning Kit (Clontech, 639650)在50°C反應15分鐘，將各個所獲得之反應產物與經限制酶Hind III與Xho I裁切之pCLS05載體接合。後續程序與如上所述之關於羧基端Fc融合蛋白之建構相同。
〔表4〕人類Lefty A變體之建構所使用的引子
引子名稱 序列 (5’->3’) SEQ ID NOS:
L12_F ACTCTAGAGGATCGAACCCTT 24
L12_R GCTGGCAACTAGAAGGCACAGCTCGAGTCATTTACCCGGAGACAGGGAGAGGCT 25
L13_F GGGGCCGCTCTCACAGRGGAGCAGKTGCTCGGGTCATTGTTG 26
L13_R CAACAATGACCCGAGCAMCTGCTCCYCTGTGAGAGCGGCCCC 27
L14_F CTCGGGTCATTGTTGAGGCAGCTTCAGCTTTCC 28
L14_R GGAAAGCTGAAGCTGCCTCAACAATGACCCGAG 29
L15_F CTTCAGCTTTCCGAAGTGCCCGTCCTGGACAAG 30
L15_R CTTGTCCAGGACGGGCACTTCGGAAAGCTGAAG 31
L16_F CCACCCGTCCTGGACARGGCCGATRTGGAGGGGCTCGTTATC 32
L16_R GATAACGAGCCCCTCCAYATCGGCCYTGTCCAGGACGGGTGG 33
L17_F AAGGCCGATGTCGAGAAGCTCGTTATCCCATCC 34
L17_R GGATGGGATAACGAGCTTCTCGACATCGGCCTT 35
L18_F GGGCTCGTTATCCCAGCCCATGTCCGGGCTCAG 36
L18_R CTGAGCCCGGACATGGGCTGGGATAACGAGCCC 37
L19_F CGGGCTCAGTACGTTGTGTTGCTGCAACATTCA 38
L19_R TGAATGTTGCAGCAACACAACGTACTGAGCCCG 39
L20_F TACGTTGCCTTGCTGAGACGGTCACACGCTAGTAGA 40
L20_R TCTACTAGCGTGTGACCGTCTCAGCAAGGCAACGTA 41
L21_F CTGCAACATTCACACGSAKMCAGAAGTGGAGGCAAG 42
L21_R CTTGCCTCCACTTCTGKMTSCGTGTGAATGTTGCAG 43
L22_F TACGTTGCCTTGCTGCRGCRCTCACACGCTAGTAGA 44
L22_R TCTACTAGCGTGTGAGYGCYGCAGCAAGGCAACGTA 45
L23_F GGGGCCGCCCTCACCGGCGAGCAGTTGTTGGGC 46
L23_R GCCCAACAACTGCTCGCCGGTGAGGGCGGCCCC 47
L24_F CGCGCCCAATATGTGGYCCTGCTCCRGCGATCTCACGGAGAT 48
L24_R ATCTCCGTGAGATCGCYGGAGCAGGRCCACATATTGGGCGCG 49
L25_F CGCGCCCAATATGTGGCCCTGCTCCRGCACTCTCACGGAGATAGG 50
L25_R CCTATCTCCGTGAGAGTGCYGGAGCAGGGCCACATATTGGGCGCG 51
L26_F AAGGCCGATGTCGAGAAGCTCGTTATCCCAGCCCATGTCCGGGCTCAG 52
L26_R CTGAGCCCGGACATGGGCTGGGATAACGAGCTTCTCGACATCGGCCTT 53
L27_F AAGGCTGCCCTGCACCGGCATGGTCGTCTCTCCCCCCGAAGC 54
L27_R GCTTCGGGGGGAGAGACGACCATGCCGGTGCAGGGCAGCCTT 55
L28_F CTGCACGGCCATGGTGGCCTCTCCCCCCGAAGC 56
L28_R GCTTCGGGGGGAGAGGCCACCATGGCCGTGCAG 57
L29_F AGGAGCAGGGGCAAGGYCTTCAGCCAATCATTC 58
L29_R GAATGATTGGCTGAAGRCCTTGCCCCTGCTCCT 59
L30_F CTGCACCGGCATGGTGYCCTCTCCCCCCGAAGC 60
L30_R GCTTCGGGGGGAGAGGRCACCATGCCGGTGCAG 61
L31_F CTGCACCGGCATGGTGGCCTCTCCCCCCGAAGC 62
L31_R GCTTCGGGGGGAGAGGCCACCATGCCGGTGCAG 63
L32_F CTCCTTCTGCAAGTGNNKGTCCAGCGCGAACAC 64
L32_R GTGTTCGCGCTGGACMNNCACTTGCAGAAGGAG 65
L33_F CTGGTGCGATTCGCTNNKCAGGGTGCACCAGCC 66
L33_R GGCTGGTGCACCCTGMNNAGCGAATCGCACCAG 67
L34_F TTCAACTGGCCCTTTGASGGACCTCGGCAATGTATTGCCAGC 68
L34_R GCTGGCAATACATTGCCGAGGTCCSTCAAAGGGCCAGTTGAA 69
L35_F TTCAACTGGCCCTTTCTCGGAGASCGGCAATGTATTGCCAGC 70
L35_R GCTGGCAATACATTGCCGSTCTCCGAGAAAGGGCCAGTTGAA 71
L36_F TTCAACTGGCCCTTTCTCGGATCCCGGCAATGTATTGCCAGC 72
L36_R GCTGGCAATACATTGCCGGGATCCGAGAAAGGGCCAGTTGAA 73
L37_F TTCAACTGGCCCTTTCTCGGACCTMAGCAATGTATTGCCAGC 74
L37_R GCTGGCAATACATTGCTKAGGTCCGAGAAAGGGCCAGTTGAA 75
L38_F GCCTCTGACGGGGCTGASGTCCCAAGACGATTGCAACCTTCT 76
L38_R AGAAGGTTGCAATCGTCTTGGGACSTCAGCCCCGTCAGAGGC 77
L39_F GCCTCTGACGGGGCTCTTGTCGASAGACGATTGCAACCTTCT 78
L39_R AGAAGGTTGCAATCGTCTSTCGACAAGAGCCCCGTCAGAGGC 79
L40_F GCCTCTGACGGGGCTCTTGTCTCCAGACGATTGCAACCTTCT 80
L40_R AGAAGGTTGCAATCGTCTGGAGACAAGAGCCCCGTCAGAGGC 81
L41_F GCCTCTGACGGGGCTCTTGTCCCAMAGCGATTGCAACCTTCT 82
L41_R AGAAGGTTGCAATCGCTKTGGGACAAGAGCCCCGTCAGAGGC 83
L42_F GCCTCTGACGGGGCTCTTGTCGACCAGCGATTGCAACCTTCT 84
L42_R AGAAGGTTGCAATCGCTGGTCGACAAGAGCCCCGTCAGAGGC 85
變體的胺基酸序列揭示於下表5，在變體中發生在42 LFc之序列中在原胜肽域(L22至S73)之胺基酸殘基的取代。
〔表5〕人類Lefty A融合蛋白變體(原胜肽域變體)的胺基酸序列
  胺基酸序列 SEQ ID NOS:
42 LFc (V63A) MWPLWLCWALWVLPLAGPGAA LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVALLRRSHGDRSGGKGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHGHGRLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 86
42 LFc (R66Q) MWPLWLCWALWVLPLAGPGAA LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVVLLQRSHGDRSGGKGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHGHGRLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 87
42 LFc (V63A/R66Q) MWPLWLCWALWVLPLAGPGAA LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVALLQRSHGDRSGGKGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHGHGRLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 88
42 LFc (V63A/R67H) MWPLWLCWALWVLPLAGPGAA LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVALLRHSHGDRSGGKGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHGHGRLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 89
42 LFc (V63A/R66Q/R67H) MWPLWLCWALWVLPLAGPGAA LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVALLQHSHGDRSGGKGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHGHGRLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 90
LFB 42 LFc MWPLWLCWALWVLPLAGPGAA LTGEQLLGSLLRQLQLKEVPTLDRADMEELVIPTHVRAQYVALLQRSHGDRSGGKGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHGHGRLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 91
LFB 42 LFc為一變體，在此變體中發生在42 LFc之序列中E24G、S38K、V42T、K50E、A55T、V63A及R66Q的胺基酸殘基取代。
變體的胺基酸序列揭示於下表6，在變體中發生在42 LFc之序列中在修飾位點(R74至R77及R132至R135)之胺基酸殘基的取代。
〔表6〕人類Lefty A融合蛋白變體(修飾位點變體)的胺基酸序列
  胺基酸序列 SEQ ID NOS:
42 LFc V1 MWPLWLCWALWVLPLAGPGAA LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVVLLRRSHGDRSGGKGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHRHGRLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 92
42 LFc V2 MWPLWLCWALWVLPLAGPGAA LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVVLLRRSHGDRSGGKGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHRHGGLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 93
42 LFc V3 MWPLWLCWALWVLPLAGPGAA LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVVLLRRSHGDRSGGKGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHRHERLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 94
42 LFc V4 MWPLWLCWALWVLPLAGPGAA LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVVLLRRSHGDRSGGKGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHGHGGLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 95
42 LFc V5 MWPLWLCWALWVLPLAGPGAA LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVVLLRRSHGDRSRGKAFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHGHGRLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 96
42 LFc V6 MWPLWLCWALWVLPLAGPGAA LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVVLLRRSHGDRSRGKAFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHRHGALSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 97
42 LFc V7 MWPLWLCWALWVLPLAGPGAA LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVVLLRRSHGDRSRGKAFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHRHGVLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 98
42 LFc V8 MWPLWLCWALWVLPLAGPGAA LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVVLLRRSHGDRSRGKVFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHGHGRLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 99
42 LFc V9 MWPLWLCWALWVLPLAGPGAA LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVVLLRRSHGDRSRGKVFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHRHGALSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 100
42 LFc V10 MWPLWLCWALWVLPLAGPGAA LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVVLLRRSHGDRSRGKVFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHRHGVLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 101
42 LFc V11 MWPLWLCWALWVLPLAGPGAA LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVVLLRRSHGDRSRHGGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHRHGGLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 102
42 LFc V12 MWPLWLCWALWVLPLAGPGAA LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVVLLRRSHGDRSRGKGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHRHGGLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 103
42 LFc V13 MWPLWLCWALWVLPLAGPGAA LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVVLLRRSHGDRSRGKAFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHRHGGLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 104
42 LFc V1為一變體，在此變體中發生在42 LFc之序列中G132R的胺基酸殘基取代；42 LFc V2為一變體，在此變體中發生在42 LFc之序列中G132R及R135G的胺基酸殘基取代；42 LFc V3為一變體，在此變體中發生在42 LFc之序列中G132R及G134E的胺基酸殘基取代。42 LFc V4為一變體，在此變體中發生在42 LFc之序列中R135G的胺基酸殘基取代；42 LFc V5為一變體，在此變體中發生在42 LFc之序列中G74R及G77A的胺基酸殘基取代；42 LFc V6為一變體，在此變體中發生在42 LFc之序列中G74R、G77A、G132R及R135A的胺基酸殘基取代；42 LFc V7為一變體，在此變體中發生在42 LFc之序列中G74R、G77A、G132R及R135V的胺基酸殘基取代；42 LFc V8為一變體，在此變體中發生在42 LFc之序列中G74R及G77V的胺基酸殘基取代；42 LFc V9為一變體，在此變體中發生在42 LFc之序列中G74R、G77V、G132R及R135A的胺基酸殘基取代；42 LFc V10為一變體，在此變體中發生在42 LFc之序列中G74R、G77V、G132R及R135V的胺基酸殘基取代；42 LFc V11為一變體，在此變體中發生在42 LFc之序列中G74R、G75H、K76G、G132R及R135G的胺基酸殘基取代；42 LFc V12為一變體，在此變體中發生在42 LFc之序列中G74R、G132R及R135G的胺基酸殘基取代；42 LFc V13為一變體，在此變體中發生在42 LFc之序列中G74R、G77A、G132R及R135G的胺基酸殘基取代。
下表7揭示變體的胺基酸序列，在變體中發生下述胺基酸殘基的取代：如上述表5所示之在原胜肽域(L22至S73)之胺基酸殘基的取代；如上述表6所示之在修飾位點(R74至R77及R132至R135)之胺基酸殘基的取代；以及額外在斷裂位點(S202或S223)之胺基酸殘基的取代。
〔表7〕Lefty A 融合蛋白變體(組合)的胺基酸序列
  胺基酸序列 SEQ ID NOS:
CX196 MWPLWLCWALWVLPLAGPGAA LTGEQLLGSLLRQLQLKEVPTLDRADMEELVIPTHVRAQYVALLQRSHGDRSGGKGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHRHGGLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 105
CX197 MWPLWLCWALWVLPLAGPGAA LTGEQLLGSLLRQLQLKEVPTLDRADMEELVIPTHVRAQYVALLQRSHGDRSGGKGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHRHGALSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 106
CX201 MWPLWLCWALWVLPLAGPGAA LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVALLQRSHGDRSGGKGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHRHGGLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 107
CX203 MWPLWLCWALWVLPLAGPGAA LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVALLQRSHGDRSGGKGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHRHERLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 108
CX206 MWPLWLCWALWVLPLAGPGAA LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVALLQRSHGDRSGGKGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHRHGGLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVTVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 109
CX207 MWPLWLCWALWVLPLAGPGAA LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVALLQRSHGDRSGGKGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHRHGGLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFAGQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 110
CX208 MWPLWLCWALWVLPLAGPGAA LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVALLQRSHGDRSGGKGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHRHGGLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVTVQREHLGPLASGAHKLVRFAGQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 111
CX196為一變體，在此變體中發生在42 LFc之序列中E24G、S38K、V42T、K50E、A55T、V63A、R66Q、G132R及R135G的胺基酸殘基取代；CX197為一變體，在此變體中發生在42 LFc之序列中E24G、S38K、V42T、K50E、A55T、V63A、R66Q、G132R及R135A的胺基酸殘基取代。
CX201為一變體，在此變體中發生在42 LFc之序列中V63A、R66Q、G132R及R135A的胺基酸殘基取代；CX203為一變體，在此變體中發生在42 LFc之序列中V63A、R66Q、G132R及G134E的胺基酸殘基取代。
CX206為一變體，在此變體中發生在42 LFc之序列中V63A、R66Q、G132R、R135G及S202T的胺基酸殘基取代；CX207為一變體，在此變體中發生在42 LFc之序列中V63A、R66Q、G132R、R135G及S223G的胺基酸殘基取代；CX208為一變體，在此變體中發生在42 LFc之序列中V63A、R66Q、G132R、R135G、S202T及S223G的胺基酸殘基取代。
下表8揭示變體的胺基酸序列，在變體中發生在CX201之序列中在凝血酶切割位點(L311、P313、R314、L359、P361或R362)之胺基酸殘基的取代，CX201如上述表7所示。
〔表8〕人類Lefty A融合蛋白變體(凝血酶切割位點)的胺基酸序列
  胺基酸序列 SEQ ID NOS:
CX201 (L311D) MDMRVPAQLLGLLLLWFPGSRC LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVALLQRSHGDRSGGKGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHRHGGLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFDGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 112
CX201 (L311E) MDMRVPAQLLGLLLLWFPGSRC LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVALLQRSHGDRSGGKGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHRHGGLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFEGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 113
CX201 (P313D) MDMRVPAQLLGLLLLWFPGSRC LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVALLQRSHGDRSGGKGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHRHGGLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGDRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 114
CX201 (P313E) MDMRVPAQLLGLLLLWFPGSRC LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVALLQRSHGDRSGGKGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHRHGGLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGERQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 115
CX201 (P313S) MDMRVPAQLLGLLLLWFPGSRC LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVALLQRSHGDRSGGKGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHRHGGLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGSRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 116
CX201 (R314K) MDMRVPAQLLGLLLLWFPGSRC LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVALLQRSHGDRSGGKGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHRHGGLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPKQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 117
CX201 (R314Q) MDMRVPAQLLGLLLLWFPGSRC LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVALLQRSHGDRSGGKGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHRHGGLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPQQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 118
CX201 (L359D) MDMRVPAQLLGLLLLWFPGSRC LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVALLQRSHGDRSGGKGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHRHGGLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGADVPRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 119
CX201 (L359E) MDMRVPAQLLGLLLLWFPGSRC LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVALLQRSHGDRSGGKGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHRHGGLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGAEVPRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 120
CX201 (P361D) MDMRVPAQLLGLLLLWFPGSRC LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVALLQRSHGDRSGGKGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHRHGGLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVDRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 121
CX201 (P361E) MDMRVPAQLLGLLLLWFPGSRC LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVALLQRSHGDRSGGKGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHRHGGLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVERRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 122
CX201 (P361S) MDMRVPAQLLGLLLLWFPGSRC LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVALLQRSHGDRSGGKGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHRHGGLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVSRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 123
CX201 (R362K) MDMRVPAQLLGLLLLWFPGSRC LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVALLQRSHGDRSGGKGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHRHGGLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPKRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 124
CX201 (R362Q) MDMRVPAQLLGLLLLWFPGSRC LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVALLQRSHGDRSGGKGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHRHGGLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPQRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 125
CX201 (L311D/R362Q) MDMRVPAQLLGLLLLWFPGSRC LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVALLQRSHGDRSGGKGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHRHGGLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFDGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPQRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 126
CX201 (L311E/R362Q) MDMRVPAQLLGLLLLWFPGSRC LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVALLQRSHGDRSGGKGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHRHGGLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFEGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPQRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 127
CX201 (L311D/P361D/R362Q) MDMRVPAQLLGLLLLWFPGSRC LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVALLQRSHGDRSGGKGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHRHGGLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFDGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVDQRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 128
CX201 (L311E/P361D/R362Q) MDMRVPAQLLGLLLLWFPGSRC LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVALLQRSHGDRSGGKGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHRHGGLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFEGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVDQRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 129
對於凝血酶切割位點，使用抗體衍生之MDMRVPAQLLGLLLLWFPGSRC (UniProt: A0A0C4DH73；SEQ ID NO: 132)序列作為訊息序列。
實施例2-2：暫時表現與純化
將所建構之表現載體轉染，以相同於實施例1之方法表現蛋白質並純化，然後分析蛋白質的表現程度及純度。結果揭示於下表9至12。
在第一次親和性純化後，用作為變體建構之基礎的42-LFc融合蛋白顯示約2.8 μg/ml的表現程度，當以SE-HPLC量測時顯示約64.3%的平均蛋白質純度。以LFB取代原胜肽域而獲得之Lefty A變體在表現上顯示約7.5倍的提升，當以SE-HPLC量測時顯示約83%的平均蛋白質純度。對於人類Lefty A之原胜肽域的V63A之取代提升約2倍之表現程度，V63A/R66Q之雙取代提升約2.3倍之表現程度 (表9)。
〔表9〕人類Lefty A融合蛋白變體(原胜肽域變體)的表現程度與純度
蛋白質名稱 表現程度(μg/ml) 表現程度倍數 SE-HPLC純度(%)
42 LFc 2.8 1.0 64.3
LFB 42 LFc 21.0 7.5 83.2
42 LFc(V63A) 5.2 1.9 81.7
42 LFc(R66Q) 1.8 0.6 65.3
42 LFc(V63A/R66Q) 6.5 2.3 78.2
42 LFc(V63A/R67H) 6.2 2.2 65.8
42 LFc(V63A/R66Q/R67H) 5.5 2.0 72.9
在修飾位點導入序列突變，結果在42 LFc V2以SE-HPLC量測之蛋白質純度為84.1%，42 LFc V2的表現程度與導入突變前的表現程度相似。42 LFc V6顯示90.9%之最高的蛋白質純度，但相較於導入突變前，42 LFc V6的表現程度降低至約60% (表10)。
［表10］人類Lefty A融合蛋白變體(修飾位點變體)的表現程度與純度
蛋白質名稱 表現程度 (μg/ml) 表現程度倍數 SE-HPLC 純度(%)
42 LFc 2.8 1.0 64.3
42 LFc V1 1.6 0.6 71.6
42 LFc V2 2.3 0.8 84.1
42 LFc V4 1.6 0.6 63.6
42 LFc V6 1.8 0.6 90.9
42 LFc V7 1.7 0.6 -
42 LFc V10 1.5 0.5 -
42 LFc V11 1.9 0.7 79.9
42 LFc V12 2.4 0.9 81.4
42 LFc V13 3.0 1.1 84.3
分析人類Lefty A融合蛋白變體(組合)，結果使用LFB原胜肽所獲得之CX196在表現程度上顯示約1.8倍的提升，以及在蛋白質純度上提升至94.1%；使用人類原胜肽所獲得之CX201在表現程度上顯示約1.9倍的提升，以及在蛋白質純度上提升至91.3% (表11及圖4)。
〔表11〕人類Lefty A融合蛋白變體(組合)的表現程度與純度
蛋白質名稱 表現程度 (μg/ml) 表現程度 fold SE-HPLC 純度 (%)
42 LFc 2.8 1.0 64.3
CX196 5.1 1.8 94.1
CX197 5.1 1.8 88.2
CX201 5.2 1.9 91.3
CX206 5.9 2.1 90.6
CX207 6.1 2.2 86.8
CX208 6.1 2.2 85.5
分析人類Lefty A融合蛋白變體(凝血酶切割位點)，結果P361S之單一突變在表現程度顯示1.5倍的提升。L311D/R362Q之雙突變、L311E/R362Q之雙突變、L311D/P361D/R362Q之三突變及L311E/P361D/R362Q之三突變皆顯示約95%的蛋白質純度(對應為約9%之提升)以及在表現程度1.5倍的提升(表12)。
〔表12〕人類Lefty A融合蛋白變體(凝血酶切割位點)的表現程度與純度
蛋白質名稱 表現程度 (μg/ml) 表現程度倍數 SE-HPLC 純度 (%)
CX201 6.9 1.0 85.9
CX201(L311D) 8.6 1.2 91.7
CX201(L311E) 7.8 1.1 91.8
CX201(P313D) 6.4 0.9 88.6
CX201(P313E) 7.1 1.0 84.9
CX201(P313S) 6.5 0.9 79.9
CX201(R314K) 7.2 1.0 91.1
CX201(R314Q) 6.4 0.9 92.3
CX201(L359D) 5.9 0.9 88.0
CX201(L359E) 6.3 0.9 87.9
CX201(P361D) 6.1 0.9 90.6
CX201(P361E) 6.9 1.0 86.7
CX201(P361S) 10.1 1.5 84.5
CX201(R362K) 9.1 1.3 85.4
CX201(R362Q) 9.5 1.4 87.5
CX201(L311D/R362Q) 10.1 1.5 95.4
CX201(L311E/R362Q) 10.8 1.6 96.6
CX201(L311D/P361D/R362Q) 10.1 1.5 95.3
CX201(L311E/P361D/R362Q) 10.7 1.5 95.6
實施例3：在血清中之穩定性的改善
使用在實施例2所建構之人類Lefty A融合蛋白變體(凝血酶切割位點)，進行體外血清穩定性測試。各蛋白變體稀釋於小鼠血清或血漿至最終濃度為10 μg/ml，在37°C培養4小時，然後由夾心式酵素免疫吸附法(Sandwich ELISA)分析。藉由在體外環境下量測血清中之各人類Lefty A變體的相對剩餘量以分析在小鼠血清中的穩定性，相對於CX201之各個變體的相對穩定性揭示於下表13。證實當發生諸如L311D、L311E、P361D或R362Q之假定的凝血酶切割位點突變時，在血清中變體的穩定性提升。
〔表13〕在37°C培養4小時後在血清中的相對穩定性
蛋白質樣本 在血清中的相對穩定性
CX201(L311D) 1.31
CX201(L311E) 1.32
CX201(P313D) 1.12
CX201(P313E) 0.97
CX201(P313S) 0.90
CX201(R314K) 1.03
CX201(R314Q) 1.08
CX201(L359D) 1.19
CX201(L359E) 1.18
CX201(P361D) 1.23
CX201(P361E) 1.13
CX201(P361S) 0.83
CX201(R362K) 1.17
CX201(R362Q) 1.27
CX201(L311D/R362Q) 1.13
CX201(L311E/R362Q) 1.22
CX201(L311D/P361D/R362Q) 1.15
CX201(L311E/P361D/R362Q) 1.16
CX201 1.00
實施例4：對Nodal之結合親和性的量測
使用BIAcore量測人類Nodal蛋白與人類Lefty A融合蛋白變體之間的結合親和性。
具體而言，將50 RU之人類Nodal (R&D systems, 3218-ND-025/CF)蛋白固定於CM5感測器晶片(CM5 sensor chip)。將人類Lefty A融合蛋白及其變體稀釋成500、250、125、62.5及31.25 nM之濃度，並從較低濃度開始依序注入。接著，以30 μl/min之流速注射3分鐘使各稀釋液連結(associate)，並使用運行緩衝液(running buffer)使各稀釋液解離(dissociate)5分鐘。使用15 μl之50 mM氫氧化鈉將晶片再生。使用BIAevaluation軟體版本4.1之「Bivalent analyte」模式，評估各循環的連結與解離，BIAcore數據統整於下表14。
〔表14〕Lefty A融合蛋白及其變體對人類Nodal的親和性
  ka1 kd1 ka2 kd2 KD (nM)
42 LFc 1.18 x 104 8.6 x 10-4 8.19 x 10-3 4.46 x 10-2 72.9
CX197 3.11 x 102 1.66 x 10-3 2.77 x 10-4 2.3 x 10-5 533.8
CX201 8.71 x 102 1.08 x 10-3 5.46 x 10-3 3.41 x 10-2 124
實施例5：藉由人類Lefty A蛋白預防內質網壓力誘導之許旺細胞的凋亡
在本研究中，為了辨識用以治療遺傳性周邊神經病變的物質，使用誘導內質網壓力之藥物(endoplasmic reticulum stress-inducing drug)開發了許旺細胞模型，並將許旺細胞模型用於藥物辨識。
首先，當間質幹細胞(mesenchymal stem cell)共培養於內質網壓力細胞模型時，細胞死亡被有效抑制而內質網壓力降低。當與間質幹細胞共培養時，可防止內質網壓力誘導之許旺細胞的凋亡。具體而言，將毒胡蘿蔔素(thapsigargin)誘導之內質網壓力誘導至通孔反應室(transwell chamber)中的S16許旺細胞，然後在上腔室共培養臍帶衍生之間質幹細胞(umbilical cord-derived mesenchymal stem cell，MSC)(圖5中之「+ MSC」)，分析S16細胞的死亡。此時，臍帶衍生之間質幹細胞的共培養抑制S16許旺細胞的死亡約30%或更多(圖5，「Thap」表示毒胡蘿蔔素，「Thap 3h」及「Thap 3h w/o」表示以毒胡蘿蔔素處理3小時後再洗掉。)。
從此結果，可推斷由臍帶幹細胞(umbilical cord stem cell)分泌的旁泌因子(paracrine factor)抑制許旺細胞的死亡。再者，進行細胞介素抗體陣列(cytokine antibody array)以辨識從間質幹細胞分泌的治療性蛋白質。在許旺細胞增加為2倍或更多的情況下，分析在與許旺細胞共培養的過程中從臍帶幹細胞分泌之蛋白質。尤其，觀察到Lefty A蛋白的分泌有效增加。
實施例6：在Tr-J小鼠中藉由人類Lefty A融合蛋白改善神經功能
為了測試人類Lefty A融合蛋白是否改善神經功能，使用Trembler-J (Tr-J)小鼠進行電生理研究，Trembler-J (Tr-J)小鼠為用於CMT1的動物模型(Meekins et al., J Peripher Nerv Syst 9(3):177-82 (2004))。Tr-J小鼠為自發突變小鼠，其中在PMP22基因發生L16P突變。Tr-J小鼠具有周邊神經脫髓鞘(peripheral nerve demyelination)的表現型並在神經傳導速度及複合肌肉動作電位(compound muscle action potential，CMAP)表現降低，如在CMT1患者所見(Henry et al., J Neuropathol Exp Neurol 2(6):688-706 (1983); Valentijin et al., Nat Genet 2(4):288-911992 (1992))。
從出生後第6天(p6)至出生後第20天(p20)每兩天一次使用PBS或人類Lefty A融合蛋白(1 μg/kg)腹腔內注射Tr-J小鼠，共注射8次。在神經傳導研究的前一天，將覆蓋後肢的毛剔除並脫毛。隔天，麻醉小鼠，將活性誘導針電極(active recording needle electrode)放置於腓肚肌(gastrocnemius muscle)，參考電極放置於誘導電極之下，以評估在小鼠之坐骨神經(sciatic nerve)的神經傳導。刺激陰極(stimulus cathode)放置於距離誘導電極6毫米之髖部(hip region)，使用Nicolet VikingQuest (Natus Medical, San Carlos, CA)裝置量測複合肌肉動作電位(CMAP)的振幅與運動神經傳導速度(the motor nerve conduction velocity，MNCV)。
如圖6及下表15所示，神經傳導研究顯示42 LFc融合蛋白改善Tr-J小鼠的神經功能。
〔表15〕在Tr-J小鼠中Lefty A融合蛋白對神經傳導的電生理影響
藥物 遠端CMAP (mV) 近端CMAP (mV) MNCV (m/s)
PBS 13.7 ± 1.1 11.8 ± 1.2 13.9 ± 0.9
42-LFc 16.9 ± 1.1* 15.6 ± 1.1* 16.2 ± 1.7
42-HSA 11.6 ± 0.8 10.1 ± 0.7 14.7 ± 0.8
*p>0.05
在1 μg/kg之劑量時，相較於PBS或HSA融合蛋白，LFc融合人類Lefty A蛋白顯著提升Tr-J小鼠的複合肌肉動作電位(CMAP)與運動神經傳導速度(MNCV)。這些數據顯示人類Lefty A融合蛋白可使用於改善神經病變患者的神經功能。
實施例7：藉由人類Lefty A融合蛋白變體促進許旺細胞髓鞘化(Myelination)
在RT4-D6P2T許旺細胞之Lefty A融合蛋白變體(42 LFc; X-42)的處理，造成Krox20及髓鞘鹼性蛋白(myelin basic protein，MBP)的表現增加(圖7A)，Krox20為許旺細胞髓鞘化之重要的轉錄調控子，髓鞘鹼性蛋白在髓鞘化的過程中被誘導。
另一方面，在RT4-D6P2T許旺細胞之Nodal的處理造成Krox20的表現降低，而藉由Lefty A融合蛋白變體可恢復由Nodal造成之髓鞘化的抑制(圖7B及圖7C)。這些結果顯示Lefty A融合蛋白變體可促進許旺細胞髓鞘化，可由抑制作為許旺細胞髓鞘化之負調控子的Nodal來達成。
實施例8：在C 22小鼠(p6小鼠)中藉由人類Lefty A融合蛋白變體(X-42)的腹腔內注射(Intraperitoneal Injection，IP)改善神經和運動功能
C22 [品系來源: (C57BL/6J x CBA/CA)F1]小鼠為基因轉殖小鼠，攜帶7份人類PMP22基因並具有嚴重之周邊神經脫髓鞘化的表現型，C22小鼠作為夏馬杜三氏病1A型(CMT1A)動物模型已被廣泛研究(Robertson et al., J Anat 200(4):377-90 (2002); Norreel et al., Neuroscience 116(3):695-703 (2003))。從出生後第6天(p6)至出生後第24天(p24)每兩天一次將10 μg/kg之劑量的人類Lefty A融合蛋白變體(42 LFc; X-42)腹腔內給予小鼠，共10次，評估神經傳導與肌肉運動表現。
實施例8-1：神經傳導研究
在神經傳導研究的前一天，將覆蓋後肢的毛剔除並脫毛。隔天，麻醉小鼠，將活性誘導針電極(active recording needle electrode)放置於腓肚肌(gastrocnemius muscle)，參考電極放置於誘導電極之下，以評估在小鼠之坐骨神經(sciatic nerve)的神經傳導。刺激陰極(stimulus cathode)放置於距離誘導電極6毫米之髖部(hip region)，使用Nicolet VikingQuest (Natus Medical, San Carlos, CA)裝置量測複合肌肉動作電位(CMAP)的振幅與運動神經傳導速度(the motor nerve conduction velocity，MNCV)。相較於野生型小鼠，C22小鼠在運動神經傳導速度(MNCV)與複合肌肉動作電位(CMAP)上顯示出顯著的降低。在另一方面，相較於給予載體組(vehicle-administered group)，給予人類Lefty A融合蛋白變體之C22小鼠在運動神經傳遞速度(MNCV)與複合肌肉動作電位(CMAP)上顯示出顯著的提升(圖8)。
實施例8-2：行為分析
為了評估運動功能，進行滾輪測試(rotarod test)及後肢握力分析(hindlimb grip strength analysis)。
具體上，藉由將小鼠放置於3公分水平轉動桿(2 m/min)然後量測維持時間來進行滾輪測試。小鼠在測試前受訓3天，每周進行四次測試。記錄從滾輪掉落的潛伏時間(latency)，最大限制設為5分鐘。如圖9所示，C22小鼠的運動能力(locomotor performance)遠低於野生型(WT)小鼠的運動能力。在滾輪測試中，給予人類Lefty A融合蛋白變體顯著改善C22小鼠的運動能力(圖9A)。
使用握力測量計(grip strength meter)評估3至4週齡之C22小鼠的後肢握力。使小鼠背向測量計並以其後肢擱置於傾斜的網格組件(angled mesh assembly)。一旦小鼠以其後腳趾抓住金屬柵或三角形拉桿，小鼠將會以固定速度由尾巴直接拉向測量計。力的峰值以克為單位由裝置記錄。相較於野生型小鼠，C22小鼠具有降低的後肢握力，而人類Lefty A蛋白變體的治療對握力顯示出顯著的治療效果(圖9B)。給予人類Lefty A融合蛋白變體之C22小鼠的後肢握力增加約3倍(圖9B)。
實施例9：在C22小鼠(p6小鼠)中藉由人類Lefty A融合蛋白變體(X-42)的腹腔內注射(Intraperitoneal Injection，IP)增加肌肉質量(muscle mass)
使用6天大(p6)之野生型(WT)小鼠或C22小鼠測試由人類Lefty A融合蛋白變體所造成之肌肉質量的改變。從出生後第6天(p6)至出生後第24天(p24)每兩天一次將PBS或人類Lefty A融合蛋白變體(10 μg/kg)腹腔內給予小鼠，共10次，然後使用磁振造影(magnetic resonance imaging)量測腓肚肌區域。人類Lefty A融合蛋白變體的給藥顯示在CMT1模型小鼠以及野生型小鼠中肌肉質量顯著提升(圖10)。
實施例10：在C22小鼠(p6小鼠)中藉由人類Lefty A融合蛋白變體(X-42)的腹腔內注射(Intraperitoneal Injection，IP)改善步態(Gait)
為了闡明Lefty A融合蛋白變體對C22小鼠之步態的影響，將PBS或人類Lefty A融合蛋白變體(10 μg/kg)腹腔內給予6天大之小鼠，共10次(每兩天一次)。在允許小鼠通過受限路徑後，監測步態，分析髖、膝蓋及踝關節角度以及兩個參數(步幅(stride length)和支撐基礎(base of support，BOS))(圖11)。步幅由追蹤右後爪及左後爪來計算，BOS值計算步幅的左右來決定。結果，在使用Lefty A融合蛋白變體給藥的小鼠組可觀察到骨盆跨度長度(pelvic stride length)的改善(圖11之右圖)。
相較於野生型小鼠，由於步態異常C22小鼠在髖、膝蓋及踝關節角度顯示出顯著的差異。然而，當將lefty A融合蛋白給予C22小鼠時，C22小鼠之在角度上的變化減少(圖11之左下圖)。此結果顯示神經肌肉功能可被改善至某程度，但不及野生型小鼠的程度。
實施例11：在C22小鼠(p6小鼠)中藉由人類Lefty A融合蛋白變體(CX201)的腹腔內注射(Intraperitoneal Injection，IP)改善神經與運動功能
使用0.2 mg/kg之劑量的人類Lefty A 融合蛋白變體CX201每兩天一次共10次腹腔內注射C22小鼠。注射早在出生後第6天開始，即使在正常情況下髓鞘化尚未開始。接著，如上述實施例8所述，進行神經傳導研究與行為分析。
相較於給予載體組(vehicle-administered group)，使用人類Lefty A融合蛋白變體 CX201注射的C22小鼠在運動神經傳遞速度(MNCV)與複合肌肉動作電位(CMAP)上顯現顯著的提升(圖12，「TG」表示基因轉殖(transgenic) C22小鼠。)。
此外，如圖13所示，相較於載體控制組，注射CX201之C22小鼠在後肢握力與滾輪(rotarod)之運動表現上顯示統計學上顯著的改善(圖13，「TG」表示基因轉殖C22小鼠。)。
實施例12：在C22小鼠(p6小鼠)中藉由人類Lefty A融合蛋白變體(CX201)的腹腔內注射(Intraperitoneal Injection，IP)對步態的影響
為了闡明Lefty A 融合蛋白變體 CX201對C22小鼠之步態的影響，將PBS或人類Lefty A融合蛋白變體(200 μg/kg) 腹腔內給予6天大之小鼠，共10次(每兩天一次)，然後進行如實施例10所述之步態分析。
尤其，從一腳跟到下一腳跟之步幅的分析顯示使用Lefty A 融合蛋白變體給予C22小鼠的步態受到顯著改善(圖14)。
實施例13：在C22小鼠(p21小鼠)中藉由人類Lefty A融合蛋白變體的皮下注射(Subcutaneous Injection)改善神經與運動功能
在出生後第21天(p21)，髓鞘化發展主要出現時，將人類Lefty A融合蛋白變體CX201皮下注射C22小鼠，然後如上述實施例8所述，進行神經傳導研究與行為分析。
相較於給予載體組，使用CX201給藥4周的C22小鼠在運動神經傳導速度與複合肌肉動作電位兩者上顯現顯著的增加(圖15，「CX201(0.2)」表示給予0.2 mg/kg之劑量的CX201，「CX201(1)」表示給予1 mg/kg之劑量的CX201。)。尤其，雄鼠的後肢握力增加，具有統計顯著性(圖16，「TG」表示基因轉殖C22小鼠，「CX201(0.2)」表示給予0.2 mg/kg之劑量的CX201，「CX201(1)」表示給予1 mg/kg之劑量的CX201。)。這些數據顯示在髓鞘分化晚期以及產後早期給予融合蛋白變體CX201可改善神經及運動功能。
實施例14：藉由人類Lefty A融合蛋白變體抑制肌肉生長抑制素傳訊
使用報導基因(Reporter gene)以評估人類Lefty A融合蛋白變體是否可抑制肌肉生長抑制素傳訊。使用Smad-反應性螢光素酶報導載體pGL4.48 (Smad-reactive luciferase reporter vector pGL4.48，Promega, USA)轉染橫紋肌肉瘤(Rhabdomyosarcoma) A204細胞，然後透過抗生素篩選以篩選出與載體穩定轉染的細胞。將肌肉生長抑制素與濃度漸增之人類Lefty A 融合蛋白變體預培養(pre-incubate)45分鐘。在加入培養基之後，將細胞培養6小時，然後使用bio-glo螢光素酶分析試劑(bio-glo lucierase assay reagent，Promega, USA)偵測由肌肉生長抑制素誘導之螢光素酶活性。肌肉生長抑制素在穩定導入載體之細胞株(cell line)中誘導出強的螢光素酶表現，人類Lefty A融合蛋白變體劑量依賴地抑制肌肉生長抑制素傳訊(圖17)。
實施例15：藉由人類Lefty A融合蛋白變體抑制p38傳訊
已知TGF-β家族BMP7藉由p38的磷酸化來抑制髓鞘基因(myelin gene)的表現並延遲周邊髓鞘化(Liu X et al., Sci Rep 6:31049 (2016))。因此，探討人類Lefty A融合蛋白變體是否可抑制p38磷酸化。具體而言，如實施例7所述，將人類Lefty A融合蛋白變體給予C22小鼠，使用西方墨點法分析坐骨神經之磷酸化的p38。
如圖18所示，在給予人類Lefty A融合蛋白變體之C22小鼠的坐骨神經中，p38的磷酸化受到抑制，MBP蛋白的表現增增加。這些數據顯示人類Lefty A融合蛋白變體可藉由阻擋髓鞘化之負調控子之p38傳訊來促進髓鞘化。因此，人類Lefty A融合蛋白可用作為治療周邊神經病變的試劑，周邊神經病變例如由脫髓鞘化所造成之神經退化性疾病(neurodegenerative disease)。
實施例16：生產人類Lefty A融合蛋白變體之細胞株的建構
在125毫升錐形瓶中以密度1x106 細胞/毫升(cells/mL)將CHO-S (cGMP-banked)細胞接種至30毫升之CD-FortiCHO培養基。將50微克之插入有人類Lefty A融合蛋白變體 (CX201；在CX201融合蛋白中之包含抗體衍生之MDMRVPAQLLGLLLLWFPGSRC序列作為訊息序列；透過SGGGGSGGGGSGGGGS連接鏈將人類Lefty A連接至人類IgG1 Fc；如表16所示之SEQ ID NO: 133)基因的表現載體放入50毫升之錐形管，加入OptiPRO SFM至最終體積為1.5毫升，然後渦旋震盪(vortexing)。將Freestyle MAX溶液加入DNA溶液，然後使溶液靜置於室溫10分鐘。10分鐘後，將包含細胞的錐形瓶以DNA-Freestyle MAX試劑(DNA-Freestyle MAX reagent complex)處理以轉形細胞。
依序進行第一次篩選和第二次篩選以誘導基因擴增。使用ClonePix從第一次和第二次篩選完成後所獲得之池(pool)中顯示最高表現程度之池中選擇生產細胞株的CX201。將所選之殖株(clone)種菌培養(seed-cultured) 6天，然後懸浮於冷凍培養基(CD-FortiCHO medium 90% + DMSO 10%)至濃度1.0 x 107 細胞/毫升(cells/mL)，將1毫升之懸浮液分配至各個冷凍管(cryotube)，進而製備研究細胞庫(research cell bank，RCD)。
〔表16〕人類Lefty A融合蛋白變體的胺基酸序列
  胺基酸序列 SEQ ID NO:
CX201s MDMRVPAQLLGLLLLWFPGSRC LTEEQLLGSLLRQLQLSEVPVLDRADMEKLVIPAHVRAQYVALLQRSHGDRSGGKGFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSELVQAVLRLFQEPVPKAALHRHGGLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVHESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAGLGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPPGFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNMRVQKCSCASDGALVPRRLQPSGGGGSGGGGSGGGGS EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 133
CX201為一變體，在此變體中發生在42 LFc之序列中V63A、R66Q、G132R及R135A的胺基酸殘基取代；CX203為一變體，在此變體中發生在42 LFc之序列中V63A、R66Q、G132R及G134E的胺基酸殘基取代
實施例17：在C22小鼠(p35小鼠)中藉由人類Lefty A融合蛋白變體的皮下注射(Subcutaneous Injection)改善神經運動功能
使用人類Lefty A融合蛋白變體CX201皮下給予經歷周邊神經髓鞘化之五週齡的C22小鼠(p35)，以5 mg/kg之劑量一週一次或兩次或以10 mg/kg之劑量一週一次的頻率。如實施例8所述，進行神經功能的電生理評估。相較於給予載體組，給予CX201的C22小鼠在神經傳導速度(NCV)與複合肌肉動作電位(CMAP)兩者上顯示出顯著的提升(圖19，「5 mpk」表示5 mg/kg之劑量，「10 mpk」表示10 mg/kg之劑量，「QW」表示一周一次，「BIW」表示一周兩次。)。
進行滾輪測試與握力分析以評估運動功能。對於滾輪測試，小鼠放置於以12 rpm轉動的桿子上，記錄從桿子掉落的潛伏時間，最大限制設為200秒鐘。如圖19所示，相較於載體控制組，注射CX201之C22小鼠之在滾輪上的運動能力受到顯著改善。此外，使用握力測量計量測小鼠的全肢(whole-limb)握力以評估小鼠的神經肌肉功能。當使用CX201以5 mg/kg之劑量一週兩次的頻率注射C22小鼠時，全肢握力受到統計學上顯著改善(圖20，「5 mpk」表示5 mg/kg之劑量，「10 mpk」表示10 mg/kg之劑量，「QW」表示一周一次，「BIW」表示一周兩次。)。
綜上所述，將人類Lefty A融合蛋白變體 CX201皮下注射至5週齡之C22小鼠四週或更久會改善C22小鼠的神經傳導與運動功能。尤其，以5 mg/kg之劑量一週兩次的頻率給予CX201為最有效。
實施例18：藉由人類Lefty A融合蛋白變體抑制Nodal傳訊
Nodal為TGF-β的一員，Nodal活化Smad傳訊(Smad signaling)。一旦Nodal結合促進素受體(activin receptor)，Smad2與Smad3會被磷酸化並結合Smad4移動至細胞核，然後調控多種基因的轉錄。使用Nodal反應性P19小鼠胚胎癌細胞株(Nodal-responsive P19 mouse embryonic cancer cell line)來評估人類Lefty A融合蛋白變體對Nodal誘導之Smad傳訊的影響。
將Nodal與多種濃度之人類Lefty A融合蛋白變體CX201預培養30分鐘。單獨以Nodal或以Nodal-Lefty A融合蛋白變體處理細胞1小時，然後使用細胞裂解物由西方墨點法分析評估由Nodal誘導之Smad3磷酸化。以Nodal蛋白單獨處理細胞誘導出強的Smad3磷酸化，Smad3磷酸化被人類Lefty A融合蛋白變體劑量依賴地抑制(圖21)。
根據本發明，建構一種人類Lefty A蛋白變體及包含此變體之融合蛋白，相較於天然產生之人類Lefty A蛋白具有較佳的穩定性，因此在動物細胞中以高程度表現並以高產量生產。此外，給予所建構之人類Lefty A蛋白變體或融合蛋白可恢復周邊神經病變之動物模型的神經及運動功能。因此，使用人類Lefty A蛋白變體或融合蛋白可有效預防或治療多種神經疾病及肌肉疾病。
儘管已參考圖式詳細描述本發明，但對本領域中具有通常知識者顯而易見，這些描述僅用於較佳的實施例，並不限制本發明的範圍。因此，本發明的實質範圍由申請專利範圍及其同等物來限定。
無。
圖1為人類Lefty A融合蛋白的示意圖。 圖2顯示培養上清液的西方墨點法分析(Western blot analysis)，以評估融合人類血清白蛋白(human serum albumin，HSA-fused)之人類Lefty A蛋白變體的表現。 圖3顯示經ProA親和性純化(ProA Affinity purification)後之42 LFc蛋白的SDS-PAGE分析。 圖4顯示經ProA親和性純化後之Lefty A蛋白變體(組合)的SDS-PAGE分析及粒徑篩析層析法(size exclusion chromatography，SEC)分析。 圖5顯示使用抗PARP抗體(anti-PARP antibody)的細胞活力分析(cell viability assay)和西方墨點法分析，以評估與人類花頓氏膠衍生之人類間質幹細胞(human Wharton's jelly-derived human mesenchymal stem cell，MSC)共培養之對由毒胡蘿蔔素(thapsigargin)誘導之S16許旺細胞(Schwann cell)凋亡的影響。 圖6顯示人類Lefty A 融合蛋白變體在Tr-J小鼠中之治療效果的電生理評估(electrophysiological assessment)。 圖7顯示西方墨點法分析，以評估在使用Nodal或/及人類LeftyA融合蛋白變體處理之RT4許旺細胞中(A)Krox20與MBP或(B)、(C)Krox20與磷酸化/未磷酸化p35的表現。 圖8顯示在C22小鼠中腹腔內注射(intraperitoneal injection)人類Lefty A融合蛋白變體之治療效果的電生理評估。 圖9顯示腹腔內注射人類Lefty A融合蛋白變體之C22小鼠的(A)滾輪測試(rotarod test)及(B)後肢握力測試(hindlimb grip strength)。 圖10顯示腹腔內注射人類Lefty A融合蛋白變體之C22小鼠之腓肚肌(gastrocnemius muscle)的磁振造影分析(magnetic resonance imaging analysis)。 圖11顯示腹腔內注射人類Lefty A融合蛋白變體之野生型小鼠及C22小鼠的步態分析(gait analysis)。 圖12顯示在C22小鼠腹腔內注射人類Lefty A融合蛋白變體之治療效果的電生理評估。 圖13顯示腹腔內注射人類Lefty A融合蛋白變體之C22小鼠的(A)後肢握力測試及(B)滾輪測試。 圖14顯示腹腔內注射人類Lefty A融合蛋白變體之C22小鼠的步態分析。 圖15顯示從3週齡開始皮下注射人類Lefty A融合蛋白變體4週之C22小鼠的電生理分析。 圖16顯示從3週齡開始皮下注射人類Lefty A融合蛋白變體4週之C22小鼠的後肢握力測試。 圖17顯示依據A204細胞之螢光素酶報導分析(A204 cell-based luciferase reporter assay)，以評估人類Lefty A融合蛋白變體對藉由肌肉生長抑制素之傳訊的影響。 圖18顯示注射人類Lefty A融合蛋白變體之C22小鼠之坐骨神經(sciatic nerve)裂解物的西方墨點法分析。 圖19顯示從5週齡開始皮下注射人類Lefty A融合蛋白變體4週之C22小鼠的電生理分析。 圖20顯示從5週齡開始皮下注射人類Lefty A融合蛋白變體4週之C22小鼠的(A)滾輪測試及(B)全肢握力測試。 圖21顯示西方墨點法分析以評估人類Lefty A融合蛋白變體對P19細胞中Nodal傳訊的影響。 圖22a~22j和圖23a~23m顯示根據本發明之人類Lefty A融合蛋白變體的胺基酸序列。
<110> 南韓商鐘根堂股份有限公司(CHONG KUN DANG PHARMACEUTICAL CORP.) 社會福祉法人三星生命公益財團(SAMSUNG LIFE PUBLIC WELFARE FOUNDATION)
<120> 包含人類Lefty A蛋白變體的融合蛋白及其用途
<130> P19-B239
<150> KR 2018-0166802
<151> 2018-12-20
<160> 178
<170> KoPatentIn 3.0
<210> 1
<211> 598
<212> 蛋白質
<213> 人工序列
<220>
<223> 42 Fc
<400> 1
Figure 108146308-A0305-02-0108-1
His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu 100                 105                 110 Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala 115                 120                 125 Ala Leu His Gly His Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg 130                 135                 140 Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr 145                 150                 155                 160 Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys 165                 170                 175 Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg 180                 185                 190 Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu 195                 200                 205 Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln 210                 215                 220 Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu 225                 230                 235                 240 Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro 245                 250                 255 Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu 260                 265                 270 Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe 275                 280                 285 Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu 290                 295                 300 Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu 305                 310                 315                 320 Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr 325                 330                 335 Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser 340                 345                 350 Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Glu Pro 355                 360                 365 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 370                 375                 380 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 385                 390                 395                 400 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 405                 410                 415 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 420                 425                 430 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 435                 440                 445 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 450                 455                 460 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 465                 470                 475                 480 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 485                 490                 495 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 500                 505                 510 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 515                 520                 525 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 530                 535                 540 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 545                 550                 555                 560 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 565                 570                 575 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 580                 585                 590 Ser Leu Ser Pro Gly Lys 595 >210>    2 >211>    542 >212>    蛋白質 >213>    人工序列 >220> >223>    34 Fc >400>    2 Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala 1               5                  10                  15 Gly Pro Gly Ala Ala Phe Ser Gln Ser Phe Arg Glu Val Ala Gly Arg 20                  25                  30 Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe Gly Met Glu 35                  40                  45 Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val Leu Arg Leu 50                  55                  60 Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Gly His Gly Arg Leu 65                  70                  75                  80 Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp Leu Arg Val 85                  90                  95 Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser Arg Leu Val 100                 105                 110 Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr Glu Ala Val 115                 120                 125 Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu Leu Leu Gln 130                 135                 140 Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser Gly Ala His 145                 150                 155                 160 Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly Leu Gly Glu 165                 170                 175 Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr Gly Ala Gln 180                 185                 190 Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr Arg Cys Cys 195                 200                 205 Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp Ala Lys Asn 210                 215                 220 Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys Val Gly Thr 225                 230                 235                 240 Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro Phe Leu Gly 245                 250                 255 Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro Met Ile Val 260                 265                 270 Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val Ser Leu Pro 275                 280                 285 Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly Ala Leu Val 290                 295                 300 Pro Arg Arg Leu Gln Pro Glu Pro Lys Ser Cys Asp Lys Thr His Thr 305                 310                 315                 320 Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe 325                 330                 335 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 340                 345                 350 Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 355                 360                 365 Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 370                 375                 380 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 385                 390                 395                 400 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 405                 410                 415 Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser 420                 425                 430 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 435                 440                 445 Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 450                 455                 460 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 465                 470                 475                 480 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 485                 490                 495 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 500                 505                 510 Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 515                 520                 525 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 530                 535                 540 >210>    3 >211>    484 >212>    蛋白質 >213>    人工序列 >220> >223>    28 Fc >400>    3 Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala 1               5                  10                  15 Gly Pro Gly Ala Ala Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr 20                  25                  30 Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu 35                  40                  45 Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe 50                  55                  60 Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg 65                  70                  75                  80 Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro 85                  90                  95 Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala 100                 105                 110 Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu 115                 120                 125 Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr 130                 135                 140 Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly 145                 150                 155                 160 Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala 165                 170                 175 Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe 180                 185                 190 Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala 195                 200                 205 Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro 210                 215                 220 Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala 225                 230                 235                 240 Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Glu Pro Lys Ser 245                 250                 255 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 260                 265                 270 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 275                 280                 285 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 290                 295                 300 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 305                 310                 315                 320 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 325                 330                 335 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 340                 345                 350 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 355                 360                 365 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 370                 375                 380 Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val 385                 390                 395                 400 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 405                 410                 415 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 420                 425                 430 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 435                 440                 445 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 450                 455                 460 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 465                 470                 475                 480 Ser Pro Gly Lys >210>    4 >211>    614 >212>    蛋白質 >213>    人工序列 >220> >223>    42 LFc >400>    4 Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala 1               5                  10                  15 Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu 20                  25                  30 Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met 35                  40                  45 Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Val Leu 50                  55                  60 Leu Arg Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln 65                  70                  75                  80 Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr 85                  90                  95 His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu 100                 105                 110 Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala 115                 120                 125 Ala Leu His Gly His Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg 130                 135                 140 Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr 145                 150                 155                 160 Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys 165                 170                 175 Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg 180                 185                 190 Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu 195                 200                 205 Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln 210                 215                 220 Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu 225                 230                 235                 240 Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro 245                 250                 255 Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu 260                 265                 270 Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe 275                 280                 285 Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu 290                 295                 300 Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu 305                 310                 315                 320 Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr 325                 330                 335 Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser 340                 345                 350 Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly 355                 360                 365 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro 370                 375                 380 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 385                 390                 395                 400 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 405                 410                 415 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 420                 425                 430 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 435                 440                 445 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 450                 455                 460 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 465                 470                 475                 480 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 485                 490                 495 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 500                 505                 510 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 515                 520                 525 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 530                 535                 540 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 545                 550                 555                 560 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 565                 570                 575 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 580                 585                 590 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 595                 600                 605 Ser Leu Ser Pro Gly Lys 610 >210>    5 >211>    558 >212>    蛋白質 >213>    人工序列 >220> >223>    34 LFc >400>    5 Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala 1               5                  10                  15 Gly Pro Gly Ala Ala Phe Ser Gln Ser Phe Arg Glu Val Ala Gly Arg 20                  25                  30 Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe Gly Met Glu 35                  40                  45 Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val Leu Arg Leu 50                  55                  60 Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Gly His Gly Arg Leu 65                  70                  75                  80 Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp Leu Arg Val 85                  90                  95 Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser Arg Leu Val 100                 105                 110 Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr Glu Ala Val 115                 120                 125 Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu Leu Leu Gln 130                 135                 140 Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser Gly Ala His 145                 150                 155                 160 Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly Leu Gly Glu 165                 170                 175 Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr Gly Ala Gln 180                 185                 190 Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr Arg Cys Cys 195                 200                 205 Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp Ala Lys Asn 210                 215                 220 Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys Val Gly Thr 225                 230                 235                 240 Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro Phe Leu Gly 245                 250                 255 Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro Met Ile Val 260                 265                 270 Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val Ser Leu Pro 275                 280                 285 Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly Ala Leu Val 290                 295                 300 Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly 305                 310                 315                 320 Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys Thr His Thr 325                 330                 335 Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe 340                 345                 350 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 355                 360                 365 Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 370                 375                 380 Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 385                 390                 395                 400 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 405                 410                 415 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 420                 425                 430 Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser 435                 440                 445 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 450                 455                 460 Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 465                 470                 475                 480 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 485                 490                 495 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 500                 505                 510 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 515                 520                 525 Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 530                 535                 540 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 545                 550                 555 >210>    6 >211>    500 >212>    蛋白質 >213>    人工序列 >220> >223>    28 LFc >400>    6 Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala 1               5                  10                  15 Gly Pro Gly Ala Ala Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr 20                  25                  30 Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu 35                  40                  45 Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe 50                  55                  60 Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg 65                  70                  75                  80 Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro 85                  90                  95 Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala 100                 105                 110 Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu 115                 120                 125 Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr 130                 135                 140 Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly 145                 150                 155                 160 Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala 165                 170                 175 Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe 180                 185                 190 Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala 195                 200                 205 Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro 210                 215                 220 Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala 225                 230                 235                 240 Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly 245                 250                 255 Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser 260                 265                 270 Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu 275                 280                 285 Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu 290                 295                 300 Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser 305                 310                 315                 320 His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu 325                 330                 335 Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr 340                 345                 350 Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn 355                 360                 365 Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro 370                 375                 380 Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln 385                 390                 395                 400 Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val 405                 410                 415 Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val 420                 425                 430 Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro 435                 440                 445 Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr 450                 455                 460 Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val 465                 470                 475                 480 Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu 485                 490                 495 Ser Pro Gly Lys 500 >210>    7 >211>    596 >212>    蛋白質 >213>    人工序列 >220> >223>    Fc 42 >400>    7 Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly 1               5                  10                  15 Val His Ser Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro 20                  25                  30 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 35                  40                  45 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 50                  55                  60 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 65                  70                  75                  80 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 85                  90                  95 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 100                 105                 110 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 115                 120                 125 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 130                 135                 140 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp 145                 150                 155                 160 Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 165                 170                 175 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 180                 185                 190 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 195                 200                 205 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 210                 215                 220 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 225                 230                 235                 240 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Leu Thr Glu Glu Gln 245                 250                 255 Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu Ser Glu Val Pro Val 260                 265                 270 Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile Pro Ala His Val Arg 275                 280                 285 Ala Gln Tyr Val Val Leu Leu Arg Arg Ser His Gly Asp Arg Ser Arg 290                 295                 300 Gly Lys Arg Phe Ser Gln Ser Phe Arg Glu Val Ala Gly Arg Phe Leu 305                 310                 315                 320 Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe Gly Met Glu Gln Arg 325                 330                 335 Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val Leu Arg Leu Phe Gln 340                 345                 350 Glu Pro Val Pro Lys Ala Ala Leu His Arg His Gly Arg Leu Ser Pro 355                 360                 365 Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp 370                 375                 380 Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val 385                 390                 395                 400 His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe 405                 410                 415 Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser 420                 425                 430 Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu 435                 440                 445 Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln 450                 455                 460 Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp 465                 470                 475                 480 Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln 485                 490                 495 Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val 500                 505                 510 Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln 515                 520                 525 Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg 530                 535                 540 Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile 545                 550                 555                 560 Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met 565                 570                 575 Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly Ala Leu Val Pro Arg 580                 585                 590 Arg Leu Gln Pro 595 >210>    8 >211>    540 >212>    蛋白質 >213>    人工序列 >220> >223>    Fc 34 >400>    8 Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly 1               5                  10                  15 Val His Ser Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro 20                  25                  30 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 35                  40                  45 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 50                  55                  60 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 65                  70                  75                  80 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 85                  90                  95 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 100                 105                 110 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 115                 120                 125 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 130                 135                 140 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp 145                 150                 155                 160 Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 165                 170                 175 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 180                 185                 190 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 195                 200                 205 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 210                 215                 220 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 225                 230                 235                 240 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Phe Ser Gln Ser Phe 245                 250                 255 Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu 260                 265                 270 Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val 275                 280                 285 Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu 290                 295                 300 His Arg His Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr 305                 310                 315                 320 Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu 325                 330                 335 Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe 340                 345                 350 Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg 355                 360                 365 Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro 370                 375                 380 Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala 385                 390                 395                 400 Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu 405                 410                 415 Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr 420                 425                 430 Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly 435                 440                 445 Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala 450                 455                 460 Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe 465                 470                 475                 480 Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala 485                 490                 495 Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro 500                 505                 510 Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala 515                 520                 525 Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro 530                 535                 540 >210>    9 >211>    482 >212>    蛋白質 >213>    人工序列 >220> >223>    Fc 28 >400>    9 Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly 1               5                  10                  15 Val His Ser Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro 20                  25                  30 Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro 35                  40                  45 Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr 50                  55                  60 Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn 65                  70                  75                  80 Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg 85                  90                  95 Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val 100                 105                 110 Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser 115                 120                 125 Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys 130                 135                 140 Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp 145                 150                 155                 160 Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe 165                 170                 175 Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu 180                 185                 190 Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe 195                 200                 205 Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly 210                 215                 220 Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr 225                 230                 235                 240 Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Leu Ser Pro Arg Ser 245                 250                 255 Ala Gln Ala Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly 260                 265                 270 Ser Asn Arg Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu 275                 280                 285 Ser Gly Trp Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln 290                 295                 300 Gln Leu Ser Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln 305                 310                 315                 320 Arg Glu His Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg 325                 330                 335 Phe Ala Ser Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu 340                 345                 350 Leu His Thr Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp 355                 360                 365 Pro Glu Ala Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met 370                 375                 380 Tyr Ile Asp Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu 385                 390                 395                 400 Pro Pro Gly Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro 405                 410                 415 Pro Glu Ala Leu Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys 420                 425                 430 Ile Ala Ser Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu 435                 440                 445 Gly Gly Arg Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val 450                 455                 460 Gln Lys Cys Ser Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu 465                 470                 475                 480 Gln Pro >210>    10 >211>    951 >212>    蛋白質 >213>    人工序列 >220> >223>    42 HSA >400>    10 Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala 1               5                  10                  15 Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu 20                  25                  30 Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met 35                  40                  45 Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Val Leu 50                  55                  60 Leu Arg Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln 65                  70                  75                  80 Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr 85                  90                  95 His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu 100                 105                 110 Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala 115                 120                 125 Ala Leu His Gly His Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg 130                 135                 140 Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr 145                 150                 155                 160 Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys 165                 170                 175 Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg 180                 185                 190 Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu 195                 200                 205 Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln 210                 215                 220 Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu 225                 230                 235                 240 Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro 245                 250                 255 Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu 260                 265                 270 Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe 275                 280                 285 Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu 290                 295                 300 Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu 305                 310                 315                 320 Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr 325                 330                 335 Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser 340                 345                 350 Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Asp Ala 355                 360                 365 His Lys Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu Glu Asn 370                 375                 380 Phe Lys Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys 385                 390                 395                 400 Pro Phe Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu Phe Ala 405                 410                 415 Lys Thr Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu 420                 425                 430 His Thr Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu Arg Glu 435                 440                 445 Thr Tyr Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg 450                 455                 460 Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu Pro Arg 465                 470                 475                 480 Leu Val Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His Asp Asn 485                 490                 495 Glu Glu Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His 500                 505                 510 Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys 515                 520                 525 Ala Ala Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu 530                 535                 540 Leu Pro Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala 545                 550                 555                 560 Lys Gln Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala 565                 570                 575 Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala 580                 585                 590 Glu Phe Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys Val His 595                 600                 605 Thr Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala 610                 615                 620 Asp Leu Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys 625                 630                 635                 640 Leu Lys Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His Cys Ile 645                 650                 655 Ala Glu Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser Leu Ala 660                 665                 670 Ala Asp Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala 675                 680                 685 Lys Asp Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg Arg His 690                 695                 700 Pro Asp Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu 705                 710                 715                 720 Thr Thr Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu Cys Tyr 725                 730                 735 Ala Lys Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro Gln Asn 740                 745                 750 Leu Ile Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys 755                 760                 765 Phe Gln Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro Gln Val 770                 775                 780 Ser Thr Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys Val Gly 785                 790                 795                 800 Ser Lys Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys Ala Glu 805                 810                 815 Asp Tyr Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His Glu Lys 820                 825                 830 Thr Pro Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser Leu Val 835                 840                 845 Asn Arg Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr Tyr Val 850                 855                 860 Pro Lys Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp Ile Cys 865                 870                 875                 880 Thr Leu Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala Leu Val 885                 890                 895 Glu Leu Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala 900                 905                 910 Val Met Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys Ala Asp 915                 920                 925 Asp Lys Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val Ala Ala 930                 935                 940 Ser Gln Ala Ala Leu Gly Leu 945                 950 >210>    11 >211>    895 >212>    蛋白質 >213>    人工序列 >220> >223>    34 HSA >400>    11 Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala 1               5                  10                  15 Gly Pro Gly Ala Ala Phe Ser Gln Ser Phe Arg Glu Val Ala Gly Arg 20                  25                  30 Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe Gly Met Glu 35                  40                  45 Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val Leu Arg Leu 50                  55                  60 Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Gly His Gly Arg Leu 65                  70                  75                  80 Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp Leu Arg Val 85                  90                  95 Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser Arg Leu Val 100                 105                 110 Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr Glu Ala Val 115                 120                 125 Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu Leu Leu Gln 130                 135                 140 Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser Gly Ala His 145                 150                 155                 160 Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly Leu Gly Glu 165                 170                 175 Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr Gly Ala Gln 180                 185                 190 Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr Arg Cys Cys 195                 200                 205 Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp Ala Lys Asn 210                 215                 220 Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys Val Gly Thr 225                 230                 235                 240 Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro Phe Leu Gly 245                 250                 255 Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro Met Ile Val 260                 265                 270 Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val Ser Leu Pro 275                 280                 285 Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly Ala Leu Val 290                 295                 300 Pro Arg Arg Leu Gln Pro Asp Ala His Lys Ser Glu Val Ala His Arg 305                 310                 315                 320 Phe Lys Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu Val Leu Ile Ala 325                 330                 335 Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp His Val Lys Leu 340                 345                 350 Val Asn Glu Val Thr Glu Phe Ala Lys Thr Cys Val Ala Asp Glu Ser 355                 360                 365 Ala Glu Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp Lys Leu 370                 375                 380 Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met Ala Asp Cys 385                 390                 395                 400 Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln His Lys 405                 410                 415 Asp Asp Asn Pro Asn Leu Pro Arg Leu Val Arg Pro Glu Val Asp Val 420                 425                 430 Met Cys Thr Ala Phe His Asp Asn Glu Glu Thr Phe Leu Lys Lys Tyr 435                 440                 445 Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu 450                 455                 460 Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr Glu Cys Cys Gln 465                 470                 475                 480 Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp Glu Leu Arg 485                 490                 495 Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu Lys Cys Ala Ser 500                 505                 510 Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val Ala Arg 515                 520                 525 Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu Val Ser Lys Leu 530                 535                 540 Val Thr Asp Leu Thr Lys Val His Thr Glu Cys Cys His Gly Asp Leu 545                 550                 555                 560 Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Ile Cys Glu 565                 570                 575 Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys Glu Lys Pro 580                 585                 590 Leu Leu Glu Lys Ser His Cys Ile Ala Glu Val Glu Asn Asp Glu Met 595                 600                 605 Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp Phe Val Glu Ser Lys Asp 610                 615                 620 Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly Met Phe 625                 630                 635                 640 Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser Val Val Leu Leu 645                 650                 655 Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys Cys Cys Ala 660                 665                 670 Ala Ala Asp Pro His Glu Cys Tyr Ala Lys Val Phe Asp Glu Phe Lys 675                 680                 685 Pro Leu Val Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys Glu Leu 690                 695                 700 Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Leu Val Arg 705                 710                 715                 720 Tyr Thr Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val Glu Val 725                 730                 735 Ser Arg Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His Pro Glu 740                 745                 750 Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser Val Val Leu Asn 755                 760                 765 Gln Leu Cys Val Leu His Glu Lys Thr Pro Val Ser Asp Arg Val Thr 770                 775                 780 Lys Cys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro Cys Phe Ser Ala 785                 790                 795                 800 Leu Glu Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala Glu Thr 805                 810                 815 Phe Thr Phe His Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu Arg Gln 820                 825                 830 Ile Lys Lys Gln Thr Ala Leu Val Glu Leu Val Lys His Lys Pro Lys 835                 840                 845 Ala Thr Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe Ala Ala Phe 850                 855                 860 Val Glu Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe Ala Glu 865                 870                 875                 880 Glu Gly Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly Leu 885                 890                 895 >210>    12 >211>    837 >212>    蛋白質 >213>    人工序列 >220> >223>    28 HSA >400>    12 Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala 1               5                  10                  15 Gly Pro Gly Ala Ala Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr 20                  25                  30 Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu 35                  40                  45 Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe 50                  55                  60 Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg 65                  70                  75                  80 Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro 85                  90                  95 Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala 100                 105                 110 Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu 115                 120                 125 Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr 130                 135                 140 Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly 145                 150                 155                 160 Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala 165                 170                 175 Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe 180                 185                 190 Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala 195                 200                 205 Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro 210                 215                 220 Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala 225                 230                 235                 240 Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Asp Ala His Lys 245                 250                 255 Ser Glu Val Ala His Arg Phe Lys Asp Leu Gly Glu Glu Asn Phe Lys 260                 265                 270 Ala Leu Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe 275                 280                 285 Glu Asp His Val Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys Thr 290                 295                 300 Cys Val Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr 305                 310                 315                 320 Leu Phe Gly Asp Lys Leu Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr 325                 330                 335 Gly Glu Met Ala Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu 340                 345                 350 Cys Phe Leu Gln His Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu Val 355                 360                 365 Arg Pro Glu Val Asp Val Met Cys Thr Ala Phe His Asp Asn Glu Glu 370                 375                 380 Thr Phe Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr 385                 390                 395                 400 Phe Tyr Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala 405                 410                 415 Phe Thr Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro 420                 425                 430 Lys Leu Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln 435                 440                 445 Arg Leu Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys 450                 455                 460 Ala Trp Ala Val Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe 465                 470                 475                 480 Ala Glu Val Ser Lys Leu Val Thr Asp Leu Thr Lys Val His Thr Glu 485                 490                 495 Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu 500                 505                 510 Ala Lys Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys 515                 520                 525 Glu Cys Cys Glu Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala Glu 530                 535                 540 Val Glu Asn Asp Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp 545                 550                 555                 560 Phe Val Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp 565                 570                 575 Val Phe Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp 580                 585                 590 Tyr Ser Val Val Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr 595                 600                 605 Leu Glu Lys Cys Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala Lys 610                 615                 620 Val Phe Asp Glu Phe Lys Pro Leu Val Glu Glu Pro Gln Asn Leu Ile 625                 630                 635                 640 Lys Gln Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln 645                 650                 655 Asn Ala Leu Leu Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr 660                 665                 670 Pro Thr Leu Val Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ser Lys 675                 680                 685 Cys Cys Lys His Pro Glu Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr 690                 695                 700 Leu Ser Val Val Leu Asn Gln Leu Cys Val Leu His Glu Lys Thr Pro 705                 710                 715                 720 Val Ser Asp Arg Val Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Arg 725                 730                 735 Arg Pro Cys Phe Ser Ala Leu Glu Val Asp Glu Thr Tyr Val Pro Lys 740                 745                 750 Glu Phe Asn Ala Glu Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu 755                 760                 765 Ser Glu Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu 770                 775                 780 Val Lys His Lys Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala Val Met 785                 790                 795                 800 Asp Asp Phe Ala Ala Phe Val Glu Lys Cys Cys Lys Ala Asp Asp Lys 805                 810                 815 Glu Thr Cys Phe Ala Glu Glu Gly Lys Lys Leu Val Ala Ala Ser Gln 820                 825                 830 Ala Ala Leu Gly Leu 835 >210>    13 >211>    36 >212>    DNA >213>    人工序列 >220> >223>    L1_F >400>    13 aattaagctt gccaccatgt ggcctctgtg gctctg                                   36 >210>    14 >211>    24 >212>    DNA >213>    人工序列 >220> >223>    L2_R >400>    14 aggttgcaat cgtcttggga caag                                                24 >210>    15 >211>    45 >212>    DNA >213>    人工序列 >220> >223>    L3_F >400>    15 cttgtcccaa gacgattgca acctgagccc aaatcttgtg acaaa                         45 >210>    16 >211>    31 >212>    DNA >213>    人工序列 >220> >223>    L4_R >400>    16 aattctcgag tcatttaccc ggagacaggg a                                        31 >210>    17 >211>    87 >212>    DNA >213>    人工序列 >220> >223>    L5_F >400>    17 gtcccaagac gattgcaacc tagcggcggt ggcggttctg gcggtggtgg aagtggcggt         60 ggcgggtctg agcccaaatc ttgtgac                                             87 >210>    18 >211>    42 >212>    DNA >213>    人工序列 >220> >223>    L6_F >400>    18 ctctccctgt ctccgggtaa actcaccgaa gagcagttgt tg                            42 >210>    19 >211>    42 >212>    DNA >213>    人工序列 >220> >223>    L7_F >400>    19 ctctccctgt ctccgggtaa attcagccaa tcattccgtg ag                            42 >210>    20 >211>    42 >212>    DNA >213>    人工序列 >220> >223>    L8_F >400>    20 ctctccctgt ctccgggtaa actctccccc cgaagcgccc ag                            42 >210>    21 >211>    43 >212>    DNA >213>    人工序列 >220> >223>    L9_R >400>    21 gaaggcacag ctcgagtcaa ggttgcaatc gtcttgggac aag                           43 >210>    22 >211>    45 >212>    DNA >213>    人工序列 >220> >223>    L10_F >400>    22 gtcccaagac gattgcaacc tgacgctcac aagtctgaag ttgct                         45 >210>    23 >211>    48 >212>    DNA >213>    人工序列 >220> >223>    L11_R >400>    23 agatccacgc ggaaccagct cgagtcacag ccccaaagcg gcctgtga                      48 >210>    24 >211>    21 >212>    DNA >213>    人工序列 >220> >223>    L12_F >400>    24 actctagagg atcgaaccct t                                                   21 >210>    25 >211>    54 >212>    DNA >213>    人工序列 >220> >223>    L12_R >400>    25 gctggcaact agaaggcaca gctcgagtca tttacccgga gacagggaga ggct               54 >210>    26 >211>    42 >212>    DNA >213>    人工序列 >220> >223>    L13_F >400>    26 ggggccgctc tcacagrgga gcagktgctc gggtcattgt tg                            42 >210>    27 >211>    42 >212>    DNA >213>    人工序列 >220> >223>    L13_R >400>    27 caacaatgac ccgagcamct gctccyctgt gagagcggcc cc                            42 >210>    28 >211>    33 >212>    DNA >213>    人工序列 >220> >223>    L14_F >400>    28 ctcgggtcat tgttgaggca gcttcagctt tcc                                      33 >210>    29 >211>    33 >212>    DNA >213>    人工序列 >220> >223>    L14_R >400>    29 ggaaagctga agctgcctca acaatgaccc gag                                      33 >210>    30 >211>    33 >212>    DNA >213>    人工序列 >220> >223>    L15_F >400>    30 cttcagcttt ccgaagtgcc cgtcctggac aag                                      33 >210>    31 >211>    33 >212>    DNA >213>    人工序列 >220> >223>    L15_R >400>    31 cttgtccagg acgggcactt cggaaagctg aag                                      33 >210>    32 >211>    42 >212>    DNA >213>    人工序列 >220> >223>    L16_F >400>    32 ccacccgtcc tggacarggc cgatrtggag gggctcgtta tc                            42 >210>    33 >211>    42 >212>    DNA >213>    人工序列 >220> >223>    L16_R >400>    33 gataacgagc ccctccayat cggccytgtc caggacgggt gg                            42 >210>    34 >211>    33 >212>    DNA >213>    人工序列 >220> >223>    L17_F >400>    34 aaggccgatg tcgagaagct cgttatccca tcc                                      33 >210>    35 >211>    33 >212>    DNA >213>    人工序列 >220> >223>    L17_R >400>    35 ggatgggata acgagcttct cgacatcggc ctt                                      33 >210>    36 >211>    33 >212>    DNA >213>    人工序列 >220> >223>    L18_F >400>    36 gggctcgtta tcccagccca tgtccgggct cag                                      33 >210>    37 >211>    33 >212>    DNA >213>    人工序列 >220> >223>    L18_R >400>    37 ctgagcccgg acatgggctg ggataacgag ccc                                      33 >210>    38 >211>    33 >212>    DNA >213>    人工序列 >220> >223>    L19_F >400>    38 cgggctcagt acgttgtgtt gctgcaacat tca                                      33 >210>    39 >211>    33 >212>    DNA >213>    人工序列 >220> >223>    L19_R >400>    39 tgaatgttgc agcaacacaa cgtactgagc ccg                                      33 >210>    40 >211>    36 >212>    DNA >213>    人工序列 >220> >223>    L20_F >400>    40 tacgttgcct tgctgagacg gtcacacgct agtaga                                   36 >210>    41 >211>    36 >212>    DNA >213>    人工序列 >220> >223>    L20_R >400>    41 tctactagcg tgtgaccgtc tcagcaaggc aacgta                                   36 >210>    42 >211>    36 >212>    DNA >213>    人工序列 >220> >223>    L21_F >400>    42 ctgcaacatt cacacgsakm cagaagtgga ggcaag                                   36 >210>    43 >211>    36 >212>    DNA >213>    人工序列 >220> >223>    L21_R >400>    43 cttgcctcca cttctgkmts cgtgtgaatg ttgcag                                   36 >210>    44 >211>    36 >212>    DNA >213>    人工序列 >220> >223>    L22_F >400>    44 tacgttgcct tgctgcrgcr ctcacacgct agtaga                                   36 >210>    45 >211>    36 >212>    DNA >213>    人工序列 >220> >223>    L22_R >400>    45 tctactagcg tgtgagygcy gcagcaaggc aacgta                                   36 >210>    46 >211>    33 >212>    DNA >213>    人工序列 >220> >223>    L23_F >400>    46 ggggccgccc tcaccggcga gcagttgttg ggc                                      33 >210>    47 >211>    33 >212>    DNA >213>    人工序列 >220> >223>    L23_R >400>    47 gcccaacaac tgctcgccgg tgagggcggc ccc                                      33 >210>    48 >211>    42 >212>    DNA >213>    人工序列 >220> >223>    L24_F >400>    48 cgcgcccaat atgtggycct gctccrgcga tctcacggag at                            42 >210>    49 >211>    42 >212>    DNA >213>    人工序列 >220> >223>    L24_R >400>    49 atctccgtga gatcgcygga gcaggrccac atattgggcg cg                            42 >210>    50 >211>    45 >212>    DNA >213>    人工序列 >220> >223>    L25_F >400>    50 cgcgcccaat atgtggccct gctccrgcac tctcacggag atagg                         45 >210>    51 >211>    45 >212>    DNA >213>    人工序列 >220> >223>    L25_R >400>    51 cctatctccg tgagagtgcy ggagcagggc cacatattgg gcgcg                         45 >210>    52 >211>    48 >212>    DNA >213>    人工序列 >220> >223>    L26_F >400>    52 aaggccgatg tcgagaagct cgttatccca gcccatgtcc gggctcag                      48 >210>    53 >211>    48 >212>    DNA >213>    人工序列 >220> >223>    L26_R >400>    53 ctgagcccgg acatgggctg ggataacgag cttctcgaca tcggcctt                      48 >210>    54 >211>    42 >212>    DNA >213>    人工序列 >220> >223>    L27_F >400>    54 aaggctgccc tgcaccggca tggtcgtctc tccccccgaa gc                            42 >210>    55 >211>    42 >212>    DNA >213>    人工序列 >220> >223>    L27_R >400>    55 gcttcggggg gagagacgac catgccggtg cagggcagcc tt                            42 >210>    56 >211>    33 >212>    DNA >213>    人工序列 >220> >223>    L28_F >400>    56 ctgcacggcc atggtggcct ctccccccga agc                                      33 >210>    57 >211>    33 >212>    DNA >213>    人工序列 >220> >223>    L28_R >400>    57 gcttcggggg gagaggccac catggccgtg cag                                      33 >210>    58 >211>    33 >212>    DNA >213>    人工序列 >220> >223>    L29_F >400>    58 aggagcaggg gcaaggyctt cagccaatca ttc                                      33 >210>    59 >211>    33 >212>    DNA >213>    人工序列 >220> >223>    L29_R >400>    59 gaatgattgg ctgaagrcct tgcccctgct cct                                      33 >210>    60 >211>    33 >212>    DNA >213>    人工序列 >220> >223>    L30_F >400>    60 ctgcaccggc atggtgycct ctccccccga agc                                      33 >210>    61 >211>    33 >212>    DNA >213>    人工序列 >220> >223>    L30_R >400>    61 gcttcggggg gagaggrcac catgccggtg cag                                      33 >210>    62 >211>    33 >212>    DNA >213>    人工序列 >220> >223>    L31_F >400>    62 ctgcaccggc atggtggcct ctccccccga agc                                      33 >210>    63 >211>    33 >212>    DNA >213>    人工序列 >220> >223>    L31_R >400>    63 gcttcggggg gagaggccac catgccggtg cag                                      33 >210>    64 >211>    33 >212>    DNA >213>    人工序列 >220> >223>    L32_F >400>    64 ctccttctgc aagtgnnkgt ccagcgcgaa cac                                      33 >210>    65 >211>    33 >212>    DNA >213>    人工序列 >220> >223>    L32_R >400>    65 gtgttcgcgc tggacmnnca cttgcagaag gag                                      33 >210>    66 >211>    33 >212>    DNA >213>    人工序列 >220> >223>    L33_F >400>    66 ctggtgcgat tcgctnnkca gggtgcacca gcc                                      33 >210>    67 >211>    33 >212>    DNA >213>    人工序列 >220> >223>    L33_R >400>    67 ggctggtgca ccctgmnnag cgaatcgcac cag                                      33 >210>    68 >211>    42 >212>    DNA >213>    人工序列 >220> >223>    L34_F >400>    68 ttcaactggc cctttgasgg acctcggcaa tgtattgcca gc                            42 >210>    69 >211>    42 >212>    DNA >213>    人工序列 >220> >223>    L34_R >400>    69 gctggcaata cattgccgag gtccstcaaa gggccagttg aa                            42 >210>    70 >211>    42 >212>    DNA >213>    人工序列 >220> >223>    L35_F >400>    70 ttcaactggc cctttctcgg agascggcaa tgtattgcca gc                            42 >210>    71 >211>    42 >212>    DNA >213>    人工序列 >220> >223>    L35_R >400>    71 gctggcaata cattgccgst ctccgagaaa gggccagttg aa                            42 >210>    72 >211>    42 >212>    DNA >213>    人工序列 >220> >223>    L36_F >400>    72 ttcaactggc cctttctcgg atcccggcaa tgtattgcca gc                            42 >210>    73 >211>    42 >212>    DNA >213>    人工序列 >220> >223>    L36_R >400>    73 gctggcaata cattgccggg atccgagaaa gggccagttg aa                            42 >210>    74 >211>    42 >212>    DNA >213>    人工序列 >220> >223>    L37_F >400>    74 ttcaactggc cctttctcgg acctmagcaa tgtattgcca gc                            42 >210>    75 >211>    42 >212>    DNA >213>    人工序列 >220> >223>    L37_R >400>    75 gctggcaata cattgctkag gtccgagaaa gggccagttg aa                            42 >210>    76 >211>    42 >212>    DNA >213>    人工序列 >220> >223>    L38_F >400>    76 gcctctgacg gggctgasgt cccaagacga ttgcaacctt ct                            42 >210>    77 >211>    42 >212>    DNA >213>    人工序列 >220> >223>    L38_R >400>    77 agaaggttgc aatcgtcttg ggacstcagc cccgtcagag gc                            42 >210>    78 >211>    42 >212>    DNA >213>    人工序列 >220> >223>    L39_F >400>    78 gcctctgacg gggctcttgt cgasagacga ttgcaacctt ct                            42 >210>    79 >211>    42 >212>    DNA >213>    人工序列 >220> >223>    L39_R >400>    79 agaaggttgc aatcgtctst cgacaagagc cccgtcagag gc                            42 >210>    80 >211>    42 >212>    DNA >213>    人工序列 >220> >223>    L40_F >400>    80 gcctctgacg gggctcttgt ctccagacga ttgcaacctt ct                            42 >210>    81 >211>    42 >212>    DNA >213>    人工序列 >220> >223>    L40_R >400>    81 agaaggttgc aatcgtctgg agacaagagc cccgtcagag gc                            42 >210>    82 >211>    42 >212>    DNA >213>    人工序列 >220> >223>    L41_F >400>    82 gcctctgacg gggctcttgt cccamagcga ttgcaacctt ct                            42 >210>    83 >211>    42 >212>    DNA >213>    人工序列 >220> >223>    L41_R >400>    83 agaaggttgc aatcgctktg ggacaagagc cccgtcagag gc                            42 >210>    84 >211>    42 >212>    DNA >213>    人工序列 >220> >223>    L42_F >400>    84 gcctctgacg gggctcttgt cgaccagcga ttgcaacctt ct                            42 >210>    85 >211>    42 >212>    DNA >213>    人工序列 >220> >223>    L42_R >400>    85 agaaggttgc aatcgctggt cgacaagagc cccgtcagag gc                            42 >210>    86 >211>    614 >212>    蛋白質 >213>    人工序列 >220> >223>    42 LFc(V63A) >400>    86 Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala 1               5                  10                  15 Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu 20                  25                  30 Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met 35                  40                  45 Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu 50                  55                  60 Leu Arg Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln 65                  70                  75                  80 Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr 85                  90                  95 His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu 100                 105                 110 Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala 115                 120                 125 Ala Leu His Gly His Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg 130                 135                 140 Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr 145                 150                 155                 160 Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys 165                 170                 175 Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg 180                 185                 190 Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu 195                 200                 205 Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln 210                 215                 220 Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu 225                 230                 235                 240 Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro 245                 250                 255 Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu 260                 265                 270 Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe 275                 280                 285 Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu 290                 295                 300 Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu 305                 310                 315                 320 Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr 325                 330                 335 Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser 340                 345                 350 Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly 355                 360                 365 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro 370                 375                 380 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 385                 390                 395                 400 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 405                 410                 415 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 420                 425                 430 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 435                 440                 445 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 450                 455                 460 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 465                 470                 475                 480 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 485                 490                 495 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 500                 505                 510 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 515                 520                 525 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 530                 535                 540 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 545                 550                 555                 560 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 565                 570                 575 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 580                 585                 590 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 595                 600                 605 Ser Leu Ser Pro Gly Lys 610 >210>    87 >211>    614 >212>    蛋白質 >213>    人工序列 >220> >223>    42 LFc(R66Q) >400>    87 Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala 1               5                  10                  15 Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu 20                  25                  30 Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met 35                  40                  45 Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Val Leu 50                  55                  60 Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln 65                  70                  75                  80 Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr 85                  90                  95 His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu 100                 105                 110 Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala 115                 120                 125 Ala Leu His Gly His Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg 130                 135                 140 Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr 145                 150                 155                 160 Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys 165                 170                 175 Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg 180                 185                 190 Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu 195                 200                 205 Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln 210                 215                 220 Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu 225                 230                 235                 240 Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro 245                 250                 255 Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu 260                 265                 270 Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe 275                 280                 285 Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu 290                 295                 300 Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu 305                 310                 315                 320 Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr 325                 330                 335 Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser 340                 345                 350 Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly 355                 360                 365 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro 370                 375                 380 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 385                 390                 395                 400 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 405                 410                 415 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 420                 425                 430 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 435                 440                 445 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 450                 455                 460 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 465                 470                 475                 480 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 485                 490                 495 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 500                 505                 510 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 515                 520                 525 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 530                 535                 540 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 545                 550                 555                 560 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 565                 570                 575 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 580                 585                 590 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 595                 600                 605 Ser Leu Ser Pro Gly Lys 610 >210>    88 >211>    614 >212>    蛋白質 >213>    人工序列 >220> >223>    42 LFc(V63A/R66Q) >400>    88 Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala 1               5                  10                  15 Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu 20                  25                  30 Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met 35                  40                  45 Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu 50                  55                  60 Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln 65                  70                  75                  80 Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr 85                  90                  95 His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu 100                 105                 110 Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala 115                 120                 125 Ala Leu His Gly His Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg 130                 135                 140 Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr 145                 150                 155                 160 Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys 165                 170                 175 Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg 180                 185                 190 Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu 195                 200                 205 Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln 210                 215                 220 Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu 225                 230                 235                 240 Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro 245                 250                 255 Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu 260                 265                 270 Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe 275                 280                 285 Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu 290                 295                 300 Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu 305                 310                 315                 320 Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr 325                 330                 335 Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser 340                 345                 350 Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly 355                 360                 365 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro 370                 375                 380 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 385                 390                 395                 400 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 405                 410                 415 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 420                 425                 430 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 435                 440                 445 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 450                 455                 460 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 465                 470                 475                 480 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 485                 490                 495 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 500                 505                 510 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 515                 520                 525 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 530                 535                 540 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 545                 550                 555                 560 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 565                 570                 575 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 580                 585                 590 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 595                 600                 605 Ser Leu Ser Pro Gly Lys 610 >210>    89 >211>    614 >212>    蛋白質 >213>    人工序列 >220> >223>    42 LFc(V63A/R67H) >400>    89 Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala 1               5                  10                  15 Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu 20                  25                  30 Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met 35                  40                  45 Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu 50                  55                  60 Leu Arg His Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln 65                  70                  75                  80 Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr 85                  90                  95 His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu 100                 105                 110 Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala 115                 120                 125 Ala Leu His Gly His Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg 130                 135                 140 Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr 145                 150                 155                 160 Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys 165                 170                 175 Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg 180                 185                 190 Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu 195                 200                 205 Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln 210                 215                 220 Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu 225                 230                 235                 240 Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro 245                 250                 255 Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu 260                 265                 270 Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe 275                 280                 285 Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu 290                 295                 300 Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu 305                 310                 315                 320 Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr 325                 330                 335 Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser 340                 345                 350 Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly 355                 360                 365 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro 370                 375                 380 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 385                 390                 395                 400 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 405                 410                 415 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 420                 425                 430 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 435                 440                 445 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 450                 455                 460 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 465                 470                 475                 480 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 485                 490                 495 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 500                 505                 510 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 515                 520                 525 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 530                 535                 540 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 545                 550                 555                 560 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 565                 570                 575 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 580                 585                 590 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 595                 600                 605 Ser Leu Ser Pro Gly Lys 610 >210>    90 >211>    614 >212>    蛋白質 >213>    人工序列 >220> >223>    42 LFc(V63A/R66Q/R67H) >400>    90 Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala 1               5                  10                  15 Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu 20                  25                  30 Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met 35                  40                  45 Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu 50                  55                  60 Leu Gln His Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln 65                  70                  75                  80 Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr 85                  90                  95 His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu 100                 105                 110 Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala 115                 120                 125 Ala Leu His Gly His Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg 130                 135                 140 Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr 145                 150                 155                 160 Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys 165                 170                 175 Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg 180                 185                 190 Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu 195                 200                 205 Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln 210                 215                 220 Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu 225                 230                 235                 240 Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro 245                 250                 255 Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu 260                 265                 270 Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe 275                 280                 285 Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu 290                 295                 300 Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu 305                 310                 315                 320 Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr 325                 330                 335 Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser 340                 345                 350 Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly 355                 360                 365 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro 370                 375                 380 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 385                 390                 395                 400 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 405                 410                 415 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 420                 425                 430 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 435                 440                 445 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 450                 455                 460 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 465                 470                 475                 480 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 485                 490                 495 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 500                 505                 510 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 515                 520                 525 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 530                 535                 540 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 545                 550                 555                 560 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 565                 570                 575 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 580                 585                 590 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 595                 600                 605 Ser Leu Ser Pro Gly Lys 610 >210>    91 >211>    614 >212>    蛋白質 >213>    人工序列 >220> >223>    LFB 42 LFc >400>    91 Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala 1               5                  10                  15 Gly Pro Gly Ala Ala Leu Thr Gly Glu Gln Leu Leu Gly Ser Leu Leu 20                  25                  30 Arg Gln Leu Gln Leu Lys Glu Val Pro Thr Leu Asp Arg Ala Asp Met 35                  40                  45 Glu Glu Leu Val Ile Pro Thr His Val Arg Ala Gln Tyr Val Ala Leu 50                  55                  60 Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln 65                  70                  75                  80 Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr 85                  90                  95 His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu 100                 105                 110 Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala 115                 120                 125 Ala Leu His Gly His Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg 130                 135                 140 Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr 145                 150                 155                 160 Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys 165                 170                 175 Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg 180                 185                 190 Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu 195                 200                 205 Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln 210                 215                 220 Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu 225                 230                 235                 240 Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro 245                 250                 255 Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu 260                 265                 270 Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe 275                 280                 285 Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu 290                 295                 300 Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu 305                 310                 315                 320 Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr 325                 330                 335 Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser 340                 345                 350 Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly 355                 360                 365 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro 370                 375                 380 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 385                 390                 395                 400 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 405                 410                 415 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 420                 425                 430 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 435                 440                 445 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 450                 455                 460 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 465                 470                 475                 480 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 485                 490                 495 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 500                 505                 510 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 515                 520                 525 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 530                 535                 540 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 545                 550                 555                 560 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 565                 570                 575 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 580                 585                 590 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 595                 600                 605 Ser Leu Ser Pro Gly Lys 610 >210>    92 >211>    614 >212>    蛋白質 >213>    人工序列 >220> >223>    42 LFc V1 >400>    92 Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala 1               5                  10                  15 Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu 20                  25                  30 Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met 35                  40                  45 Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Val Leu 50                  55                  60 Leu Arg Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln 65                  70                  75                  80 Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr 85                  90                  95 His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu 100                 105                 110 Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala 115                 120                 125 Ala Leu His Arg His Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg 130                 135                 140 Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr 145                 150                 155                 160 Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys 165                 170                 175 Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg 180                 185                 190 Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu 195                 200                 205 Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln 210                 215                 220 Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu 225                 230                 235                 240 Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro 245                 250                 255 Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu 260                 265                 270 Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe 275                 280                 285 Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu 290                 295                 300 Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu 305                 310                 315                 320 Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr 325                 330                 335 Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser 340                 345                 350 Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly 355                 360                 365 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro 370                 375                 380 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 385                 390                 395                 400 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 405                 410                 415 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 420                 425                 430 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 435                 440                 445 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 450                 455                 460 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 465                 470                 475                 480 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 485                 490                 495 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 500                 505                 510 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 515                 520                 525 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 530                 535                 540 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 545                 550                 555                 560 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 565                 570                 575 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 580                 585                 590 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 595                 600                 605 Ser Leu Ser Pro Gly Lys 610 >210>    93 >211>    614 >212>    蛋白質 >213>    人工序列 >220> >223>    42 LFc V2 >400>    93 Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala 1               5                  10                  15 Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu 20                  25                  30 Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met 35                  40                  45 Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Val Leu 50                  55                  60 Leu Arg Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln 65                  70                  75                  80 Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr 85                  90                  95 His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu 100                 105                 110 Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala 115                 120                 125 Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg 130                 135                 140 Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr 145                 150                 155                 160 Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys 165                 170                 175 Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg 180                 185                 190 Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu 195                 200                 205 Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln 210                 215                 220 Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu 225                 230                 235                 240 Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro 245                 250                 255 Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu 260                 265                 270 Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe 275                 280                 285 Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu 290                 295                 300 Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu 305                 310                 315                 320 Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr 325                 330                 335 Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser 340                 345                 350 Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly 355                 360                 365 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro 370                 375                 380 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 385                 390                 395                 400 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 405                 410                 415 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 420                 425                 430 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 435                 440                 445 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 450                 455                 460 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 465                 470                 475                 480 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 485                 490                 495 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 500                 505                 510 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 515                 520                 525 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 530                 535                 540 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 545                 550                 555                 560 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 565                 570                 575 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 580                 585                 590 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 595                 600                 605 Ser Leu Ser Pro Gly Lys 610 >210>    94 >211>    614 >212>    蛋白質 >213>    人工序列 >220> >223>    42 LFc V3 >400>    94 Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala 1               5                  10                  15 Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu 20                  25                  30 Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met 35                  40                  45 Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Val Leu 50                  55                  60 Leu Arg Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln 65                  70                  75                  80 Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr 85                  90                  95 His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu 100                 105                 110 Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala 115                 120                 125 Ala Leu His Arg His Glu Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg 130                 135                 140 Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr 145                 150                 155                 160 Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys 165                 170                 175 Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg 180                 185                 190 Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu 195                 200                 205 Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln 210                 215                 220 Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu 225                 230                 235                 240 Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro 245                 250                 255 Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu 260                 265                 270 Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe 275                 280                 285 Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu 290                 295                 300 Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu 305                 310                 315                 320 Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr 325                 330                 335 Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser 340                 345                 350 Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly 355                 360                 365 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro 370                 375                 380 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 385                 390                 395                 400 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 405                 410                 415 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 420                 425                 430 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 435                 440                 445 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 450                 455                 460 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 465                 470                 475                 480 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 485                 490                 495 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 500                 505                 510 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 515                 520                 525 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 530                 535                 540 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 545                 550                 555                 560 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 565                 570                 575 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 580                 585                 590 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 595                 600                 605 Ser Leu Ser Pro Gly Lys 610 >210>    95 >211>    614 >212>    蛋白質 >213>    人工序列 >220> >223>    42 LFc V4 >400>    95 Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala 1               5                  10                  15 Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu 20                  25                  30 Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met 35                  40                  45 Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Val Leu 50                  55                  60 Leu Arg Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln 65                  70                  75                  80 Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr 85                  90                  95 His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu 100                 105                 110 Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala 115                 120                 125 Ala Leu His Gly His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg 130                 135                 140 Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr 145                 150                 155                 160 Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys 165                 170                 175 Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg 180                 185                 190 Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu 195                 200                 205 Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln 210                 215                 220 Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu 225                 230                 235                 240 Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro 245                 250                 255 Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu 260                 265                 270 Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe 275                 280                 285 Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu 290                 295                 300 Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu 305                 310                 315                 320 Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr 325                 330                 335 Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser 340                 345                 350 Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly 355                 360                 365 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro 370                 375                 380 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 385                 390                 395                 400 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 405                 410                 415 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 420                 425                 430 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 435                 440                 445 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 450                 455                 460 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 465                 470                 475                 480 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 485                 490                 495 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 500                 505                 510 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 515                 520                 525 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 530                 535                 540 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 545                 550                 555                 560 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 565                 570                 575 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 580                 585                 590 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 595                 600                 605 Ser Leu Ser Pro Gly Lys 610 >210>    96 >211>    614 >212>    蛋白質 >213>    人工序列 >220> >223>    42 LFc V5 >400>    96 Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala 1               5                  10                  15 Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu 20                  25                  30 Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met 35                  40                  45 Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Val Leu 50                  55                  60 Leu Arg Arg Ser His Gly Asp Arg Ser Arg Gly Lys Ala Phe Ser Gln 65                  70                  75                  80 Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr 85                  90                  95 His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu 100                 105                 110 Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala 115                 120                 125 Ala Leu His Gly His Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg 130                 135                 140 Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr 145                 150                 155                 160 Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys 165                 170                 175 Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg 180                 185                 190 Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu 195                 200                 205 Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln 210                 215                 220 Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu 225                 230                 235                 240 Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro 245                 250                 255 Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu 260                 265                 270 Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe 275                 280                 285 Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu 290                 295                 300 Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu 305                 310                 315                 320 Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr 325                 330                 335 Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser 340                 345                 350 Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly 355                 360                 365 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro 370                 375                 380 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 385                 390                 395                 400 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 405                 410                 415 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 420                 425                 430 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 435                 440                 445 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 450                 455                 460 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 465                 470                 475                 480 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 485                 490                 495 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 500                 505                 510 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 515                 520                 525 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 530                 535                 540 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 545                 550                 555                 560 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 565                 570                 575 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 580                 585                 590 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 595                 600                 605 Ser Leu Ser Pro Gly Lys 610 >210>    97 >211>    614 >212>    蛋白質 >213>    人工序列 >220> >223>    42 LFc V6 >400>    97 Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala 1               5                  10                  15 Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu 20                  25                  30 Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met 35                  40                  45 Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Val Leu 50                  55                  60 Leu Arg Arg Ser His Gly Asp Arg Ser Arg Gly Lys Ala Phe Ser Gln 65                  70                  75                  80 Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr 85                  90                  95 His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu 100                 105                 110 Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala 115                 120                 125 Ala Leu His Arg His Gly Ala Leu Ser Pro Arg Ser Ala Gln Ala Arg 130                 135                 140 Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr 145                 150                 155                 160 Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys 165                 170                 175 Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg 180                 185                 190 Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu 195                 200                 205 Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln 210                 215                 220 Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu 225                 230                 235                 240 Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro 245                 250                 255 Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu 260                 265                 270 Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe 275                 280                 285 Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu 290                 295                 300 Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu 305                 310                 315                 320 Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr 325                 330                 335 Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser 340                 345                 350 Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly 355                 360                 365 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro 370                 375                 380 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 385                 390                 395                 400 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 405                 410                 415 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 420                 425                 430 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 435                 440                 445 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 450                 455                 460 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 465                 470                 475                 480 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 485                 490                 495 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 500                 505                 510 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 515                 520                 525 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 530                 535                 540 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 545                 550                 555                 560 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 565                 570                 575 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 580                 585                 590 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 595                 600                 605 Ser Leu Ser Pro Gly Lys 610 >210>    98 >211>    614 >212>    蛋白質 >213>    人工序列 >220> >223>    42 LFc V7 >400>    98 Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala 1               5                  10                  15 Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu 20                  25                  30 Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met 35                  40                  45 Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Val Leu 50                  55                  60 Leu Arg Arg Ser His Gly Asp Arg Ser Arg Gly Lys Ala Phe Ser Gln 65                  70                  75                  80 Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr 85                  90                  95 His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu 100                 105                 110 Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala 115                 120                 125 Ala Leu His Arg His Gly Val Leu Ser Pro Arg Ser Ala Gln Ala Arg 130                 135                 140 Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr 145                 150                 155                 160 Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys 165                 170                 175 Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg 180                 185                 190 Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu 195                 200                 205 Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln 210                 215                 220 Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu 225                 230                 235                 240 Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro 245                 250                 255 Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu 260                 265                 270 Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe 275                 280                 285 Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu 290                 295                 300 Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu 305                 310                 315                 320 Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr 325                 330                 335 Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser 340                 345                 350 Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly 355                 360                 365 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro 370                 375                 380 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 385                 390                 395                 400 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 405                 410                 415 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 420                 425                 430 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 435                 440                 445 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 450                 455                 460 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 465                 470                 475                 480 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 485                 490                 495 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 500                 505                 510 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 515                 520                 525 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 530                 535                 540 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 545                 550                 555                 560 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 565                 570                 575 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 580                 585                 590 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 595                 600                 605 Ser Leu Ser Pro Gly Lys 610 >210>    99 >211>    614 >212>    蛋白質 >213>    人工序列 >220> >223>    42 LFc V8 >400>    99 Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala 1               5                  10                  15 Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu 20                  25                  30 Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met 35                  40                  45 Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Val Leu 50                  55                  60 Leu Arg Arg Ser His Gly Asp Arg Ser Arg Gly Lys Val Phe Ser Gln 65                  70                  75                  80 Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr 85                  90                  95 His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu 100                 105                 110 Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala 115                 120                 125 Ala Leu His Gly His Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg 130                 135                 140 Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr 145                 150                 155                 160 Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys 165                 170                 175 Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg 180                 185                 190 Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu 195                 200                 205 Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln 210                 215                 220 Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu 225                 230                 235                 240 Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro 245                 250                 255 Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu 260                 265                 270 Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe 275                 280                 285 Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu 290                 295                 300 Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu 305                 310                 315                 320 Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr 325                 330                 335 Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser 340                 345                 350 Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly 355                 360                 365 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro 370                 375                 380 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 385                 390                 395                 400 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 405                 410                 415 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 420                 425                 430 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 435                 440                 445 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 450                 455                 460 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 465                 470                 475                 480 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 485                 490                 495 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 500                 505                 510 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 515                 520                 525 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 530                 535                 540 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 545                 550                 555                 560 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 565                 570                 575 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 580                 585                 590 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 595                 600                 605 Ser Leu Ser Pro Gly Lys 610 >210>    100 >211>    614 >212>    蛋白質 >213>    人工序列 >220> >223>    42 LFc V9 >400>    100 Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala 1               5                  10                  15 Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu 20                  25                  30 Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met 35                  40                  45 Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Val Leu 50                  55                  60 Leu Arg Arg Ser His Gly Asp Arg Ser Arg Gly Lys Val Phe Ser Gln 65                  70                  75                  80 Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr 85                  90                  95 His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu 100                 105                 110 Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala 115                 120                 125 Ala Leu His Arg His Gly Ala Leu Ser Pro Arg Ser Ala Gln Ala Arg 130                 135                 140 Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr 145                 150                 155                 160 Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys 165                 170                 175 Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg 180                 185                 190 Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu 195                 200                 205 Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln 210                 215                 220 Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu 225                 230                 235                 240 Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro 245                 250                 255 Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu 260                 265                 270 Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe 275                 280                 285 Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu 290                 295                 300 Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu 305                 310                 315                 320 Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr 325                 330                 335 Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser 340                 345                 350 Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly 355                 360                 365 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro 370                 375                 380 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 385                 390                 395                 400 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 405                 410                 415 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 420                 425                 430 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 435                 440                 445 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 450                 455                 460 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 465                 470                 475                 480 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 485                 490                 495 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 500                 505                 510 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 515                 520                 525 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 530                 535                 540 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 545                 550                 555                 560 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 565                 570                 575 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 580                 585                 590 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 595                 600                 605 Ser Leu Ser Pro Gly Lys 610 >210>    101 >211>    614 >212>    蛋白質 >213>    人工序列 >220> >223>    42 LFc V10 >400>    101 Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala 1               5                  10                  15 Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu 20                  25                  30 Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met 35                  40                  45 Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Val Leu 50                  55                  60 Leu Arg Arg Ser His Gly Asp Arg Ser Arg Gly Lys Val Phe Ser Gln 65                  70                  75                  80 Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr 85                  90                  95 His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu 100                 105                 110 Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala 115                 120                 125 Ala Leu His Arg His Gly Val Leu Ser Pro Arg Ser Ala Gln Ala Arg 130                 135                 140 Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr 145                 150                 155                 160 Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys 165                 170                 175 Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg 180                 185                 190 Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu 195                 200                 205 Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln 210                 215                 220 Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu 225                 230                 235                 240 Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro 245                 250                 255 Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu 260                 265                 270 Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe 275                 280                 285 Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu 290                 295                 300 Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu 305                 310                 315                 320 Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr 325                 330                 335 Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser 340                 345                 350 Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly 355                 360                 365 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro 370                 375                 380 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 385                 390                 395                 400 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 405                 410                 415 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 420                 425                 430 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 435                 440                 445 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 450                 455                 460 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 465                 470                 475                 480 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 485                 490                 495 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 500                 505                 510 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 515                 520                 525 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 530                 535                 540 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 545                 550                 555                 560 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 565                 570                 575 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 580                 585                 590 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 595                 600                 605 Ser Leu Ser Pro Gly Lys 610 >210>    102 >211>    614 >212>    蛋白質 >213>    人工序列 >220> >223>    42 LFc V11 >400>    102 Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala 1               5                  10                  15 Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu 20                  25                  30 Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met 35                  40                  45 Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Val Leu 50                  55                  60 Leu Arg Arg Ser His Gly Asp Arg Ser Arg His Gly Gly Phe Ser Gln 65                  70                  75                  80 Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr 85                  90                  95 His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu 100                 105                 110 Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala 115                 120                 125 Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg 130                 135                 140 Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr 145                 150                 155                 160 Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys 165                 170                 175 Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg 180                 185                 190 Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu 195                 200                 205 Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln 210                 215                 220 Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu 225                 230                 235                 240 Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro 245                 250                 255 Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu 260                 265                 270 Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe 275                 280                 285 Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu 290                 295                 300 Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu 305                 310                 315                 320 Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr 325                 330                 335 Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser 340                 345                 350 Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly 355                 360                 365 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro 370                 375                 380 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 385                 390                 395                 400 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 405                 410                 415 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 420                 425                 430 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 435                 440                 445 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 450                 455                 460 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 465                 470                 475                 480 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 485                 490                 495 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 500                 505                 510 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 515                 520                 525 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 530                 535                 540 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 545                 550                 555                 560 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 565                 570                 575 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 580                 585                 590 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 595                 600                 605 Ser Leu Ser Pro Gly Lys 610 >210>    103 >211>    614 >212>    蛋白質 >213>    人工序列 >220> >223>    42 LFc V12 >400>    103 Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala 1               5                  10                  15 Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu 20                  25                  30 Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met 35                  40                  45 Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Val Leu 50                  55                  60 Leu Arg Arg Ser His Gly Asp Arg Ser Arg Gly Lys Gly Phe Ser Gln 65                  70                  75                  80 Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr 85                  90                  95 His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu 100                 105                 110 Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala 115                 120                 125 Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg 130                 135                 140 Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr 145                 150                 155                 160 Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys 165                 170                 175 Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg 180                 185                 190 Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu 195                 200                 205 Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln 210                 215                 220 Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu 225                 230                 235                 240 Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro 245                 250                 255 Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu 260                 265                 270 Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe 275                 280                 285 Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu 290                 295                 300 Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu 305                 310                 315                 320 Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr 325                 330                 335 Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser 340                 345                 350 Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly 355                 360                 365 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro 370                 375                 380 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 385                 390                 395                 400 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 405                 410                 415 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 420                 425                 430 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 435                 440                 445 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 450                 455                 460 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 465                 470                 475                 480 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 485                 490                 495 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 500                 505                 510 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 515                 520                 525 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 530                 535                 540 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 545                 550                 555                 560 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 565                 570                 575 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 580                 585                 590 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 595                 600                 605 Ser Leu Ser Pro Gly Lys 610 >210>    104 >211>    614 >212>    蛋白質 >213>    人工序列 >220> >223>    42 LFc V13 >400>    104 Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala 1               5                  10                  15 Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu 20                  25                  30 Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met 35                  40                  45 Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Val Leu 50                  55                  60 Leu Arg Arg Ser His Gly Asp Arg Ser Arg Gly Lys Ala Phe Ser Gln 65                  70                  75                  80 Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr 85                  90                  95 His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu 100                 105                 110 Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala 115                 120                 125 Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg 130                 135                 140 Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr 145                 150                 155                 160 Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys 165                 170                 175 Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg 180                 185                 190 Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu 195                 200                 205 Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln 210                 215                 220 Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu 225                 230                 235                 240 Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro 245                 250                 255 Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu 260                 265                 270 Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe 275                 280                 285 Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu 290                 295                 300 Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu 305                 310                 315                 320 Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr 325                 330                 335 Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser 340                 345                 350 Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly 355                 360                 365 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro 370                 375                 380 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 385                 390                 395                 400 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 405                 410                 415 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 420                 425                 430 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 435                 440                 445 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 450                 455                 460 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 465                 470                 475                 480 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 485                 490                 495 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 500                 505                 510 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 515                 520                 525 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 530                 535                 540 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 545                 550                 555                 560 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 565                 570                 575 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 580                 585                 590 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 595                 600                 605 Ser Leu Ser Pro Gly Lys 610 >210>    105 >211>    614 >212>    蛋白質 >213>    人工序列 >220> >223>    CX196 >400>    105 Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala 1               5                  10                  15 Gly Pro Gly Ala Ala Leu Thr Gly Glu Gln Leu Leu Gly Ser Leu Leu 20                  25                  30 Arg Gln Leu Gln Leu Lys Glu Val Pro Thr Leu Asp Arg Ala Asp Met 35                  40                  45 Glu Glu Leu Val Ile Pro Thr His Val Arg Ala Gln Tyr Val Ala Leu 50                  55                  60 Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln 65                  70                  75                  80 Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr 85                  90                  95 His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu 100                 105                 110 Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala 115                 120                 125 Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg 130                 135                 140 Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr 145                 150                 155                 160 Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys 165                 170                 175 Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg 180                 185                 190 Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu 195                 200                 205 Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln 210                 215                 220 Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu 225                 230                 235                 240 Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro 245                 250                 255 Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu 260                 265                 270 Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe 275                 280                 285 Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu 290                 295                 300 Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu 305                 310                 315                 320 Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr 325                 330                 335 Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser 340                 345                 350 Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly 355                 360                 365 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro 370                 375                 380 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 385                 390                 395                 400 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 405                 410                 415 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 420                 425                 430 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 435                 440                 445 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 450                 455                 460 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 465                 470                 475                 480 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 485                 490                 495 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 500                 505                 510 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 515                 520                 525 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 530                 535                 540 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 545                 550                 555                 560 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 565                 570                 575 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 580                 585                 590 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 595                 600                 605 Ser Leu Ser Pro Gly Lys 610 >210>    106 >211>    614 >212>    蛋白質 >213>    人工序列 >220> >223>    CX197 >400>    106 Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala 1               5                  10                  15 Gly Pro Gly Ala Ala Leu Thr Gly Glu Gln Leu Leu Gly Ser Leu Leu 20                  25                  30 Arg Gln Leu Gln Leu Lys Glu Val Pro Thr Leu Asp Arg Ala Asp Met 35                  40                  45 Glu Glu Leu Val Ile Pro Thr His Val Arg Ala Gln Tyr Val Ala Leu 50                  55                  60 Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln 65                  70                  75                  80 Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr 85                  90                  95 His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu 100                 105                 110 Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala 115                 120                 125 Ala Leu His Arg His Gly Ala Leu Ser Pro Arg Ser Ala Gln Ala Arg 130                 135                 140 Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr 145                 150                 155                 160 Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys 165                 170                 175 Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg 180                 185                 190 Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu 195                 200                 205 Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln 210                 215                 220 Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu 225                 230                 235                 240 Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro 245                 250                 255 Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu 260                 265                 270 Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe 275                 280                 285 Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu 290                 295                 300 Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu 305                 310                 315                 320 Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr 325                 330                 335 Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser 340                 345                 350 Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly 355                 360                 365 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro 370                 375                 380 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 385                 390                 395                 400 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 405                 410                 415 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 420                 425                 430 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 435                 440                 445 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 450                 455                 460 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 465                 470                 475                 480 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 485                 490                 495 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 500                 505                 510 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 515                 520                 525 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 530                 535                 540 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 545                 550                 555                 560 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 565                 570                 575 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 580                 585                 590 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 595                 600                 605 Ser Leu Ser Pro Gly Lys 610 >210>    107 >211>    614 >212>    蛋白質 >213>    人工序列 >220> >223>    CX201 >400>    107 Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala 1               5                  10                  15 Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu 20                  25                  30 Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met 35                  40                  45 Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu 50                  55                  60 Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln 65                  70                  75                  80 Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr 85                  90                  95 His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu 100                 105                 110 Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala 115                 120                 125 Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg 130                 135                 140 Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr 145                 150                 155                 160 Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys 165                 170                 175 Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg 180                 185                 190 Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu 195                 200                 205 Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln 210                 215                 220 Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu 225                 230                 235                 240 Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro 245                 250                 255 Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu 260                 265                 270 Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe 275                 280                 285 Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu 290                 295                 300 Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu 305                 310                 315                 320 Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr 325                 330                 335 Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser 340                 345                 350 Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly 355                 360                 365 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro 370                 375                 380 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 385                 390                 395                 400 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 405                 410                 415 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 420                 425                 430 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 435                 440                 445 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 450                 455                 460 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 465                 470                 475                 480 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 485                 490                 495 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 500                 505                 510 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 515                 520                 525 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 530                 535                 540 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 545                 550                 555                 560 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 565                 570                 575 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 580                 585                 590 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 595                 600                 605 Ser Leu Ser Pro Gly Lys 610 >210>    108 >211>    614 >212>    蛋白質 >213>    人工序列 >220> >223>    CX203 >400>    108 Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala 1               5                  10                  15 Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu 20                  25                  30 Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met 35                  40                  45 Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu 50                  55                  60 Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln 65                  70                  75                  80 Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr 85                  90                  95 His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu 100                 105                 110 Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala 115                 120                 125 Ala Leu His Arg His Glu Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg 130                 135                 140 Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr 145                 150                 155                 160 Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys 165                 170                 175 Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg 180                 185                 190 Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu 195                 200                 205 Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln 210                 215                 220 Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu 225                 230                 235                 240 Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro 245                 250                 255 Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu 260                 265                 270 Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe 275                 280                 285 Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu 290                 295                 300 Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu 305                 310                 315                 320 Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr 325                 330                 335 Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser 340                 345                 350 Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly 355                 360                 365 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro 370                 375                 380 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 385                 390                 395                 400 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 405                 410                 415 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 420                 425                 430 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 435                 440                 445 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 450                 455                 460 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 465                 470                 475                 480 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 485                 490                 495 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 500                 505                 510 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 515                 520                 525 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 530                 535                 540 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 545                 550                 555                 560 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 565                 570                 575 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 580                 585                 590 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 595                 600                 605 Ser Leu Ser Pro Gly Lys 610 >210>    109 >211>    614 >212>    蛋白質 >213>    人工序列 >220> >223>    CX206 >400>    109 Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala 1               5                  10                  15 Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu 20                  25                  30 Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met 35                  40                  45 Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu 50                  55                  60 Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln 65                  70                  75                  80 Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr 85                  90                  95 His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu 100                 105                 110 Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala 115                 120                 125 Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg 130                 135                 140 Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr 145                 150                 155                 160 Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys 165                 170                 175 Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg 180                 185                 190 Pro Arg Gln Pro Leu Leu Leu Gln Val Thr Val Gln Arg Glu His Leu 195                 200                 205 Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln 210                 215                 220 Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu 225                 230                 235                 240 Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro 245                 250                 255 Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu 260                 265                 270 Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe 275                 280                 285 Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu 290                 295                 300 Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu 305                 310                 315                 320 Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr 325                 330                 335 Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser 340                 345                 350 Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly 355                 360                 365 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro 370                 375                 380 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 385                 390                 395                 400 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 405                 410                 415 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 420                 425                 430 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 435                 440                 445 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 450                 455                 460 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 465                 470                 475                 480 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 485                 490                 495 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 500                 505                 510 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 515                 520                 525 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 530                 535                 540 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 545                 550                 555                 560 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 565                 570                 575 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 580                 585                 590 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 595                 600                 605 Ser Leu Ser Pro Gly Lys 610 >210>    110 >211>    614 >212>    蛋白質 >213>    人工序列 >220> >223>    CX207 >400>    110 Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala 1               5                  10                  15 Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu 20                  25                  30 Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met 35                  40                  45 Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu 50                  55                  60 Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln 65                  70                  75                  80 Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr 85                  90                  95 His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu 100                 105                 110 Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala 115                 120                 125 Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg 130                 135                 140 Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr 145                 150                 155                 160 Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys 165                 170                 175 Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg 180                 185                 190 Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu 195                 200                 205 Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Gly Gln 210                 215                 220 Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu 225                 230                 235                 240 Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro 245                 250                 255 Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu 260                 265                 270 Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe 275                 280                 285 Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu 290                 295                 300 Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu 305                 310                 315                 320 Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr 325                 330                 335 Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser 340                 345                 350 Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly 355                 360                 365 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro 370                 375                 380 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 385                 390                 395                 400 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 405                 410                 415 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 420                 425                 430 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 435                 440                 445 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 450                 455                 460 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 465                 470                 475                 480 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 485                 490                 495 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 500                 505                 510 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 515                 520                 525 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 530                 535                 540 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 545                 550                 555                 560 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 565                 570                 575 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 580                 585                 590 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 595                 600                 605 Ser Leu Ser Pro Gly Lys 610 >210>    111 >211>    614 >212>    蛋白質 >213>    人工序列 >220> >223>    CX208 >400>    111 Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala 1               5                  10                  15 Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu 20                  25                  30 Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met 35                  40                  45 Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu 50                  55                  60 Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln 65                  70                  75                  80 Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr 85                  90                  95 His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu 100                 105                 110 Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala 115                 120                 125 Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg 130                 135                 140 Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr 145                 150                 155                 160 Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys 165                 170                 175 Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg 180                 185                 190 Pro Arg Gln Pro Leu Leu Leu Gln Val Thr Val Gln Arg Glu His Leu 195                 200                 205 Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Gly Gln 210                 215                 220 Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu 225                 230                 235                 240 Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro 245                 250                 255 Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu 260                 265                 270 Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe 275                 280                 285 Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu 290                 295                 300 Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu 305                 310                 315                 320 Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr 325                 330                 335 Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser 340                 345                 350 Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly 355                 360                 365 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro 370                 375                 380 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu 385                 390                 395                 400 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp 405                 410                 415 Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp 420                 425                 430 Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 435                 440                 445 Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 450                 455                 460 Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 465                 470                 475                 480 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro 485                 490                 495 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu 500                 505                 510 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn 515                 520                 525 Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile 530                 535                 540 Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr 545                 550                 555                 560 Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 565                 570                 575 Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 580                 585                 590 Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 595                 600                 605 Ser Leu Ser Pro Gly Lys 610 >210>    112 >211>    615 >212>    蛋白質 >213>    人工序列 >220> >223>    CX201(L311D) >400>    112 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1               5                  10                  15 Phe Pro Gly Ser Arg Cys Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu 20                  25                  30 Leu Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp 35                  40                  45 Met Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala 50                  55                  60 Leu Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser 65                  70                  75                  80 Gln Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser 85                  90                  95 Thr His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser 100                 105                 110 Glu Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys 115                 120                 125 Ala Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala 130                 135                 140 Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg 145                 150                 155                 160 Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp 165                 170                 175 Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser 180                 185                 190 Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His 195                 200                 205 Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser 210                 215                 220 Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr 225                 230                 235                 240 Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala 245                 250                 255 Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp 260                 265                 270 Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly 275                 280                 285 Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala 290                 295                 300 Leu Ala Phe Asn Trp Pro Phe Asp Gly Pro Arg Gln Cys Ile Ala Ser 305                 310                 315                 320 Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg 325                 330                 335 Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys 340                 345                 350 Ser Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser 355                 360                 365 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu 370                 375                 380 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 385                 390                 395                 400 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 405                 410                 415 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 420                 425                 430 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 435                 440                 445 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 450                 455                 460 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 465                 470                 475                 480 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 485                 490                 495 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 500                 505                 510 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 515                 520                 525 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 530                 535                 540 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 545                 550                 555                 560 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 565                 570                 575 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 580                 585                 590 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 595                 600                 605 Leu Ser Leu Ser Pro Gly Lys 610                 615 >210>    113 >211>    615 >212>    蛋白質 >213>    人工序列 >220> >223>    CX201(L311E) >400>    113 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1               5                  10                  15 Phe Pro Gly Ser Arg Cys Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu 20                  25                  30 Leu Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp 35                  40                  45 Met Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala 50                  55                  60 Leu Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser 65                  70                  75                  80 Gln Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser 85                  90                  95 Thr His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser 100                 105                 110 Glu Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys 115                 120                 125 Ala Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala 130                 135                 140 Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg 145                 150                 155                 160 Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp 165                 170                 175 Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser 180                 185                 190 Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His 195                 200                 205 Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser 210                 215                 220 Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr 225                 230                 235                 240 Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala 245                 250                 255 Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp 260                 265                 270 Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly 275                 280                 285 Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala 290                 295                 300 Leu Ala Phe Asn Trp Pro Phe Glu Gly Pro Arg Gln Cys Ile Ala Ser 305                 310                 315                 320 Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg 325                 330                 335 Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys 340                 345                 350 Ser Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser 355                 360                 365 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu 370                 375                 380 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 385                 390                 395                 400 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 405                 410                 415 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 420                 425                 430 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 435                 440                 445 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 450                 455                 460 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 465                 470                 475                 480 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 485                 490                 495 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 500                 505                 510 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 515                 520                 525 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 530                 535                 540 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 545                 550                 555                 560 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 565                 570                 575 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 580                 585                 590 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 595                 600                 605 Leu Ser Leu Ser Pro Gly Lys 610                 615 >210>    114 >211>    615 >212>    蛋白質 >213>    人工序列 >220> >223>    CX201(P313D) >400>    114 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1               5                  10                  15 Phe Pro Gly Ser Arg Cys Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu 20                  25                  30 Leu Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp 35                  40                  45 Met Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala 50                  55                  60 Leu Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser 65                  70                  75                  80 Gln Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser 85                  90                  95 Thr His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser 100                 105                 110 Glu Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys 115                 120                 125 Ala Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala 130                 135                 140 Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg 145                 150                 155                 160 Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp 165                 170                 175 Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser 180                 185                 190 Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His 195                 200                 205 Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser 210                 215                 220 Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr 225                 230                 235                 240 Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala 245                 250                 255 Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp 260                 265                 270 Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly 275                 280                 285 Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala 290                 295                 300 Leu Ala Phe Asn Trp Pro Phe Leu Gly Asp Arg Gln Cys Ile Ala Ser 305                 310                 315                 320 Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg 325                 330                 335 Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys 340                 345                 350 Ser Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser 355                 360                 365 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu 370                 375                 380 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 385                 390                 395                 400 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 405                 410                 415 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 420                 425                 430 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 435                 440                 445 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 450                 455                 460 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 465                 470                 475                 480 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 485                 490                 495 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 500                 505                 510 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 515                 520                 525 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 530                 535                 540 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 545                 550                 555                 560 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 565                 570                 575 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 580                 585                 590 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 595                 600                 605 Leu Ser Leu Ser Pro Gly Lys 610                 615 >210>    115 >211>    615 >212>    蛋白質 >213>    人工序列 >220> >223>    CX201(P313E) >400>    115 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1               5                  10                  15 Phe Pro Gly Ser Arg Cys Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu 20                  25                  30 Leu Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp 35                  40                  45 Met Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala 50                  55                  60 Leu Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser 65                  70                  75                  80 Gln Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser 85                  90                  95 Thr His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser 100                 105                 110 Glu Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys 115                 120                 125 Ala Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala 130                 135                 140 Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg 145                 150                 155                 160 Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp 165                 170                 175 Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser 180                 185                 190 Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His 195                 200                 205 Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser 210                 215                 220 Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr 225                 230                 235                 240 Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala 245                 250                 255 Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp 260                 265                 270 Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly 275                 280                 285 Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala 290                 295                 300 Leu Ala Phe Asn Trp Pro Phe Leu Gly Glu Arg Gln Cys Ile Ala Ser 305                 310                 315                 320 Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg 325                 330                 335 Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys 340                 345                 350 Ser Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser 355                 360                 365 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu 370                 375                 380 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 385                 390                 395                 400 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 405                 410                 415 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 420                 425                 430 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 435                 440                 445 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 450                 455                 460 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 465                 470                 475                 480 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 485                 490                 495 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 500                 505                 510 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 515                 520                 525 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 530                 535                 540 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 545                 550                 555                 560 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 565                 570                 575 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 580                 585                 590 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 595                 600                 605 Leu Ser Leu Ser Pro Gly Lys 610                 615 >210>    116 >211>    615 >212>    蛋白質 >213>    人工序列 >220> >223>    CX201(P313S) >400>    116 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1               5                  10                  15 Phe Pro Gly Ser Arg Cys Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu 20                  25                  30 Leu Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp 35                  40                  45 Met Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala 50                  55                  60 Leu Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser 65                  70                  75                  80 Gln Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser 85                  90                  95 Thr His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser 100                 105                 110 Glu Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys 115                 120                 125 Ala Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala 130                 135                 140 Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg 145                 150                 155                 160 Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp 165                 170                 175 Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser 180                 185                 190 Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His 195                 200                 205 Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser 210                 215                 220 Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr 225                 230                 235                 240 Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala 245                 250                 255 Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp 260                 265                 270 Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly 275                 280                 285 Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala 290                 295                 300 Leu Ala Phe Asn Trp Pro Phe Leu Gly Ser Arg Gln Cys Ile Ala Ser 305                 310                 315                 320 Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg 325                 330                 335 Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys 340                 345                 350 Ser Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser 355                 360                 365 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu 370                 375                 380 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 385                 390                 395                 400 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 405                 410                 415 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 420                 425                 430 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 435                 440                 445 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 450                 455                 460 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 465                 470                 475                 480 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 485                 490                 495 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 500                 505                 510 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 515                 520                 525 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 530                 535                 540 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 545                 550                 555                 560 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 565                 570                 575 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 580                 585                 590 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 595                 600                 605 Leu Ser Leu Ser Pro Gly Lys 610                 615 >210>    117 >211>    615 >212>    蛋白質 >213>    人工序列 >220> >223>    CX201(R314K) >400>    117 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1               5                  10                  15 Phe Pro Gly Ser Arg Cys Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu 20                  25                  30 Leu Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp 35                  40                  45 Met Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala 50                  55                  60 Leu Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser 65                  70                  75                  80 Gln Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser 85                  90                  95 Thr His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser 100                 105                 110 Glu Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys 115                 120                 125 Ala Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala 130                 135                 140 Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg 145                 150                 155                 160 Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp 165                 170                 175 Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser 180                 185                 190 Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His 195                 200                 205 Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser 210                 215                 220 Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr 225                 230                 235                 240 Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala 245                 250                 255 Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp 260                 265                 270 Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly 275                 280                 285 Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala 290                 295                 300 Leu Ala Phe Asn Trp Pro Phe Leu Gly Pro Lys Gln Cys Ile Ala Ser 305                 310                 315                 320 Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg 325                 330                 335 Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys 340                 345                 350 Ser Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser 355                 360                 365 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu 370                 375                 380 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 385                 390                 395                 400 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 405                 410                 415 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 420                 425                 430 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 435                 440                 445 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 450                 455                 460 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 465                 470                 475                 480 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 485                 490                 495 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 500                 505                 510 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 515                 520                 525 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 530                 535                 540 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 545                 550                 555                 560 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 565                 570                 575 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 580                 585                 590 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 595                 600                 605 Leu Ser Leu Ser Pro Gly Lys 610                 615 >210>    118 >211>    615 >212>    蛋白質 >213>    人工序列 >220> >223>    CX201(R314Q) >400>    118 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1               5                  10                  15 Phe Pro Gly Ser Arg Cys Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu 20                  25                  30 Leu Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp 35                  40                  45 Met Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala 50                  55                  60 Leu Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser 65                  70                  75                  80 Gln Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser 85                  90                  95 Thr His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser 100                 105                 110 Glu Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys 115                 120                 125 Ala Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala 130                 135                 140 Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg 145                 150                 155                 160 Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp 165                 170                 175 Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser 180                 185                 190 Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His 195                 200                 205 Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser 210                 215                 220 Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr 225                 230                 235                 240 Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala 245                 250                 255 Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp 260                 265                 270 Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly 275                 280                 285 Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala 290                 295                 300 Leu Ala Phe Asn Trp Pro Phe Leu Gly Pro Gln Gln Cys Ile Ala Ser 305                 310                 315                 320 Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg 325                 330                 335 Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys 340                 345                 350 Ser Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser 355                 360                 365 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu 370                 375                 380 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 385                 390                 395                 400 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 405                 410                 415 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 420                 425                 430 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 435                 440                 445 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 450                 455                 460 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 465                 470                 475                 480 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 485                 490                 495 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 500                 505                 510 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 515                 520                 525 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 530                 535                 540 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 545                 550                 555                 560 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 565                 570                 575 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 580                 585                 590 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 595                 600                 605 Leu Ser Leu Ser Pro Gly Lys 610                 615 >210>    119 >211>    615 >212>    蛋白質 >213>    人工序列 >220> >223>    CX201(L359D) >400>    119 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1               5                  10                  15 Phe Pro Gly Ser Arg Cys Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu 20                  25                  30 Leu Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp 35                  40                  45 Met Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala 50                  55                  60 Leu Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser 65                  70                  75                  80 Gln Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser 85                  90                  95 Thr His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser 100                 105                 110 Glu Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys 115                 120                 125 Ala Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala 130                 135                 140 Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg 145                 150                 155                 160 Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp 165                 170                 175 Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser 180                 185                 190 Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His 195                 200                 205 Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser 210                 215                 220 Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr 225                 230                 235                 240 Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala 245                 250                 255 Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp 260                 265                 270 Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly 275                 280                 285 Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala 290                 295                 300 Leu Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser 305                 310                 315                 320 Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg 325                 330                 335 Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys 340                 345                 350 Ser Cys Ala Ser Asp Gly Ala Asp Val Pro Arg Arg Leu Gln Pro Ser 355                 360                 365 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu 370                 375                 380 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 385                 390                 395                 400 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 405                 410                 415 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 420                 425                 430 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 435                 440                 445 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 450                 455                 460 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 465                 470                 475                 480 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 485                 490                 495 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 500                 505                 510 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 515                 520                 525 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 530                 535                 540 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 545                 550                 555                 560 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 565                 570                 575 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 580                 585                 590 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 595                 600                 605 Leu Ser Leu Ser Pro Gly Lys 610                 615 >210>    120 >211>    615 >212>    蛋白質 >213>    人工序列 >220> >223>    CX201(L359E) >400>    120 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1               5                  10                  15 Phe Pro Gly Ser Arg Cys Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu 20                  25                  30 Leu Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp 35                  40                  45 Met Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala 50                  55                  60 Leu Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser 65                  70                  75                  80 Gln Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser 85                  90                  95 Thr His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser 100                 105                 110 Glu Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys 115                 120                 125 Ala Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala 130                 135                 140 Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg 145                 150                 155                 160 Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp 165                 170                 175 Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser 180                 185                 190 Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His 195                 200                 205 Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser 210                 215                 220 Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr 225                 230                 235                 240 Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala 245                 250                 255 Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp 260                 265                 270 Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly 275                 280                 285 Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala 290                 295                 300 Leu Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser 305                 310                 315                 320 Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg 325                 330                 335 Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys 340                 345                 350 Ser Cys Ala Ser Asp Gly Ala Glu Val Pro Arg Arg Leu Gln Pro Ser 355                 360                 365 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu 370                 375                 380 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 385                 390                 395                 400 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 405                 410                 415 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 420                 425                 430 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 435                 440                 445 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 450                 455                 460 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 465                 470                 475                 480 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 485                 490                 495 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 500                 505                 510 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 515                 520                 525 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 530                 535                 540 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 545                 550                 555                 560 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 565                 570                 575 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 580                 585                 590 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 595                 600                 605 Leu Ser Leu Ser Pro Gly Lys 610                 615 >210>    121 >211>    615 >212>    蛋白質 >213>    人工序列 >220> >223>    CX201(P361D) >400>    121 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1               5                  10                  15 Phe Pro Gly Ser Arg Cys Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu 20                  25                  30 Leu Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp 35                  40                  45 Met Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala 50                  55                  60 Leu Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser 65                  70                  75                  80 Gln Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser 85                  90                  95 Thr His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser 100                 105                 110 Glu Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys 115                 120                 125 Ala Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala 130                 135                 140 Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg 145                 150                 155                 160 Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp 165                 170                 175 Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser 180                 185                 190 Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His 195                 200                 205 Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser 210                 215                 220 Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr 225                 230                 235                 240 Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala 245                 250                 255 Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp 260                 265                 270 Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly 275                 280                 285 Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala 290                 295                 300 Leu Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser 305                 310                 315                 320 Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg 325                 330                 335 Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys 340                 345                 350 Ser Cys Ala Ser Asp Gly Ala Leu Val Asp Arg Arg Leu Gln Pro Ser 355                 360                 365 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu 370                 375                 380 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 385                 390                 395                 400 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 405                 410                 415 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 420                 425                 430 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 435                 440                 445 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 450                 455                 460 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 465                 470                 475                 480 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 485                 490                 495 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 500                 505                 510 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 515                 520                 525 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 530                 535                 540 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 545                 550                 555                 560 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 565                 570                 575 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 580                 585                 590 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 595                 600                 605 Leu Ser Leu Ser Pro Gly Lys 610                 615 >210>    122 >211>    615 >212>    蛋白質 >213>    人工序列 >220> >223>    CX201(P361E) >400>    122 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1               5                  10                  15 Phe Pro Gly Ser Arg Cys Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu 20                  25                  30 Leu Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp 35                  40                  45 Met Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala 50                  55                  60 Leu Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser 65                  70                  75                  80 Gln Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser 85                  90                  95 Thr His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser 100                 105                 110 Glu Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys 115                 120                 125 Ala Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala 130                 135                 140 Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg 145                 150                 155                 160 Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp 165                 170                 175 Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser 180                 185                 190 Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His 195                 200                 205 Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser 210                 215                 220 Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr 225                 230                 235                 240 Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala 245                 250                 255 Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp 260                 265                 270 Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly 275                 280                 285 Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala 290                 295                 300 Leu Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser 305                 310                 315                 320 Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg 325                 330                 335 Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys 340                 345                 350 Ser Cys Ala Ser Asp Gly Ala Leu Val Glu Arg Arg Leu Gln Pro Ser 355                 360                 365 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu 370                 375                 380 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 385                 390                 395                 400 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 405                 410                 415 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 420                 425                 430 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 435                 440                 445 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 450                 455                 460 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 465                 470                 475                 480 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 485                 490                 495 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 500                 505                 510 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 515                 520                 525 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 530                 535                 540 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 545                 550                 555                 560 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 565                 570                 575 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 580                 585                 590 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 595                 600                 605 Leu Ser Leu Ser Pro Gly Lys 610                 615 >210>    123 >211>    615 >212>    蛋白質 >213>    人工序列 >220> >223>    CX201(P361S) >400>    123 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1               5                  10                  15 Phe Pro Gly Ser Arg Cys Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu 20                  25                  30 Leu Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp 35                  40                  45 Met Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala 50                  55                  60 Leu Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser 65                  70                  75                  80 Gln Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser 85                  90                  95 Thr His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser 100                 105                 110 Glu Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys 115                 120                 125 Ala Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala 130                 135                 140 Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg 145                 150                 155                 160 Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp 165                 170                 175 Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser 180                 185                 190 Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His 195                 200                 205 Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser 210                 215                 220 Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr 225                 230                 235                 240 Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala 245                 250                 255 Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp 260                 265                 270 Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly 275                 280                 285 Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala 290                 295                 300 Leu Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser 305                 310                 315                 320 Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg 325                 330                 335 Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys 340                 345                 350 Ser Cys Ala Ser Asp Gly Ala Leu Val Ser Arg Arg Leu Gln Pro Ser 355                 360                 365 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu 370                 375                 380 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 385                 390                 395                 400 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 405                 410                 415 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 420                 425                 430 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 435                 440                 445 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 450                 455                 460 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 465                 470                 475                 480 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 485                 490                 495 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 500                 505                 510 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 515                 520                 525 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 530                 535                 540 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 545                 550                 555                 560 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 565                 570                 575 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 580                 585                 590 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 595                 600                 605 Leu Ser Leu Ser Pro Gly Lys 610                 615 >210>    124 >211>    615 >212>    蛋白質 >213>    人工序列 >220> >223>    CX201(R362K) >400>    124 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1               5                  10                  15 Phe Pro Gly Ser Arg Cys Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu 20                  25                  30 Leu Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp 35                  40                  45 Met Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala 50                  55                  60 Leu Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser 65                  70                  75                  80 Gln Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser 85                  90                  95 Thr His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser 100                 105                 110 Glu Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys 115                 120                 125 Ala Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala 130                 135                 140 Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg 145                 150                 155                 160 Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp 165                 170                 175 Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser 180                 185                 190 Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His 195                 200                 205 Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser 210                 215                 220 Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr 225                 230                 235                 240 Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala 245                 250                 255 Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp 260                 265                 270 Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly 275                 280                 285 Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala 290                 295                 300 Leu Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser 305                 310                 315                 320 Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg 325                 330                 335 Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys 340                 345                 350 Ser Cys Ala Ser Asp Gly Ala Leu Val Pro Lys Arg Leu Gln Pro Ser 355                 360                 365 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu 370                 375                 380 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 385                 390                 395                 400 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 405                 410                 415 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 420                 425                 430 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 435                 440                 445 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 450                 455                 460 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 465                 470                 475                 480 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 485                 490                 495 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 500                 505                 510 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 515                 520                 525 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 530                 535                 540 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 545                 550                 555                 560 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 565                 570                 575 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 580                 585                 590 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 595                 600                 605 Leu Ser Leu Ser Pro Gly Lys 610                 615 >210>    125 >211>    615 >212>    蛋白質 >213>    人工序列 >220> >223>    CX201(R362Q) >400>    125 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1               5                  10                  15 Phe Pro Gly Ser Arg Cys Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu 20                  25                  30 Leu Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp 35                  40                  45 Met Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala 50                  55                  60 Leu Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser 65                  70                  75                  80 Gln Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser 85                  90                  95 Thr His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser 100                 105                 110 Glu Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys 115                 120                 125 Ala Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala 130                 135                 140 Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg 145                 150                 155                 160 Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp 165                 170                 175 Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser 180                 185                 190 Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His 195                 200                 205 Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser 210                 215                 220 Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr 225                 230                 235                 240 Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala 245                 250                 255 Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp 260                 265                 270 Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly 275                 280                 285 Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala 290                 295                 300 Leu Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser 305                 310                 315                 320 Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg 325                 330                 335 Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys 340                 345                 350 Ser Cys Ala Ser Asp Gly Ala Leu Val Pro Gln Arg Leu Gln Pro Ser 355                 360                 365 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu 370                 375                 380 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 385                 390                 395                 400 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 405                 410                 415 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 420                 425                 430 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 435                 440                 445 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 450                 455                 460 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 465                 470                 475                 480 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 485                 490                 495 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 500                 505                 510 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 515                 520                 525 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 530                 535                 540 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 545                 550                 555                 560 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 565                 570                 575 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 580                 585                 590 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 595                 600                 605 Leu Ser Leu Ser Pro Gly Lys 610                 615 >210>    126 >211>    615 >212>    蛋白質 >213>    人工序列 >220> >223>    CX201(L311D/R362Q) >400>    126 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1               5                  10                  15 Phe Pro Gly Ser Arg Cys Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu 20                  25                  30 Leu Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp 35                  40                  45 Met Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala 50                  55                  60 Leu Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser 65                  70                  75                  80 Gln Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser 85                  90                  95 Thr His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser 100                 105                 110 Glu Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys 115                 120                 125 Ala Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala 130                 135                 140 Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg 145                 150                 155                 160 Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp 165                 170                 175 Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser 180                 185                 190 Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His 195                 200                 205 Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser 210                 215                 220 Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr 225                 230                 235                 240 Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala 245                 250                 255 Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp 260                 265                 270 Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly 275                 280                 285 Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala 290                 295                 300 Leu Ala Phe Asn Trp Pro Phe Asp Gly Pro Arg Gln Cys Ile Ala Ser 305                 310                 315                 320 Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg 325                 330                 335 Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys 340                 345                 350 Ser Cys Ala Ser Asp Gly Ala Leu Val Pro Gln Arg Leu Gln Pro Ser 355                 360                 365 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu 370                 375                 380 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 385                 390                 395                 400 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 405                 410                 415 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 420                 425                 430 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 435                 440                 445 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 450                 455                 460 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 465                 470                 475                 480 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 485                 490                 495 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 500                 505                 510 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 515                 520                 525 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 530                 535                 540 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 545                 550                 555                 560 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 565                 570                 575 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 580                 585                 590 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 595                 600                 605 Leu Ser Leu Ser Pro Gly Lys 610                 615 >210>    127 >211>    615 >212>    蛋白質 >213>    人工序列 >220> >223>    CX201(L311E/R362Q) >400>    127 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1               5                  10                  15 Phe Pro Gly Ser Arg Cys Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu 20                  25                  30 Leu Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp 35                  40                  45 Met Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala 50                  55                  60 Leu Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser 65                  70                  75                  80 Gln Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser 85                  90                  95 Thr His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser 100                 105                 110 Glu Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys 115                 120                 125 Ala Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala 130                 135                 140 Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg 145                 150                 155                 160 Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp 165                 170                 175 Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser 180                 185                 190 Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His 195                 200                 205 Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser 210                 215                 220 Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr 225                 230                 235                 240 Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala 245                 250                 255 Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp 260                 265                 270 Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly 275                 280                 285 Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala 290                 295                 300 Leu Ala Phe Asn Trp Pro Phe Glu Gly Pro Arg Gln Cys Ile Ala Ser 305                 310                 315                 320 Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg 325                 330                 335 Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys 340                 345                 350 Ser Cys Ala Ser Asp Gly Ala Leu Val Pro Gln Arg Leu Gln Pro Ser 355                 360                 365 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu 370                 375                 380 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 385                 390                 395                 400 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 405                 410                 415 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 420                 425                 430 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 435                 440                 445 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 450                 455                 460 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 465                 470                 475                 480 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 485                 490                 495 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 500                 505                 510 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 515                 520                 525 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 530                 535                 540 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 545                 550                 555                 560 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 565                 570                 575 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 580                 585                 590 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 595                 600                 605 Leu Ser Leu Ser Pro Gly Lys 610                 615 >210>    128 >211>    615 >212>    蛋白質 >213>    人工序列 >220> >223>    CX201(L311D/P361D/R362Q) >400>    128 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1               5                  10                  15 Phe Pro Gly Ser Arg Cys Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu 20                  25                  30 Leu Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp 35                  40                  45 Met Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala 50                  55                  60 Leu Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser 65                  70                  75                  80 Gln Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser 85                  90                  95 Thr His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser 100                 105                 110 Glu Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys 115                 120                 125 Ala Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala 130                 135                 140 Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg 145                 150                 155                 160 Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp 165                 170                 175 Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser 180                 185                 190 Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His 195                 200                 205 Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser 210                 215                 220 Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr 225                 230                 235                 240 Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala 245                 250                 255 Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp 260                 265                 270 Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly 275                 280                 285 Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala 290                 295                 300 Leu Ala Phe Asn Trp Pro Phe Asp Gly Pro Arg Gln Cys Ile Ala Ser 305                 310                 315                 320 Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg 325                 330                 335 Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys 340                 345                 350 Ser Cys Ala Ser Asp Gly Ala Leu Val Asp Gln Arg Leu Gln Pro Ser 355                 360                 365 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu 370                 375                 380 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 385                 390                 395                 400 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 405                 410                 415 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 420                 425                 430 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 435                 440                 445 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 450                 455                 460 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 465                 470                 475                 480 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 485                 490                 495 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 500                 505                 510 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 515                 520                 525 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 530                 535                 540 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 545                 550                 555                 560 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 565                 570                 575 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 580                 585                 590 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 595                 600                 605 Leu Ser Leu Ser Pro Gly Lys 610                 615 >210>    129 >211>    615 >212>    蛋白質 >213>    人工序列 >220> >223>    CX201(L311E/P361D/R362Q) >400>    129 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1               5                  10                  15 Phe Pro Gly Ser Arg Cys Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu 20                  25                  30 Leu Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp 35                  40                  45 Met Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala 50                  55                  60 Leu Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser 65                  70                  75                  80 Gln Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser 85                  90                  95 Thr His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser 100                 105                 110 Glu Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys 115                 120                 125 Ala Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala 130                 135                 140 Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg 145                 150                 155                 160 Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp 165                 170                 175 Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser 180                 185                 190 Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His 195                 200                 205 Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser 210                 215                 220 Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr 225                 230                 235                 240 Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala 245                 250                 255 Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp 260                 265                 270 Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly 275                 280                 285 Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala 290                 295                 300 Leu Ala Phe Asn Trp Pro Phe Glu Gly Pro Arg Gln Cys Ile Ala Ser 305                 310                 315                 320 Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg 325                 330                 335 Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys 340                 345                 350 Ser Cys Ala Ser Asp Gly Ala Leu Val Asp Gln Arg Leu Gln Pro Ser 355                 360                 365 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu 370                 375                 380 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 385                 390                 395                 400 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 405                 410                 415 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 420                 425                 430 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 435                 440                 445 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 450                 455                 460 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 465                 470                 475                 480 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 485                 490                 495 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 500                 505                 510 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys 515                 520                 525 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 530                 535                 540 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 545                 550                 555                 560 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 565                 570                 575 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 580                 585                 590 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 595                 600                 605 Leu Ser Leu Ser Pro Gly Lys 610                 615 >210>    130 >211>    16 >212>    蛋白質 >213>    人工序列 >220> >223>    Linker >400>    130 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 1               5                  10                  15 >210>    131 >211>    366 >212>    蛋白質 >213>    人工序列 >220> >223>    Human Lefty A >400>    131 Met Trp Pro Leu Trp Leu Cys Trp Ala Leu Trp Val Leu Pro Leu Ala 1               5                  10                  15 Gly Pro Gly Ala Ala Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu 20                  25                  30 Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met 35                  40                  45 Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Val Leu 50                  55                  60 Leu Arg Arg Ser His Gly Asp Arg Ser Arg Gly Lys Arg Phe Ser Gln 65                  70                  75                  80 Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr 85                  90                  95 His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu 100                 105                 110 Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala 115                 120                 125 Ala Leu His Arg His Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg 130                 135                 140 Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr 145                 150                 155                 160 Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp Lys 165                 170                 175 Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg 180                 185                 190 Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His Leu 195                 200                 205 Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln 210                 215                 220 Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu 225                 230                 235                 240 Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro 245                 250                 255 Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu 260                 265                 270 Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe 275                 280                 285 Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu 290                 295                 300 Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu 305                 310                 315                 320 Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr 325                 330                 335 Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser 340                 345                 350 Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro 355                 360                 365 >210>    132 >211>    22 >212>    蛋白質 >213>    人工序列 >220> >223>    signal peptide >400>    132 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1               5                  10                  15 Phe Pro Gly Ser Arg Cys 20 >210>    133 >211>    615 >212>    蛋白質 >213>    人工序列 >220> >223>    CX201s >400>    133 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1               5                  10                  15 Phe Pro Gly Ser Arg Cys Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu 20                  25                  30 Leu Arg Gln Leu Gln Leu Ser Glu Val Pro Val Leu Asp Arg Ala Asp 35                  40                  45 Met Glu Lys Leu Val Ile Pro Ala His Val Arg Ala Gln Tyr Val Ala 50                  55                  60 Leu Leu Gln Arg Ser His Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser 65                  70                  75                  80 Gln Ser Phe Arg Glu Val Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser 85                  90                  95 Thr His Leu Leu Val Phe Gly Met Glu Gln Arg Leu Pro Pro Asn Ser 100                 105                 110 Glu Leu Val Gln Ala Val Leu Arg Leu Phe Gln Glu Pro Val Pro Lys 115                 120                 125 Ala Ala Leu His Arg His Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala 130                 135                 140 Arg Val Thr Val Glu Trp Leu Arg Val Arg Asp Asp Gly Ser Asn Arg 145                 150                 155                 160 Thr Ser Leu Ile Asp Ser Arg Leu Val Ser Val His Glu Ser Gly Trp 165                 170                 175 Lys Ala Phe Asp Val Thr Glu Ala Val Asn Phe Trp Gln Gln Leu Ser 180                 185                 190 Arg Pro Arg Gln Pro Leu Leu Leu Gln Val Ser Val Gln Arg Glu His 195                 200                 205 Leu Gly Pro Leu Ala Ser Gly Ala His Lys Leu Val Arg Phe Ala Ser 210                 215                 220 Gln Gly Ala Pro Ala Gly Leu Gly Glu Pro Gln Leu Glu Leu His Thr 225                 230                 235                 240 Leu Asp Leu Arg Asp Tyr Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala 245                 250                 255 Pro Met Thr Glu Gly Thr Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp 260                 265                 270 Leu Gln Gly Met Lys Trp Ala Lys Asn Trp Val Leu Glu Pro Pro Gly 275                 280                 285 Phe Leu Ala Tyr Glu Cys Val Gly Thr Cys Gln Gln Pro Pro Glu Ala 290                 295                 300 Leu Ala Phe Asn Trp Pro Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser 305                 310                 315                 320 Glu Thr Ala Ser Leu Pro Met Ile Val Ser Ile Lys Glu Gly Gly Arg 325                 330                 335 Thr Arg Pro Gln Val Val Ser Leu Pro Asn Met Arg Val Gln Lys Cys 340                 345                 350 Ser Cys Ala Ser Asp Gly Ala Leu Val Pro Arg Arg Leu Gln Pro Ser 355                 360                 365 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu 370                 375                 380 Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro 385                 390                 395                 400 Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys 405                 410                 415 Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val 420                 425                 430 Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp 435                 440                 445 Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr 450                 455                 460 Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp 465                 470                 475                 480 Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu 485                 490                 495 Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg 500                 505                 510 Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys 515                 520                 525 Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp 530                 535                 540 Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys 545                 550                 555                 560 Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser 565                 570                 575 Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser 580                 585                 590 Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser 595                 600                 605 Leu Ser Leu Ser Pro Gly Lys 610                 615 >210>    134 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    42 LFc(V63A) >400>    134 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Arg Arg Ser His 35                  40                  45 Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Gly His 100                 105                 110 Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    135 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    42 LFc(R66Q) >400>    135 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Val Leu Leu Gln Arg Ser His 35                  40                  45 Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Gly His 100                 105                 110 Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    136 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    42 LFc(V63A/R66Q) >400>    136 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His 35                  40                  45 Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Gly His 100                 105                 110 Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    137 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    42 LFc(V63A/R67H) >400>    137 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Arg His Ser His 35                  40                  45 Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Gly His 100                 105                 110 Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    138 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    42 LFc(V63A/R66Q/R67H) >400>    138 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln His Ser His 35                  40                  45 Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Gly His 100                 105                 110 Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    139 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    LFB 42 LFc >400>    139 Leu Thr Gly Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Lys Glu Val Pro Thr Leu Asp Arg Ala Asp Met Glu Glu Leu Val Ile 20                  25                  30 Pro Thr His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His 35                  40                  45 Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Gly His 100                 105                 110 Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    140 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    42 LFc V1 >400>    140 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Val Leu Leu Arg Arg Ser His 35                  40                  45 Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His 100                 105                 110 Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    141 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    42 LFc V2 >400>    141 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Val Leu Leu Arg Arg Ser His 35                  40                  45 Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His 100                 105                 110 Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    142 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    42 LFc V3 >400>    142 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Val Leu Leu Arg Arg Ser His 35                  40                  45 Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His 100                 105                 110 Glu Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    143 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    42 LFc V4 >400>    143 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Val Leu Leu Arg Arg Ser His 35                  40                  45 Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Gly His 100                 105                 110 Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    144 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    42 LFc V5 >400>    144 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Val Leu Leu Arg Arg Ser His 35                  40                  45 Gly Asp Arg Ser Arg Gly Lys Ala Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Gly His 100                 105                 110 Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    145 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    42 LFc V6 >400>    145 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Val Leu Leu Arg Arg Ser His 35                  40                  45 Gly Asp Arg Ser Arg Gly Lys Ala Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His 100                 105                 110 Gly Ala Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    146 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    42 LFc V7 >400>    146 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Val Leu Leu Arg Arg Ser His 35                  40                  45 Gly Asp Arg Ser Arg Gly Lys Ala Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His 100                 105                 110 Gly Val Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    147 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    42 LFc V8 >400>    147 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Val Leu Leu Arg Arg Ser His 35                  40                  45 Gly Asp Arg Ser Arg Gly Lys Val Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Gly His 100                 105                 110 Gly Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    148 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    42 LFc V9 >400>    148 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Val Leu Leu Arg Arg Ser His 35                  40                  45 Gly Asp Arg Ser Arg Gly Lys Val Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His 100                 105                 110 Gly Ala Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    149 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    42 LFc V10 >400>    149 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Val Leu Leu Arg Arg Ser His 35                  40                  45 Gly Asp Arg Ser Arg Gly Lys Val Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His 100                 105                 110 Gly Val Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    150 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    42 LFc V11 >400>    150 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Val Leu Leu Arg Arg Ser His 35                  40                  45 Gly Asp Arg Ser Arg His Gly Gly Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His 100                 105                 110 Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    151 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    42 LFc V12 >400>    151 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Val Leu Leu Arg Arg Ser His 35                  40                  45 Gly Asp Arg Ser Arg Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His 100                 105                 110 Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    152 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    42 LFc V13 >400>    152 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Val Leu Leu Arg Arg Ser His 35                  40                  45 Gly Asp Arg Ser Arg Gly Lys Ala Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His 100                 105                 110 Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    153 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    CX196 >400>    153 Leu Thr Gly Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Lys Glu Val Pro Thr Leu Asp Arg Ala Asp Met Glu Glu Leu Val Ile 20                  25                  30 Pro Thr His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His 35                  40                  45 Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His 100                 105                 110 Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    154 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    CX197 >400>    154 Leu Thr Gly Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Lys Glu Val Pro Thr Leu Asp Arg Ala Asp Met Glu Glu Leu Val Ile 20                  25                  30 Pro Thr His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His 35                  40                  45 Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His 100                 105                 110 Gly Ala Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    155 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    CX201 >400>    155 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His 35                  40                  45 Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His 100                 105                 110 Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    156 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    CX203 >400>    156 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His 35                  40                  45 Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His 100                 105                 110 Glu Arg Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    157 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    CX206 >400>    157 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His 35                  40                  45 Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His 100                 105                 110 Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Thr Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    158 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    CX207 >400>    158 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His 35                  40                  45 Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His 100                 105                 110 Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Gly Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    159 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    CX208 >400>    159 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His 35                  40                  45 Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His 100                 105                 110 Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Thr Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Gly Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    160 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    CX201(L311D) >400>    160 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His 35                  40                  45 Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His 100                 105                 110 Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Asp Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    161 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    CX201(L311E) >400>    161 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His 35                  40                  45 Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His 100                 105                 110 Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Glu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    162 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    CX201(P313D) >400>    162 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His 35                  40                  45 Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His 100                 105                 110 Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Leu Gly Asp Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    163 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    CX201(P313E) >400>    163 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His 35                  40                  45 Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His 100                 105                 110 Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Leu Gly Glu Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    164 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    CX201(P313S) >400>    164 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His 35                  40                  45 Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His 100                 105                 110 Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Leu Gly Ser Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    165 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    CX201(R314K) >400>    165 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His 35                  40                  45 Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His 100                 105                 110 Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Leu Gly Pro Lys Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    166 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    CX201(R314Q) >400>    166 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His 35                  40                  45 Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His 100                 105                 110 Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Leu Gly Pro Gln Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    167 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    CX201(L359D) >400>    167 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His 35                  40                  45 Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His 100                 105                 110 Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Asp Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    168 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    CX201(L359E) >400>    168 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His 35                  40                  45 Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His 100                 105                 110 Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Glu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    169 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    CX201(P361D) >400>    169 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His 35                  40                  45 Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His 100                 105                 110 Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Asp Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    170 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    CX201(P361E) >400>    170 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His 35                  40                  45 Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His 100                 105                 110 Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Glu Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    171 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    CX201(P361S) >400>    171 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His 35                  40                  45 Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His 100                 105                 110 Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Ser Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    172 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    CX201(R362K) >400>    172 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His 35                  40                  45 Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His 100                 105                 110 Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Pro Lys Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    173 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    CX201(R362Q) >400>    173 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His 35                  40                  45 Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His 100                 105                 110 Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Pro Gln Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    174 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    CX201(L311D/R362Q) >400>    174 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His 35                  40                  45 Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His 100                 105                 110 Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Asp Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Pro Gln Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    175 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    CX201(L311E/R362Q) >400>    175 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His 35                  40                  45 Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His 100                 105                 110 Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Glu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Pro Gln Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    176 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    CX201(L311D/P361D/R362Q) >400>    176 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His 35                  40                  45 Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His 100                 105                 110 Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Asp Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Asp Gln Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    177 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    CX201(L311E/P361D/R362Q) >400>    177 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His 35                  40                  45 Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His 100                 105                 110 Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Glu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Asp Gln Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys >210>    178 >211>    593 >212>    蛋白質 >213>    人工序列 >220> >223>    CX201s >400>    178 Leu Thr Glu Glu Gln Leu Leu Gly Ser Leu Leu Arg Gln Leu Gln Leu 1               5                  10                  15 Ser Glu Val Pro Val Leu Asp Arg Ala Asp Met Glu Lys Leu Val Ile 20                  25                  30 Pro Ala His Val Arg Ala Gln Tyr Val Ala Leu Leu Gln Arg Ser His 35                  40                  45 Gly Asp Arg Ser Gly Gly Lys Gly Phe Ser Gln Ser Phe Arg Glu Val 50                  55                  60 Ala Gly Arg Phe Leu Ala Ser Glu Ala Ser Thr His Leu Leu Val Phe 65                  70                  75                  80 Gly Met Glu Gln Arg Leu Pro Pro Asn Ser Glu Leu Val Gln Ala Val 85                  90                  95 Leu Arg Leu Phe Gln Glu Pro Val Pro Lys Ala Ala Leu His Arg His 100                 105                 110 Gly Gly Leu Ser Pro Arg Ser Ala Gln Ala Arg Val Thr Val Glu Trp 115                 120                 125 Leu Arg Val Arg Asp Asp Gly Ser Asn Arg Thr Ser Leu Ile Asp Ser 130                 135                 140 Arg Leu Val Ser Val His Glu Ser Gly Trp Lys Ala Phe Asp Val Thr 145                 150                 155                 160 Glu Ala Val Asn Phe Trp Gln Gln Leu Ser Arg Pro Arg Gln Pro Leu 165                 170                 175 Leu Leu Gln Val Ser Val Gln Arg Glu His Leu Gly Pro Leu Ala Ser 180                 185                 190 Gly Ala His Lys Leu Val Arg Phe Ala Ser Gln Gly Ala Pro Ala Gly 195                 200                 205 Leu Gly Glu Pro Gln Leu Glu Leu His Thr Leu Asp Leu Arg Asp Tyr 210                 215                 220 Gly Ala Gln Gly Asp Cys Asp Pro Glu Ala Pro Met Thr Glu Gly Thr 225                 230                 235                 240 Arg Cys Cys Arg Gln Glu Met Tyr Ile Asp Leu Gln Gly Met Lys Trp 245                 250                 255 Ala Lys Asn Trp Val Leu Glu Pro Pro Gly Phe Leu Ala Tyr Glu Cys 260                 265                 270 Val Gly Thr Cys Gln Gln Pro Pro Glu Ala Leu Ala Phe Asn Trp Pro 275                 280                 285 Phe Leu Gly Pro Arg Gln Cys Ile Ala Ser Glu Thr Ala Ser Leu Pro 290                 295                 300 Met Ile Val Ser Ile Lys Glu Gly Gly Arg Thr Arg Pro Gln Val Val 305                 310                 315                 320 Ser Leu Pro Asn Met Arg Val Gln Lys Cys Ser Cys Ala Ser Asp Gly 325                 330                 335 Ala Leu Val Pro Arg Arg Leu Gln Pro Ser Gly Gly Gly Gly Ser Gly 340                 345                 350 Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Pro Lys Ser Cys Asp Lys 355                 360                 365 Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro 370                 375                 380 Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser 385                 390                 395                 400 Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp 405                 410                 415 Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn 420                 425                 430 Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val 435                 440                 445 Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu 450                 455                 460 Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys 465                 470                 475                 480 Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr 485                 490                 495 Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr 500                 505                 510 Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu 515                 520                 525 Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu 530                 535                 540 Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys 545                 550                 555                 560 Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu 565                 570                 575 Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly 580                 585                 590 Lys

Claims (21)

  1. 一種人類Lefty A蛋白變體，包含一人類Lefty A蛋白的L22至P366之胺基酸序列，該人類Lefty A蛋白具有SEQ ID NO：131之胺基酸序列，該人類Lefty A蛋白變體包含：(1)在多個修飾位點(processing site)之一個或多個胺基酸殘基的取代，該些修飾位點為R74至R77及R132至R135；以及(2)在一原胜肽域(propeptide domain)之一個或多個胺基酸殘基的取代，該原胜肽域為L22至S73；其中在該原胜肽域之胺基酸殘基的取代係選自由E24G、S38K、V42T、K50E、A55T、V63A和R66Q組成之群組之一個或多個胺基酸殘基取代；並且在該些修飾位點之一個或多個胺基酸殘基的取代係選自由R74G、R77G、R77V、R132G和R135G組成之群組之一個或多個胺基酸殘基取代。
  2. 如請求項1所述之人類Lefty A蛋白變體，其中在該原胜肽域之胺基酸殘基的取代包含V63A，並且更包含選自由E24G、S38K、V42T、K50E、A55T和R66Q組成之群組之一個或多個胺基酸殘基取代。
  3. 如請求項1所述之人類Lefty A蛋白變體，其中位置R74至R77的胺基酸序列為RGKR、GGKG、RGKA、RGKV或RHGG，位置R132至R135的胺基酸序列為RHGR、GHGR、RHGG、 RHER、GHGG、RHGA或RHGV，其源自於在該些修飾位點之一個或多個胺基酸殘基的取代。
  4. 如請求項1所述之人類Lefty A蛋白變體，更包含在多個凝血酶切割位點(thrombin cleavage site)之一個或多個胺基酸殘基的取代，該些凝血酶切割位點為L311、P313、R314、L359、P361或R362。
  5. 如請求項4所述之人類Lefty A蛋白變體，其中在選自由該些凝血酶切割位點L311、P313、R314、L359、P361和R362組成之群組之一個或多個位置的胺基酸殘基被選自由天門冬胺酸(D)、麩胺酸(E)、絲胺酸(S)、離胺酸(K)和麩醯胺酸(Q)組成之群組之胺基酸殘基取代。
  6. 如請求項1所述之人類Lefty A蛋白變體，更包含在一斷裂位點(fragmentation site)之一個或多個胺基酸殘基以除了絲胺酸(S)和半胱胺酸(C)以外之胺基酸殘基取代，該斷裂位點為S202或S223。
  7. 如請求項1所述之人類Lefty A蛋白變體，更包含一訊息肽(signal peptide)於胺基端(N-terminus)。
  8. 一種融合蛋白，包含如請求項1至7之任一項所述之人類Lefty A蛋白變體。
  9. 如請求項8所述之融合蛋白，其中在該融合蛋白中，該人類Lefty A蛋白變體與Fc或白蛋白(albumin)融合。
  10. 如請求項9所述之融合蛋白，其中在該融合蛋白中，Fc或白蛋白融合於該人類Lefty A蛋白變體的羧基端(C-terminus)。
  11. 如請求項9所述之融合蛋白，其中該人類Lefty A蛋白變體與Fc或白蛋白透過一連接鏈(linker)融合在一起。
  12. 如請求項8所述之融合蛋白，其中該融合蛋白具有選自由SEQ ID NOS：134至178所記載之胺基酸序列組成之群組之任一胺基酸序列。
  13. 一種核酸分子，編碼如請求項8所述之融合蛋白。
  14. 一種表現載體，包含如請求項13所述之核酸分子。
  15. 一種重組細胞，導入有如請求項14所述之表現載體。
  16. 一種使用如請求項15所述之重組細胞製造包含人類Lefty A蛋白變體之融合蛋白的方法。
  17. 一種人類Lefty A蛋白變體在製造用以預防及/或治療神經肌肉疾病(neuromuscular disease)的組成物的用途，其中該組成物包含如請求項1至7之任一項所述之人類Lefty A蛋白變體或包含該人類Lefty A蛋白變體的融合蛋白。
  18. 如請求項17所述之用途，其中神經肌肉疾病為Nodal及/或肌肉生長抑制素傳訊相關疾病(myostatin signaling-related disease)。
  19. 如請求項18所述之用途，其中Nodal及/或肌肉生長抑制素傳訊相關疾病為肌病(myopathy)、周邊神經病變(peripheral neuropathy)或僵直性脊椎症候群(rigid spine syndrome)。
  20. 如請求項19所述之用途，其中肌病為選自由肌少症(sarcopenia)、肌肉失養症(muscular dystrophy)、重症肌無力(myasthenia gravis)、肌肉萎縮性脊髓側索硬化症(amyotrophic lateral sclerosis)(或魯-蓋瑞氏症，Lou Gehrig's disease)、原發性脊髓側索硬化症(primary lateral sclerosis)、漸進性肌肉萎縮症(progressive muscular atrophy)、甘迺迪氏症(Kennedy's disease)(或脊髓延髓性肌肉萎縮症，spinobulbar muscular atrophy)、脊髓性肌肉萎縮症(spinal muscular atrophy)和遠端肌病(distal myopathy)組成之群組。
  21. 如請求項19所述之用途，其中周邊神經病變為選自由夏馬杜三氏病(Charcot-Marie-Tooth disease)、慢性脫髓鞘性神經炎(chronic inflammatory demyelinating polyneuropathy)、腕隧道症候群(carpal tunnel syndrome)、糖尿病周邊神經病變(diabetic peripheral neuropathy)和格巴二氏症候群(Guillain-Barre syndrome)組成之群組。
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EP3898663A1 (en) 2021-10-27
CA3124338C (en) 2023-08-01
AU2019404719B2 (en) 2022-06-02
WO2020130594A1 (en) 2020-06-25
JP7355828B2 (ja) 2023-10-03
JP2022514939A (ja) 2022-02-16

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