專利名稱：用于分析糖尿病和/或視網(wǎng)膜血管疾病的組合物及其分析方法
技術領域：
本發(fā)明涉及用于診斷糖尿病和視網(wǎng)膜血管疾病的組合物，用于診斷視網(wǎng)膜血管疾病的試劑盒，其包括蛋白質、編碼該蛋白質的基因，和使用它們來對糖尿病和/或視網(wǎng)膜疾病產(chǎn)生的抗體進行分析的方法。
背景技術：
通常，糖尿病被認為是一種復雜的代謝疾病，其引起微血管系統(tǒng)的損傷。糖尿病是最重要的全身系統(tǒng)紊亂之一，其導致大范圍的全身組織紊亂，尤其對眼睛有影響(Tae-Hee，Lee和Young-Gil，Choi，Diabetic Vascular Complication，Seoul of Republic of Korea，Korea Medical Book publisher，1993)。已知糖尿病性視網(wǎng)膜病是最嚴重的糖尿病并發(fā)癥之一，并且，由于糖尿病患者的壽命和疾病持續(xù)時間隨著生活水平的提高和醫(yī)學的發(fā)展而不斷延長，該病已經(jīng)成為一個流行的社會問題(Klein R.等人，Arch Ophthalmol.，102，520-532，1984)。糖尿病性視網(wǎng)膜病分為兩種一種是非增生性糖尿病視網(wǎng)膜病變(NPDR)，其中，視網(wǎng)膜中由于血管紊亂而發(fā)生視網(wǎng)膜血管損傷；另一種是增生性糖尿病視網(wǎng)膜病變(PDR)，其中血管生成組織從視網(wǎng)膜滲透到玻璃體(Green，InSpencer WH，ed.，Ophthalmic Pathologyan atlas and textbook.4thed.，PhiladelphiaWB Saunder；1124-1129，1996)。在增生性糖尿病視網(wǎng)膜病變中，糖尿病性視網(wǎng)膜病引起的視力損傷源于玻璃體出血、牽拉性視網(wǎng)膜脫離和黃斑變性，已知外科手術和激光治療對于上述疾病的是有效的(DiabeticRetinopathy Study Report Number14，Int Ophthalmol Clin.，27，239-253，1987)。在上述疾病的適當發(fā)展階段，施行這樣的治療能夠減少糖尿病的副作用并防止視力喪失。所以，應該定期進行糖尿病性視網(wǎng)膜病的診斷來保證外科手術的適當時機。
可以通過測量尿或血中糖的量對糖尿病進行診斷，但是被測量的糖的量可能隨著攝入食物及其他等而發(fā)生變化，從而無法進行疾病發(fā)展進程的診斷。
糖尿病性視網(wǎng)膜病可以通過觀察眼底特征性的結構變化而得到診斷，此診斷只能在眼科醫(yī)院通過利用眼球運動照相術的眼部檢查來進行。所以，只有糖尿病人感覺到主觀癥狀如視覺紊亂、并進行定期的眼科醫(yī)生檢查，才可能對糖尿病性視網(wǎng)膜病進行診斷。其結果是，很難在早期對糖尿病性視網(wǎng)膜病進行診斷，并且因此糖尿病人常?？赡苠e失糖尿病性視網(wǎng)膜病預防和外科手術的時機。

發(fā)明內(nèi)容
發(fā)明要解決的問題因此，為了克服現(xiàn)有技術的問題，設計了本發(fā)明，因此，本發(fā)明的目的是提供一種用于診斷糖尿病的組合物，其包括從氨基酸序列SEQ ID NOs1到22描述的蛋白質組成的組中選出的至少一種蛋白質，或其片段。
此外，本發(fā)明的另一個目的是提供用于診斷血管疾病的組合物，其包括從氨基酸序列SEQ ID NOs1到9和SEQ ID NOs11到22描述的蛋白質組成的組中選出的至少一種蛋白質，或其片段。
本發(fā)明的組合物優(yōu)選包括氨基酸序列SEQ ID NO4描述的蛋白質或其片段。
本發(fā)明中，視網(wǎng)膜血管疾病包括但不限于，糖尿病性視網(wǎng)膜病、視網(wǎng)膜水腫和老年性黃斑變性。
此外，本發(fā)明的另一個目的是提供用于診斷糖尿病或視網(wǎng)膜血管疾病的試劑盒，其包括本發(fā)明的蛋白質或其片段。
此外，本發(fā)明的另一個目的是，提供用于診斷視網(wǎng)膜血管疾病的試劑盒，其包括本發(fā)明的蛋白質或其片段。本發(fā)明中，該試劑盒優(yōu)選進一步包括標記的抗免疫球蛋白G抗體蛋白。
此外，本發(fā)明的另一個目的是，提供對由視網(wǎng)膜血管疾病產(chǎn)生的抗體進行分析的方法，其包括至少一種蛋白質與血液接觸的步驟，該至少一種蛋白質選自氨基酸序列SEQ ID NOs1到9和SEQ ID NOs11到22描述的蛋白質組成的組。本發(fā)明中，對抗體進行分析的方法優(yōu)選進一步包括，加入標記的抗免疫球蛋白G抗體蛋白的步驟。
解決問題的方法以下，對本發(fā)明進行如下描述。
為了滿足上述需要，本發(fā)明提供了一種用于診斷糖尿病和視網(wǎng)膜血管疾病的蛋白質及其片段，一種用于診斷視網(wǎng)膜血管疾病的試劑盒，其包括蛋白質及其片段、編碼該蛋白質及其片段的基因，和一種使用它們來對視網(wǎng)膜疾病產(chǎn)生的抗體進行分析的方法。
為了實現(xiàn)上述目的，本發(fā)明提供了一種用于診斷糖尿病等疾病的蛋白質及其片段，一種診斷試劑盒，其包括蛋白質及其片段、編碼該蛋白質及其片段的基因，和使用它們來對視網(wǎng)膜疾病產(chǎn)生的抗體進行分析的方法。
發(fā)明人發(fā)現(xiàn)，由于眼球血管中存在血-眼屏障(blood-ocular brriers)，因此在正常狀況下視網(wǎng)膜蛋白質并不暴露于免疫系統(tǒng)，但在疾病如糖尿病的情況下，其暴露于免疫系統(tǒng)而產(chǎn)生自身抗體。而且，本發(fā)明人發(fā)現(xiàn)了一種診斷蛋白質及其片段，其用于使用血液中的自身抗體可以早期診斷視網(wǎng)膜血管疾病；一種試劑盒，其包括該蛋白質及其片段、編碼該蛋白質及其片段的基因；和一種利用它們對糖尿病產(chǎn)生的抗體進行分析的方法。
以下，對本發(fā)明的優(yōu)選實施方式進行詳細說明。
為了實現(xiàn)上述目的，本發(fā)明的一個實施方式提供了一種用于診斷視網(wǎng)膜血管疾病的蛋白質及其片段，該蛋白質及其片段由SEQ ID NOs1到9和SEQID NOs11到22的氨基酸序列組成。本發(fā)明人發(fā)現(xiàn)，本發(fā)明的蛋白質及其片段可以從視網(wǎng)膜血管疾病病人的視網(wǎng)膜血管滲出，在血液中誘導產(chǎn)生自身抗體，并因此可以使用本發(fā)明的蛋白質及其片段檢測該增多的自身抗體。
為了證實上述結果，本發(fā)明人等進行了例如一維和二維蛋白質印跡法的實驗。此外，使用能夠產(chǎn)生自身抗體的多種蛋白質，通過酶聯(lián)免疫吸附試驗(以下，稱為“ELISA”)，對病人的血液進行了分析實驗。結果證明，根據(jù)本發(fā)明的方法可以有效地診斷視網(wǎng)膜血管疾病。
該蛋白質包括來源于人和動物的蛋白質。
在本發(fā)明蛋白質的氨基酸序列中，至少一種氨基酸可以被替代、增加或刪除，而不會對該蛋白質的功能產(chǎn)生影響，并且如果必要的話，也可以使用該蛋白質的片段。這樣經(jīng)修飾的氨基酸也屬于本發(fā)明的范圍。所以，本發(fā)明的蛋白質也包括多肽，其氨基酸序列與視網(wǎng)膜血管疾病的氨基酸序列極其相似。術語“極其相似的多肽”的意思是，該多肽具有至少80％的同源序列，優(yōu)選至少90％，最優(yōu)選至少95％。
可以通過本發(fā)明的方法診斷的疾病優(yōu)選，但不限于，視網(wǎng)膜蛋白質被暴露于眼球血管中的疾病，例如糖尿病、糖尿病性視網(wǎng)膜病、老年性黃斑變性、視網(wǎng)膜水腫等，特別優(yōu)選糖尿病性視網(wǎng)膜病。
本發(fā)明的另一個實施方式提供了包括一種蛋白質或其片段的診斷試劑盒。本發(fā)明的試劑盒可以用在包括該蛋白質或其片段的ELISA方法中，并且對本領域技術人員來說顯而易見的是，多種添加劑也可以被包括在本發(fā)明的試劑盒中。優(yōu)選本發(fā)明的試劑盒具有該蛋白質或其片段結合于其上的多孔板。
本發(fā)明的診斷試劑盒優(yōu)選還包括，能夠與病人血液中由該蛋白質或其片段產(chǎn)生的自身抗體結合的抗-抗體蛋白，更優(yōu)選包括用于測量其吸光率的標記物。對本領域技術人員來說顯而易見的是，可以使用各種可用于ELISA方法的酶對該抗-抗體蛋白進行標記，例如過氧化酶、堿性磷酸酶、生物素等。
本發(fā)明的另一個實施方式提供了一種對用于診斷糖尿病的蛋白質進行編碼的基因，蛋白質由SEQ ID NOs1到9和SEQ ID NOs11到22的氨基酸序列組成。由于密碼子簡并，或者考慮到用于表達該蛋白質的生物的優(yōu)選密碼子，可以在本發(fā)明的基因的編碼區(qū)制造各種更換或修飾，而不會改變由編碼區(qū)表達的、用于診斷糖尿病的目的蛋白質的氨基酸序列，并且也可以僅在編碼區(qū)以外的區(qū)域制造各種更換或修飾，而不會對該基因的表達產(chǎn)生影響。這樣的經(jīng)修飾的基因也被包括在本發(fā)明的范圍內(nèi)。所以，本發(fā)明的基因還包括多聚核苷酸，其堿基序列與編碼該蛋白質的基因的堿基序列極其相似。術語“極其相似的多聚核苷酸”的意思是，該多聚核苷酸具有至少80％的同源堿基序列，優(yōu)選至少90％，最優(yōu)選至少95％。
本發(fā)明的另一個實施方式提供了一種對糖尿病產(chǎn)生的抗體進行分析的方法，包括診斷蛋白質與所收集的血液接觸的步驟。用于分析抗體的方法優(yōu)選進一步包括加入標記的抗-抗體蛋白的步驟。更優(yōu)選，該抗-抗體蛋白是抗-免疫球蛋白G抗體蛋白。
此外，在用于分析抗體的方法中，優(yōu)選使用吸光率檢測該標記。對本領域技術人員來說顯而易見的是，該標記物包括可以在ELISA分析中使用的多種酶，例如過氧化酶、堿性磷酸酶、生物素等。


圖1是表示健康人、糖尿病人、非增生性糖尿病視網(wǎng)膜病變病人、增生性糖尿病視網(wǎng)膜病變病人的細胞溶質部分和細胞膜部分的人視網(wǎng)膜蛋白質的蛋白質印跡的圖。
圖2是表示人視網(wǎng)膜蛋白質的二維電泳的圖。
圖3是將圖2的電泳凝膠分成四部分并使用健康男性的血清進行蛋白質印跡的圖。
圖4是將圖2的電泳凝膠分成四部分并使用非增生性糖尿病視網(wǎng)膜病變病人的血清進行蛋白質印跡的圖。
圖5是將圖2的電泳凝膠分成四部分并使用增生性糖尿病視網(wǎng)膜病變病人的血清進行蛋白質印跡的圖。
圖6是表示使用肌酸激酶B以ELISA的方式對健康人、糖尿病人、非增生性糖尿病視網(wǎng)膜病變病人、增生性糖尿病視網(wǎng)膜病變病人的血清進行診斷的結果的圖。
圖7是表示使用醛縮酶以ELISA的方式對健康人、糖尿病人、非增生性糖尿病視網(wǎng)膜病變病人、增生性糖尿病視網(wǎng)膜病變病人的血清進行診斷的結果的圖。
具體實施例方式
以下，結合附圖對本發(fā)明的實施方式進行詳細說明。因此，此處的的優(yōu)選例子僅起說明的目的，而不作為對本發(fā)明的限制，所以可以理解的是，在不背離本發(fā)明的主旨和范圍的情況下，可以做出其他等同方案和修改方案。
實施例1使用蛋白質印跡對人視網(wǎng)膜蛋白質自身抗體的分析人視網(wǎng)膜蛋白質的分離從眼球中取出僅一個視網(wǎng)膜，然后用生理鹽水清洗幾次。使用ProteoPrep通用型提取試劑盒(Sigma S2813)，將細胞溶質部分和細胞膜部分分開，然后使用Pierce BCA的蛋白濃度測定試劑盒23227(BCA Protein Assay Kit23227)(Pierce，U.S.)進行定量。
健康人和病人血清的視網(wǎng)膜蛋白質的蛋白質印跡30μg視網(wǎng)膜蛋白質在12％丙烯酰胺凝膠中進行電泳，然后將電泳后的丙烯酰胺凝膠轉移到硝酸纖維素薄膜上，并使用健康人、糖尿病人、非增生性糖尿病視網(wǎng)膜病變病人和增生性糖尿病視網(wǎng)膜病變病人的血清進行蛋白質印跡，來確定是否產(chǎn)生自身抗體。該結果如圖1和表1所示。
表1

表1中，DM代表糖尿病人，NPDR代表非增生性糖尿病視網(wǎng)膜病變病人，PDR代表增生性糖尿病視網(wǎng)膜病變病人?！?”代表觀察到陽性條帶，其數(shù)量代表該條帶的強度。
實施例2人視網(wǎng)膜蛋白質的二維凝膠蛋白質印跡二維凝膠電泳利用視網(wǎng)膜蛋白的兩種不同性質，通過逐次分離，如二維凝膠電泳，分離視網(wǎng)膜蛋白。該二維凝膠電泳分兩步進行第一步是，對該蛋白質施加電刺激，此時借助它們的pH使蛋白質移動(pH3-10)；第二步是，借助該蛋白質的分子重量使其在丙烯酰胺凝膠(8-18％)上移動。以每個凝膠50mA的電流進行12小時的一維電泳(或者，借助pH的蛋白質移動)，并以每個凝膠50mA電流在丙烯酰胺凝膠上進行6小時的二維電泳(或者，借助分子重量的蛋白質移動)。通過使用考馬斯亮蘭-250(Coomassie Brilliant Blue-250)染色法和銀染法來染色移動的蛋白質，確定是否出現(xiàn)了期望的蛋白質。四個凝膠是以同樣方式得到的。一個凝膠用來確定健康人來源的蛋白質的二維凝膠分布，其他三個凝膠的每一個都被分成四部分并用來進行蛋白質印跡。結果如圖2所示。圖2所示的號碼代表以下表2的斑點號碼。
蛋白質印跡使用健康人、非增生性糖尿病視網(wǎng)膜病變病人、增生性糖尿病視網(wǎng)膜病變病人的血清，對二維凝膠電泳中得到的凝膠進行印跡，來確定自身抗體的位置。結果如圖3，4，5所示。
使用Phoretix圖像分析軟件(Nonlinear dynamics，the United Kingdom)，通過計算機對健康人和糖尿病性視網(wǎng)膜病人來源的抗體之間的區(qū)別進行分析。對于將兩組間分析結果與二維凝膠比較得到的斑點，使用MALDI-TOF進行分析，來確定糖尿病性視網(wǎng)膜病人血液中與表1蛋白質相對的自身抗體的形成。與糖尿病性視網(wǎng)膜病人的自身抗體相對的抗原如表2所列。
表2

實施例3使用肌酸激酶B，通過ELISA對糖尿病性視網(wǎng)膜病的診斷本實驗使用肌酸激酶B，通過ELISA的方法，來區(qū)別糖尿病性視網(wǎng)膜病人的血清和糖尿病人的血清。實驗中使用了3個健康人的血清，10個沒患有糖尿病性視網(wǎng)膜病的糖尿病病人，20個患有糖尿病性視網(wǎng)膜病病人，血清由醫(yī)院提供。首先，用每孔100μl的肌酸激酶B(Sigma，C6638)(每孔1μg蛋白質)在室溫下對96孔EIA多孔板包被1小時，該肌酸激酶B是以10μg/ml的濃度溶解在包被緩沖液(50mM NaHCO3，pH 9.0)中的，用400μl PBST(磷酸鹽緩沖液生理鹽水，0.05％吐溫20)沖洗2次(每次10分鐘)，然后用含有1％BSA(牛血清清蛋白)的PBS再一次包被。向其中加入100μl用PBST稀釋的病人血清，反應1小時，用PBS沖洗5次。將100μl過氧化酶標記的抗人免疫球蛋白G抗體(KOMA Biotech Inc.，Republic of Korea)稀釋并加入到所得到的血清中，得到的混合物反應1小時。反應結束后，該混合物用PBS沖洗3次，向其中加入100μl含有1mg/ml OPD(鄰苯二胺鹽酸鹽)的0.1 M檸檬酸鹽-磷酸鹽緩沖液(pH4.9)和0.03％H2O2，在室溫下反應30分鐘，然后向反應混合物中加入100μl 3M硫酸，使反應結束。使用酶聯(lián)免疫檢測儀(ELISAreader)于450nm測量得到的反應混合物產(chǎn)物的吸光率。結果如圖6所示。作為ELISA的結果，肌酸激酶B的平均值在健康人血清中為0.04，僅患有糖尿病的病人血清中為0.06，患有非增生性糖尿病性視網(wǎng)膜病的糖尿病病人血清中為0.08，患有增生性糖尿病性視網(wǎng)膜病的糖尿病病人血清中為0.08。以上結果證明，患有非增生性和增生性糖尿病性視網(wǎng)膜病的病人血清中，肌酸激酶B的數(shù)量增高。
實施例4使用肌酸激酶B，通過ELISA對糖尿病的診斷本實驗中還使用了30個健康人和60個糖尿病人，血清由醫(yī)院提供。而且，以與實施例3同樣的方式，通過ELISA方法進行實驗。結果如表3所示。其揭示，肌酸激酶B可以用于診斷糖尿病。
表3

實施例5使用醛縮酶，通過ELISA對糖尿病性視網(wǎng)膜病的診斷本實驗使用醛縮酶，通過ELISA的方法，來區(qū)別糖尿病性視網(wǎng)膜病人的血清和糖尿病人的血清。實驗中使用了3個健康人的血清，10個沒患有糖尿病性視網(wǎng)膜病的糖尿病病人，20個患有糖尿病性視網(wǎng)膜病的病人，血清由醫(yī)院提供。首先，以每孔100μl的醛縮酶(Sigma，A2714)(每孔1μg蛋白質)在室溫下對96孔EIA多孔板包被1小時，該醛縮酶是以10μg/ml的濃度溶解在包被緩沖液(50mM NaHCO3，pH 9.0)中的，用400μl PBST沖洗2次(每次10分鐘)，然后用含有1％BSA的PBS再一次包被。向其中加入100μl用PBST稀釋的病人血清，反應1小時，用PBS沖洗5次。將100μl過氧化酶標記的抗人免疫球蛋白G抗體(KOMA Biotech Inc.，Republic of Korea)稀釋并加入到所得到的血清中，得到的混合物反應1小時。反應結束后，該混合物用PBS沖洗3次，向其中加入100μl含有1mg/ml OPD(鄰苯二胺鹽酸鹽)的0.1M檸檬酸鹽-磷酸鹽緩沖液(pH 4.9)和0.03％H2O2，在室溫下反應30分鐘，然后向反應混合物中加入100μl 3M硫酸，使反應結束。使用ELISA reader于450nm測量得到的反應混合物產(chǎn)物的吸光率。結果如圖7所示。作為ELISA的結果，醛縮酶C的平均值在健康人血清中為0.78，僅患有糖尿病的病人血清中為0.84，患有非增生性糖尿病性視網(wǎng)膜病的糖尿病病人血清中為0.98，患有增生性糖尿病性視網(wǎng)膜病的糖尿病病人血清中為1.0。以上結果證明，患有非增生性和增生性糖尿病性視網(wǎng)膜病的病人血清中，醛縮酶C的數(shù)量增高。
從實施例3和5的結果可以看出，對于患有非增生性和增生性糖尿病性視網(wǎng)膜病的病人，與健康人相比，肌酸激酶B的數(shù)量均增加了50％，醛縮酶C的數(shù)量分別增加了25％和28％。
上述結果證明，如果病人血液中的血清數(shù)量增加，則該病人可以診斷為患有糖尿病性視網(wǎng)膜病。
實施例6使用醛縮酶C，通過ELISA對糖尿病的診斷本實驗中還使用了30個健康人和60個糖尿病人，血清由醫(yī)院提供。而且，以與實施例5同樣的方式，通過ELISA方法進行實驗。結果如表4所示。其揭示，醛縮酶C可以用于診斷糖尿病。
表4

工業(yè)上的應用本發(fā)明的用于診斷糖尿病及血管疾病的蛋白質，包括該蛋白質的試劑盒和利用它們的分析方法，對于簡便、快速地診斷該疾病是十分有用的，與常規(guī)的診斷方法相比，它們也表現(xiàn)出極好的準確性和精密性。而且，根據(jù)本發(fā)明，用于診斷糖尿病和血管疾病的試劑盒和利用其的分析方法也是十分經(jīng)濟的。
序列表<110>愛吉恩公司(EYEGENE INC.)<120>用于分析糖尿病和/或視網(wǎng)膜血管疾病的組合物及其分析方法<130>PCT05-048<150>KR10-2004-0052385<151>2004-07-06<160>22<170>KopatentIn 1.71<210>1<211>434<212>PRT<213>人類(Homo sapiens)<400>1Met Ser Ile Leu Lys Ile His Ala Arg Glu Ile Phe Asp Ser Arg Gly1 5 10 15Asn Pro Thr Val Glu Val Asp Leu Phe Thr Ser Lys Gly Leu Phe Arg20 25 30Ala Ala Val Pro Ser Gly Ala Ser Thr Gly Ile Tyr Glu Ala Leu Glu35 40 45Leu Arg Asp Asn Asp Lys Thr Arg Tyr Met Gly Lys Gly Val Ser Lys50 55 60Ala Val Glu His Ile Asn Lys Thr Ile Ala Pro Ala Leu Val Ser Lys65 70 75 80Lys Leu Asn Val Thr Glu Gln Glu Lys Ile Asp Lys Leu Met Ile Glu85 90 95Met Asp Gly Thr Glu Asn Lys Ser Lys Phe Gly Ala Asn Ala Ile Leu100 105 110Gly Val Ser Leu Ala Val Cys Lys Ala Gly Ala Val Glu Lys Gly Val115 120 125Pro Leu Tyr Arg His Ile Ala Asp Leu Ala Gly Asn Ser Glu Val Ile130 135 140Leu Pro Val Pro Ala Phe Asn Val Ile Asn Gly Gly Ser His Ala Gly145 150 155 160Asn Lys Leu Ala Met Gln Glu Phe Met Ile Leu Pro Val Gly Ala Ala165 170 175Asn Phe Arg Glu Ala Met Arg Ile Gly Ala Glu Val Tyr His Asn Leu180 185 190Lys Asn Val Ile Lys Glu Lys Tyr Gly Lys Asp Ala Thr Asn Val Gly195 200 205
Asp Glu Gly Gly Phe Ala Pro Asn Ile Leu Glu Asn Lys Glu Gly Leu210 215 220Glu Leu Leu Lys Thr Ala Ile Gly Lys Ala Gly Tyr Thr Asp Lys Val225 230 235 240Val Ile Gly Met Asp Val Ala Ala Ser Glu Phe Phe Arg Ser Gly Lys245 250 255Tyr Asp Leu Asp Phe Lys Ser Pro Asp Asp Pro Ser Arg Tyr Ile Ser260 265 270Pro Asp Gln Leu Ala Asp Leu Tyr Lys Ser Phe Ile Lys Asp Tyr Pro275 280 285Val Val Ser Ile Glu Asp Pro Phe Asp Gln Asp Asp Trp Gly Ala Trp290 295 300Gln Lys Phe Thr Ala Ser Ala Gly Ile Gln Val Val Gly Asp Asp Leu305 310 315 320Thr Val Thr Asn Pro Lys Arg Ile Ala Lys Ala Val Asn Glu Lys Ser325 330 335Cys Asn Cys Leu Leu Leu Lys Val Asn Gln Ile Gly Ser Val Thr Glu340 345 350Ser Leu Gln Ala Cys Lys Leu Ala Gln Ala Asn Gly Trp Gly Val Met355 360 365Val Ser His Arg Ser Gly Glu Thr Glu Asp Thr Phe Ile Ala Asp Leu370 375 380Val Val Gly Leu Cys Thr Gly Gln Ile Lys Thr Gly Ala Pro Cys Arg385 390 395 400Ser Glu Arg Leu Ala Lys Tyr Asn Gln Leu Leu Arg Ile Glu Glu Glu405 410 415Leu Gly Ser Lys Ala Lys Phe Ala Gly Arg Asn Phe Arg Asn Pro Leu420 425 430Ala Lys<210>2<211>414<212>PRT<213>人類(Homo sapiens)<400>2Met Ala Ala Ala Pro Pro Ser Tyr Cys Phe Val Ala Phe Pro Pro Arg1 5 10 15Ala Lys Asp Gly Leu Val Val Phe Gly Lys Asn Ser Ala Arg Pro Arg
20 25 30Asp Glu Val Gln Glu Val Val Tyr Phe Ser Ala Ala Asp His Glu Pro35 40 45Glu Ser Lys Val Glu Cys Thr Tyr Ile Ser Ile Asp Gln Val Pro Arg50 55 60Thr Tyr Ala Ile Met Ile Ser Arg Pro Ala Trp Leu Trp Gly Ala Glu65 70 75 80Met Gly Ala Asn Glu His Gly Val Cys Ile Ala Asn Glu Ala Ile Asn85 90 95Thr Arg Glu Pro Ala Ala Glu Ile Glu Ala Leu Leu Gly Met Asp Leu100 105 110Val Arg Leu Gly Leu Glu Arg Gly Glu Thr Ala Lys Glu Ala Leu Asp115 120 125Val Ile Val Ser Leu Leu Glu Glu His Gly Gln Gly Gly Asn Tyr Phe130 135 140Glu Asp Ala Asn Ser Cys His Ser Phe Gln Ser Ala Tyr Leu Ile Val145 150 155 160Asp Arg Asp Glu Ala Trp Val Leu Glu Thr Ile Gly Lys Tyr Trp Ala165 170 175Ala Glu Lys Val Thr Glu Gly Val Arg Cys Ile Cys Ser Gln Leu Ser180 185 190Leu Thr Thr Lys Met Asp Ala Glu His Pro Glu Leu Arg Ser Tyr Ala195 200 205Gln Ser Gln Gly Trp Trp Thr Gly Glu Gly Glu Phe Asn Phe Ser Glu210 215 220Val Phe Ser Pro Val Glu Asp His Leu Asp Cys Gly Ala Gly Lys Asp225 230 235 240Ser Leu Glu Lys Gln Glu Glu Ser Ile Thr Val Gln Thr Met Met Asn245 250 255Thr Leu Arg Asp Lys Ala Ser Gly Val Cys Ile Asp Ser Glu Phe Phe260 265 270Leu Thr Thr Ala Ser Gly Val Ser Val Leu Pro Gln Asn Arg Ser Ser275 280 285Pro Cys Ile His Tyr Phe Thr Gly Thr Pro Asp Pro Ser Arg Ser Ile290 295 300Phe Lys Pro Phe Ile Phe Val Asp Asp Val Lys Leu Val Pro Lys Thr305 310 315 320Gln Ser Pro Cys Phe Gly Asp Asp Asp Pro Ala Lys Lys Glu Pro Arg
325 330 335Phe Gln Glu Lys Pro Asp Arg Arg His Glu Leu Tyr Lys Ala His Glu340 345 350Trp Ala Arg Ala Ile Ile Glu Ser Asp Gln Glu Gln Gly Arg Lys Leu355 360 365Arg Ser Thr Met Leu Glu Leu Glu Lys Gln Gly Leu Glu Ala Met Glu370 375 380Glu Ile Leu Thr Ser Ser Glu Pro Leu Asp Pro Ala Glu Val Gly Asp385 390 395 400Leu Phe Tyr Asp Cys Val Asp Thr Glu Ile Lys Phe Phe Lys405 410<210>3<211>490<212>PRT<213>人類(Homo sapiens)<400>3Met Glu Gln Lys Pro Ser Lys Val Glu Cys Gly Ser Asp Pro Glu Glu1 5 10 15Asn Ser Ala Arg Ser Pro Asp Gly Lys Arg Lys Arg Lys Asn Gly Gln20 25 30Cys Ser Leu Lys Ser Ser Met Ser Gly Tyr Ile Pro Ser Tyr Leu Asp35 40 45Lys Asp Glu Gln Cys Val Val Cys Gly Asp Lys Ala Thr Gly Tyr His50 55 60Tyr Arg Cys Ile Thr Cys Glu Gly Cys Lys Gly Phe Phe Arg Arg Thr65 70 75 80Ile Gln Lys Asn Leu His Pro Thr Tyr Ser Cys Lys Tyr Asp Ser Cys85 90 95Cys Val Ile Asp Lys Ile Thr Arg Asn Gln Cys Gln Leu Cys Arg Phe100 105 110Lys Lys Cys Ile Ala Val Ala Met Ala Met Asp Leu Val Leu Asp Asp115 120 125Ser Lys Arg Val Ala Lys Arg Lys Leu Ile Glu Gln Asn Arg Glu Arg130 135 140Arg Arg Lys Glu Glu Met Ile Arg Ser Leu Gln Gln Arg Pro Glu Pro145 150 155 160Thr Pro Glu Glu Trp Asp Leu Ile His Ile Ala Thr Glu Ala His Arg165 170 175
Ser Thr Asn Ala Gln Gly Ser His Trp Lys Gln Arg Arg Lys Phe Leu180 185 190Pro Asp Asp Ile Gly Gln Ser Pro Ile Val Ser Met Pro Asp Gly Asp195 200 205Lys Val Asp Leu Glu Ala Phe Ser Glu Phe Thr Lys Ile Ile Thr Pro210 215 220Ala Ile Thr Arg Val Val Asp Phe Ala Lys Lys Leu Pro Met Phe Ser225 230 235 240Glu Leu Pro Cys Glu Asp Gln Ile Ile Leu Leu Lys Gly Cys Cys Met245 250 255Glu Ile Met Ser Leu Arg Ala Ala Val Arg Tyr Asp Pro Glu Ser Asp260 265 270Thr Leu Thr Leu Ser Gly Glu Met Ala Val Lys Arg Glu Gln Leu Lys275 280 285Asn Gly Gly Leu Gly Val Val Ser Asp Ala Ile Phe Glu Leu Gly Lys290 295 300Ser Leu Ser Ala Phe Asn Leu Asp Asp Thr Glu Val Ala Leu Leu Gln305 310 315 320Ala Val Leu Leu Met Ser Thr Asp Arg Ser Gly Leu Leu Cys Val Asp325 330 335Lys Ile Glu Lys Ser Gln Glu Ala Tyr Leu Leu Ala Phe Glu His Tyr340 345 350Val Asn His Arg Lys His Asn Ile Pro His Phe Trp Pro Lys Leu Leu355 360 365Met Lys Glu Arg Glu Val Gln Ser Ser Ile Leu Tyr Lys Gly Ala Ala370 375 380Ala Glu Gly Arg Pro Gly Gly Ser Leu Gly Val His Pro Glu Gly Gln385 390 395 400Gln Leu Leu Gly Met His Val Val Gln Gly Pro Gln Val Arg Gln Leu405 410 415Glu Gln Gln Leu Gly Glu Ala Gly Ser Leu Gln Gly Pro Val Leu Gln420 425 430His Gln Ser Pro Lys Ser Pro Gln Gln Arg Leu Leu Glu Leu Leu His435 440 445Arg Ser Gly Ile Leu His Ala Arg Ala Val Cys Gly Glu Asp Asp Ser450 455 460Ser Glu Ala Asp Ser Pro Ser Ser Ser Glu Glu Glu Pro Glu Val Cys465 470 475 480
Glu Asp Leu Ala Gly Asn Ala Ala Ser Pro485 490<210>4<211>381<212>PRT<213>人類(Homo sapiens)<400>4Met Pro Phe Ser Asn Ser His Asn Ala Leu Lys Leu Arg Phe Pro Ala1 5 10 15Glu Asp Glu Phe Pro Asp Leu Ser Ala His Asn Asn His Met Ala Lys20 25 30Val Leu Thr Pro Glu Leu Tyr Ala Glu Leu Arg Ala Lys Ser Thr Pro35 40 45Ser Gly Phe Thr Leu Asp Asp Val Ile Gln Thr Gly Val Asp Asn Pro50 55 60Gly His Pro Tyr Ile Met Thr Val Gly Cys Val Ala Gly Asp Glu Glu65 70 75 80Ser Tyr Glu Val Phe Lys Asp Leu Phe Asp Pro Ile Ile Glu Asp Arg85 90 95His Gly Gly Tyr Lys Pro Ser Asp Glu His Lys Thr Asp Leu Asn Pro100 105 110Asp Asn Leu Gln Gly Gly Asp Asp Leu Asp Pro Asn Tyr Val Leu Ser115 120 125Ser Arg Val Arg Thr Gly Arg Ser Ile Arg Gly Phe Cys Leu Pro Pro130 135 140His Cys Ser Arg Gly Glu Arg Arg Ala Ile Glu Lys Leu Ala Val Glu145 150 155 160Ala Leu Ser Ser Leu Asp Gly Asp Leu Ala Gly Arg Tyr Tyr Ala Leu165 170 175Lys Ser Met Thr Glu Ala Glu Gln Gln Gln Leu Ile Asp Asp His Phe180 185 190Leu Phe Asp Lys Pro Val Ser Pro Leu Leu Leu Ala Ser Gly Met Ala195 200 205Arg Asp Trp Pro Asp Ala Arg Gly Ile Trp His Asn Asp Asn Lys Thr210 215 220Phe Leu Val Trp Val Asn Glu Glu Asp His Leu Arg Val Ile Ser Met225 230 235 240Gln Lys Gly Gly Asn Met Lys Glu Val Phe Thr Arg Phe Cys Thr Gly245 250 255
Leu Thr Gln Ile Glu Thr Leu Phe Lys Ser Lys Asp Tyr Glu Phe Met260 265 270Trp Asn Pro His Leu Gly Tyr Ile Leu Thr Cys Pro Ser Asn Leu Gly275 280 285Thr Gly Leu Arg Ala Gly Val His Ile Lys Leu Pro Asn Leu Gly Lys290 295 300His Glu Lys Phe Ser Glu Val Leu Lys Arg Leu Arg Leu Gln Lys Arg305 310 315320Gly Thr Gly Gly Val Asp Thr Ala Ala Val Gly Gly Val Phe Asp Val325 330 335Ser Asn Ala Asp Arg Leu Gly Phe Ser Glu Val Glu Leu Val Gln Met340 345 350Val Val Asp Gly Val Lys Leu Leu Ile Glu Met Glu Gln Arg Leu Glu355 360 365Gln Gly Gln Ala Ile Asp Asp Leu Met Pro Ala Gln Lys370 375 380<210>5<211>246<212>PRT<213>人類(Homo sapiens)<400>5Val Ala Arg Ala Glu Arg Gln His Gln Leu Tyr Val Gly Val Leu Gly1 5 10 15Ser Lys Leu Gly Leu Gln Val Val Glu Leu Pro Ala Asp Glu Ser Leu20 25 30Pro Asp Cys Val Phe Val Glu Asp Val Ala Val Val Cys Glu Glu Thr35 40 45Ala Leu Ile Thr Arg Pro Gly Ala Pro Ser Arg Arg Lys Glu Val Asp50 55 60Met Met Lys Glu Ala Leu Glu Lys Leu Gln Leu Asn Ile Val Glu Met65 70 75 80Lys Asp Glu Asn Ala Thr Leu Asp Gly Gly Asp Val Leu Phe Thr Gly85 90 95Arg Glu Phe Phe Val Gly Leu Ser Lys Arg Thr Asn Gln Arg Gly Ala100 105 110Glu Ile Leu Ala Asp Thr Phe Lys Asp Tyr Ala Val Ser Thr Val Pro115 120 125
Val Ala Asp Gly Leu His Leu Lys Ser Phe Cys Ser Met Ala Gly Pro130 135 140Asn Leu Ile Ala Ile Gly Ser Ser Gul Ser Ala Gln Lys Ala Leu Lys145 150 155 160Ile Met Gln Gln Met Ser Asp His Arg Tyr Asp Lys Leu Thr Val Pro165 170 175Asp Asp Ile Ala Ala Asn Cys Ile Tyr Leu Asn Ile Pro Asn Lys Gly180 185 190His Val Leu Leu His Arg Thr Pro Glu Glu Tyr Pro Glu Ser Ala Lys195 200 205Val Tyr Glu Lys Leu Lys Asp His Met Leu Ile Pro Val Ser Met Ser210 215 220Glu Leu Glu Lys Val Asp Gly Leu Leu Thr Cys Cys Ser Val Leu Ile225 230 235 240Asn Lys Lys Val Asp Ser245<210>6<211>334<212>PRT<213>人類(Homo sapiens)<400>6Met Ala Thr Leu Lys Glu Lys Leu Ile Ala Pro Val Ala Glu Glu Glu1 5 10 15Ala Thr Val Pro Asn Asn Lys Ile Thr Val Val Gly Val Gly Gln Val20 25 30Gly Met Ala Cys Ala Ile Ser Ile Leu Gly Lys Ser Leu Ala Asp Glu35 40 45Leu Ala Leu Val Asp Val Leu Glu Asp Lys Leu Lys Gly Glu Met Met50 55 60Asp Leu Gln His Gly Ser Leu Phe Leu Gln Thr Pro Lys Ile Val Ala65 70 75 80Asp Lys Asp Tyr Ser Val Thr Ala Asn Ser Lys Ile Val Val Val Thr85 90 95Ala Gly Val Arg Gln Gln Glu Gly Glu Ser Arg Leu Asn Leu Val Gln100 105 110Arg Asn Val Asn Val Phe Lys Phe Ile Ile Pro Gln Ile Val Lys Tyr115 120 125Ser Pro Asp Cys Ile Ile Ile Val Val Ser Asn Pro Val Asp Ile Leu
130 135 140Thr Tyr Val Thr Trp Lys Leu Ser Gly Leu Pro Lys His Arg Val Ile145 150 155 160Gly Ser Gly Cys Asn Leu Asp Ser Ala Arg Phe Arg Tyr Leu Met Ala165 170 175Glu Lys Leu Gly Ile His Pro Ser Ser Cys His Gly Trp Ile Leu Gly180 185 190Glu His Gly Asp Ser Ser Val Ala Val Trp Ser Gly Val Asn Val Ala195 200 205Gly Val Ser Leu Gln Glu Leu Asn Pro Glu Met Gly Thr Asp Asn Asp210 215 220Ser Glu Asn Trp Lys Glu Val His Lys Met Val Val Glu Ser Ala Tyr225 230 235 240Glu Val Ile Lys Leu Lys Gly Tyr Thr Asn Trp Ala Ile Gly Leu Ser245 250 255Val Ala Asp Leu Ile Glu Ser Met Leu Lys Asn Leu Ser Arg Ile His260 265 270Pro Val Ser Thr Met Val Lys Gly Met Tyr Gly Ile Glu Asn Glu Val275 280 285Phe Leu Ser Leu Pro Cys Ile Leu Asn Ala Arg Gly Leu Thr Ser Val290 295 300Ile Asn Gln Lys Leu Lys Asp Asp Glu Val Ala Gln Leu Lys Lys Ser305 310 315 320Ala Asp Thr Leu Trp Asp Ile Gln Lys Asp Leu Lys Asp Leu325 330<210>7<211>277<212>PRT<213>人類(Homo sapiens)<400>7Met Ser Asp Gln Gln Leu Asp Cys Ala Leu Asp Leu Met Arg Arg Leu1 5 10 15Pro Pro Gln Gln Ile Glu Lys Asn Leu Ser Asp Leu Ile Asp Leu Val20 25 30Pro Ser Leu Cys Glu Asp Leu Leu Ser Ser Val Asp Gln Pro Leu Lys35 40 45Ile Ala Arg Asp Lys Val Val Gly Lys Asp Tyr Leu Leu Cys Asp Tyr50 55 60
Asn Arg Asp Gly Asp Ser Tyr Arg Ser Pro Trp Ser Asn Lys Tyr Asp65 70 75 80Pro Pro Leu Glu Asp Gly Ala Met Pro Ser Mla Arg Leu Arg Lys Leu85 90 95Glu Val Glu Ala Asn Asn Ala Phe Asp Gln Tyr Arg Asp Leu Tyr Phe100 105 110Glu Gly Gly Val Ser Ser Val Tyr Leu Trp Asp Leu Asp His Gly Phe115 120 125Ala Gly Val Ile Leu Ile Lys Lys Ala Gly Asp Gly Ser Lys Lys Ile130 135 140Lys Gly Cys Trp Asp Ser Ile His Val Val Glu Val Gln Glu Lys Ser145 150 155 160Ser Gly Arg Thr Mla His Tyr Lys Leu Thr Ser Thr Val Met Leu Trp165 170 175Leu Gln Thr Asn Lys Ser Gly Ser Gly Thr Met Asn Leu Gly Gly Ser180 185 190Leu Thr Arg Gln Met Glu Lys Asp Glu Thr Val Ser Asp Cys Ser Pro195 200 205His Ile Ala Asn Ile Gly Arg Leu Val Glu Asp Met Glu Asn Lys Ile210 215 220Arg Ser Thr Leu Asn Glu Ile Tyr Phe Gly Lys Thr Lys Asp Ile Val225 230 235 240Asn Gly Leu Arg Ser Ile Asp Ala Ile Pro Asp Asn Gln Lys Phe Lys245 250 255Gln Leu Gln Arg Glu Leu Ser Gln Val Leu Thr Gln Arg Gln Ile Tyr260 265 270Ile Gln Pro Asp Asn275<210>8<211>619<212>PRT<213>人類(Homo sapiens)<400>8Met Ser Tyr Gln Gly Lys Lys Asn Ile Pro Arg Ile Thr Ser Asp Arg1 5 10 15Leu Leu Ile Lys Gly Gly Lys Ile Val Asn Asp Asp Gln Ser Phe Tyr20 25 30Ala Asp Ile Tyr Met Glu Asp Gly Leu Ile Lys Gln Ile Gly Glu Asn35 40 45
Leu Ile Val Pro Gly Gly Val Lys Thr Ile Glu Ala His Ser Arg Met50 55 60Val Ile Pro Gly Gly Ile Asp Val His Thr Arg Phe Gln Met Pro Asp65 70 75 80Gln Gly Met Thr Ser Ala Asp Asp Phe Phe Gln Gly Thr Lys Ala Ala85 90 95Leu Ala Gly Gly Thr Thr Met Ile Ile Asp His Val Val Pro Glu Pro100 105 110Gly Thr Ser Leu Leu Ala Ala Phe Asp Gln Trp Arg Glu Trp Ala Asp115 120 125Ser Lys Ser Cys Cys Asp Tyr Ser Leu His Val Asp Ile Ser Glu Trp130 135 140His Lys Gly Ile Gln Glu Glu Met Glu Ala Leu Val Lys Asp His Gly145 150 155 160Val Asn Ser Phe Leu Val Tyr Met Ala Phe Lys Asp Arg Phe Gln Leu165 170 175Thr Asp Cys Gln Ile Tyr Glu Val Leu Ser Val Ile Arg Asp Ile Gly180 185 190Ala Ile Ala Gln Val His Ala Glu Asn Gly Asp Ile Ile Ala Glu Glu195 200 205Gln Gln Arg Ile Leu Asp Leu Gly Ile Thr Gly Pro Glu Gly His Val2l0 215 220Leu Ser Arg Pro Glu Glu Val Glu Ala Glu Ala Val Asn Arg Ala Ile225 230 235 240Thr Ile Ala Asn Gln Thr Asn Cys Pro Leu Tyr Ile Thr Lys Val Met245 250 255Ser Lys Ser Ser Ala Glu Val Ile Ala Gln Ala Arg Lys Lys Gly Thr260 265 270Val Val Tyr Gly Glu Pro Ile Thr Ala Ser Leu Gly Thr Asp Gly Ser275 280 285His Tyr Trp Ser Lys Asn Trp Ala Lys Ala Ala Ala Phe Val Thr Ser290 295 300Pro Pro Leu Ser Pro Asp Pro Thr Thr Pro Asp Phe Leu Asn Ser Leu305 310 315 320Leu Ser Cys Gly Asp Leu Gln Val Thr Gly Ser Ala His Cys Thr Phe325 330 335Asn Thr Ala Gln Lys Ala Val Gly Lys Asp Asn Phe Thr Leu Ile Pro340 345 350
Glu Gly Thr Asn Gly Thr Glu Glu Arg Met Ser Val Ile Trp Asp Lys355 360 365Ala Val Val Thr Gly Lys Met Asp Glu Asn Gln Phe Val Ala Val Thr370 375 380Ser Thr Asn Ala Ala Lys Val Phe Asn Leu Tyr Pro Gly Ala Met Trp385 390 395 400Ser Ala Gly Arg Gly Gly Ala Ala Trp Pro Val Leu Leu Gly Leu Leu405 410 415Leu Ala Leu Leu Val Pro Gly Gly Gly Ala Ala Lys Thr Gly Ala Glu420 425 430Leu Val Thr Cys Gly Ser Val Leu Lys Leu Leu Asn Thr His His Arg435 440 445Val Arg Leu His Ser His Asp Ile Lys Tyr Gly Ser Gly Ser Gly Gln450 455 460Gln Ser Val Thr Gly Val Glu Ala Ser Asp Asp Ala Asn Ser Tyr Trp465 470 475 480Arg Ile Arg Gly Gly Ser Glu Gly Gly Cys Pro Arg Gly Ser Pro Val485 490 495Arg Cys Gly Gln Ala Val Arg Leu Thr His Val Leu Thr Gly Lys Asn500 505 510Leu His Thr His His Phe Pro Ser Pro Leu Ser Asn Asn Gln Glu Val515 520 525Ser Mla Phe Gly Glu Asp Gly Glu Gly Asp Asp Leu Asp Leu Trp Thr530 535 540Val Arg Cys Ser Gly Gln His Trp Glu Arg Glu Mla Mla Val Arg Phe545 550 555 560Gln His Val Gly Thr Ser Val Phe Leu Ser Val Thr Gly Glu Gln Tyr565 570 575Gly Ser Pro Ile Arg Gly Gln His Glu Val His Gly Met Pro Ser Mla580 585 590Asn Thr His Asn Thr Trp Lys Ala Met Glu Gly Ile Phe Ile Lys Pro595 600 605Ser Val Glu Pro Ser Ala Gly His Asp Glu Leu610 615<210>9<211>434<212>PRT<213>人類(Homo sapiens)
<400>9Met Ser Ile Leu Lys Ile His Ala Arg Glu Ile Phe Asp Ser Arg Gly1 5 10 15Asn Pro Thr Val Glu Val Asp Leu Phe Thr Ser Lys Gly Leu Phe Arg20 25 30Ala Ala Val Pro Ser Gly Ala Ser Thr Gly Ile Tyr Glu Ala Leu Glu35 40 45Leu Arg Asp Asn Asp Lys Thr Arg Tyr Met Gly Lys Gly Val Ser Lys50 55 60Ala Val Glu His Ile Asn Lys Thr Ile Ala Pro Ala Leu Val Ser Lys65 70 75 80Lys Leu Asn Val Thr Glu Gln Glu Lys Ile Asp Lys Leu Met Ile Glu85 90 95Met Asp Gly Thr Glu Asn Lys Ser Lys Phe Gly Ala Asn Ala Ile Leu100 105 110Gly Val Ser Leu Ala Val Cys Lys Ala Gly Ala Val Glu Lys Gly Val115 120 125Pro Leu Tyr Arg His Ile Ala Asp Leu Ala Gly Asn Ser Glu Val Ile130 135 140Leu Pro Val Pro Ala Phe Asn Val Ile Asn Gly Gly Ser His Ala Gly145 150 155 160Asn Lys Leu Ala Met Gln Glu Phe Met Ile Leu Pro Val Gly Ala Ala165 170 175Asn Phe Arg Glu Ala Met Arg Ile Gly Ala Glu Val Tyr His Asn Leu180 185 190Lys Asn Val Ile Lys Glu Lys Tyr Gly Lys Asp Ala Thr Asn Val Gly195 200 205Asp Glu Gly Gly Phe Ala Pro Asn Ile Leu Glu Asn Lys Glu Gly Leu210 215 220Glu Leu Leu Lys Thr Ala Ile Gly Lys Ala Gly Tyr Thr Asp Lys Val225 230 235 240Val Ile Gly Met Asp Val Ala Ala Ser Glu Phe Ser Arg Ser Gly Lys245 250 255Tyr Asp Leu Asp Phe Lys Ser Pro Asp Asp Pro Ser Arg Tyr Ile Ser260 265 270Pro Asp Gln Leu Ala Asp Leu Tyr Lys Ser Phe Ile Lys Asp Tyr Pro275 280 285Val Val Ser Ile Glu Asp Pro Phe Asp Gln Asp Asp Trp Gly Ala Trp
290 295 300Gln Lys Phe Thr Ala Ser Ala Gly Ile Gln Val Val Gly Asp Asp Leu305 310 315 320Thr Val Thr Asn Pro Lys Arg Ile Ala Lys Ala Val Asn Glu Lys Ser325 330 335Cys Asn Cys Leu Leu Leu Lys Val Asn Gln Ile Gly Ser Val Thr Glu340 345 350Ser Leu Gln Ala Cys Lys Leu Ala Gln Ala Asn Gly Trp Gly Val Met355 360 365Val Ser His Arg Ser Gly Glu Thr Glu Asp Thr Phe Ile Ala Asp Leu370 375 380Val Val Gly Leu Cys Thr Gly Gln Ile Lys Thr Gly Ala Pro Cys Arg385 390 395 400Ser Glu Arg Leu Ala Lys Tyr Asn Gln Leu Leu Arg Ile Glu Glu Glu405 410 415Leu Gly Ser Lys Ala Lys Phe Ala Gly Arg Asn Phe Arg Asn Pro Leu420 425 430Ala Lys<210>10<211>364<212>PRT<213>人類(Homo sapiens)<400>10Met Pro His Ser Tyr Pro Ala Leu Ser Ala Glu Gln Lys Lys Glu Leu1 5 10 15Ser Asp Ile Ala Leu Arg Ile Val Ala Pro Gly Lys Gly Ile Leu Ala20 25 30Ala Asp Glu Ser Val Gly Ser Met Ala Lys Arg Leu Ser Gln Ile Gly35 40 45Val Glu Asn Thr Glu Glu Asn Arg Arg Leu Tyr Arg Gln Val Leu Phe50 55 60Ser Ala Asp Asp Arg Val Lys Lys Cys Ile Gly Gly Val Ile Phe Phe65 70 75 80His Ghr Thr Leu Tyr Gln Lys Asp Asp Asn Gly Val Pro Phe Val Arg85 90 95Thr Ile Gln Asp Lys Gly Ile Val Val Gly Ile Lys Val Asp Lys Gly100 105 110
Val Val Pro Leu Ala Gly Thr Asp Gly Glu Thr Thr Thr Gln Gly Leu115 120 125Asp Gly Leu Ser Glu Arg Cys Ala Gln Tyr Lys Lys Asp Gly Ala Asp130 135 140Phe Ala Lys Trp Arg Cys Val Leu Lys Ile Ser Glu Arg Thr Pro Ser145 150 155 160Ala Leu Ala Ile Leu Glu Asn Ala Asn Val Leu Ala Arg Tyr Ala Ser165 170 175Ile Cys Gln Gln Asn Gly Ile Val Pro Ile Val Glu Pro Glu Ile Leu180 185 190Pro Asp Gly Asp His Asp Leu Lys Arg Cys Gln Tyr Val Thr Glu Lys195 200 205Val Leu Ala Ala Val Tyr Lys Ala Leu Ser Asp His His Val Tyr Leu210 215 220Glu Gly Thr Leu Leu Lys Pro Asn Met Val Thr Pro Gly His Ala Cys225 230 235 240Pro Ile Lys Tyr Thr Pro Glu Glu Ile Ala Met Ala Thr Val Thr Ala245 250 255Leu Arg Arg Thr Val Pro Pro Ala Val Pro Gly Val Thr Phe Leu Ser260 265 270Gly Gly Gln Ser Glu Glu Glu Ala Ser Phe Asn Leu Asn Ala Ile Asn275 280 285Arg Cys Pro Leu Pro Arg Pro Trp Ala Leu Thr Phe Ser Tyr Gly Arg290 295 300Ala Leu Gln Ala Ser Ala Leu Asn Ala Trp Arg Gly Gln Arg Asp Asn305 310 315 320Ala Gly Ala Ala Thr Glu Glu Phe Ile Lys Arg Ala Glu Val Asn Gly325 330 335Leu Ala Ala Gln Gly Lys Tyr Glu Gly Ser Gly Glu Asp Gly Gly Ala340 345 350Ala Ala Gln Ser Leu Tyr Ile Ala Asn His Ala Tyr355 360<210>11<211>335<212>PRT<213>人類(Homo sapiens)<400>11Met Gly Lys Val Lys Val Gly Val Asn Gly Phe Gly Arg lle Gly Arg1 5 10 15
Leu Val Thr Arg Ala Ala Phe Asn Ser Gly Lys Val Asp Ile Val Ala20 25 30Ile Asn Asp Pro Phe Ile Asp Leu Asn Tyr Met Val Tyr Met Phe Gln35 40 45Tyr Asp Ser Thr His Gly Lys Phe His Gly Thr Val Lys Ala Glu Asn50 55 60Gly Lys Leu Val Ile Asn Gly Asn Pro Ile Thr Ile Phe Gln Glu Arg65 70 75 80Asp Pro Ser Lys Ile Lys Trp Gly Asp Ala Gly Ala Glu Tyr Val Val85 90 95Glu Ser Thr Gly Val Phe Thr Thr Met Glu Lys Ala Gly Ala His Leu100 105 110Gln Gly Gly Ala Lys Arg Val Ile Ile Ser Ala Pro Ser Ala Asp Ala115 120 125Pro Met Phe Val Met Gly Val Asn His Glu Lys Tyr Asp Asn Ser Leu130 135 140Lys Ile Ile Ser Asn Ala Ser Cys Thr Thr Asn Cys Leu Ala Pro Leu145 150 155 160Ala Lys Val Ile His Asp Asn Phe Gly Ile Val Glu Gly Leu Met Thr165 170 175Thr Val His Ala Ile Thr Ala Thr Gln Lys Thr Val Asp Gly Pro Ser180 185 190Gly Lys Leu Trp Arg Asp Gly Arg Gly Ala Leu Gln Asn Ile Ile Pro195 200 205Ala Ser Thr Gly Ala Ala Lys Ala Val Gly Lys Val Ile Pro Glu Leu210 215 220Asn Gly Lys Leu Thr Gly Met Ala Phe Arg Val Pro Thr Ala Asn Val225 230 235 240Ser Val Val Asp Leu Thr Cys Arg Leu Glu Lys Pro Ala Lys Tyr Asp245 250 255Asp Ile Lys Lys Val Val Lys Gln Ala Ser Glu Gly Pro Leu Lys Gly260 265 270Ile Leu Gly Tyr Thr Glu His Gln Val Val Ser Ser Asp Phe Asn Ser275 280 285Asp Thr His Ser Ser Thr Phe Asp Ala Gly Ala Gly Ile Ala Leu Asn290 295 300Asp His Phe Val Lys Leu Ile Ser Trp Tyr Asp Asn Glu Phe Gly Tyr305 310 315 320
Ser Asn Arg Val Val Asp Leu Met Ala His Met Ala Ser Lys Glu325 330 335<210>12<211>418<212>PRT<213>人類(Homo sapiens)<400>12Met Ser Leu Ser Asn Lys Leu Thr Leu Asp Lys Leu Asp Val Lys Gly1 5 10 15Lys Arg Val Val Met Arg Val Asp Phe Asn Val Pro Met Lys Asn Asn20 25 30Gln Ile Thr Asn Asn Gln Arg Ile Lys Ala Ala Val Pro Ser Ile Lys35 40 45Phe Cys Leu Asp Asn Gly Ala Lys Ser Val Val Leu Met Ser His Leu50 55 60Gly Arg Pro Asp Gly Val Pro Met Pro Asp Lys Tyr Ser Leu Glu Pro65 70 75 80Val Ala Val Glu Leu Lys Ser Leu Leu Gly Lys Asp Val Leu Phe Leu85 90 95Lys Asp Cys Val Gly Pro Glu Val Glu Lys Ala Cys Ala Asn Pro Ala100 105 110Ala Gly Ser Val Ile Leu Leu Glu Asn Leu Arg Phe His Val Glu Glu115 120 125Glu Gly Lys Gly Lys Asp Ala Ser Gly Asn Lys Val Lys Ala Glu Pro130 135 140Ala Lys Ile Glu Ala Phe Arg Ala Ser Leu Ser Lys Leu Gly Asp Val145 150 155 160Tyr Val Asn Asp Ala Phe Gly Thr Ala His Arg Ala His Ser Ser Met165 170 175Val Gly Val Asn Leu Pro Gln Lys Ala Gly Gly Phe Leu Met Lys Lys180 185 190Glu Leu Asn Tyr Phe Ala Lys Ala Leu Glu Ser Pro Glu Arg Pro Phe195 200 205Leu Ala Ile Leu Gly Gly Ala Lys Val Ala Asp Lys Ile Gln Leu Ile210 215 220Asn Asn Met Leu Asp Lys Val Asn Glu Met Ile Ile Gly Gly Gly Met225 230 235 240Ala Phe Thr Phe Leu Lys Val Leu Asn Asn Met Glu Ile Gly Thr Ser
245 250 255Leu Phe Asp Glu Glu Gly Ala Lys Ile Val Lys Asp Leu Met Ser Lys260 265 270Ala Glu Lys Asn Gly Val Lys Ile Thr Leu Pro Val Asp Phe Val Thr275 280 285Ala Asp Lys Phe Asp Glu Asn Ala Lys Thr Gly Gln Ala Thr Val Ala290 295 300Ser Gly Ile Pro Ala Gly Trp Met Gly Leu Asp Cys Gly Pro Glu Ser305 310 315 320Ser Lys Lys Tyr Ala Glu Ala Val Thr Arg Ala Lys Gln Ile Val Trp325 330 335Asn Gly Pro Val Gly Val Phe Glu Trp Glu Ala Phe Ala Arg Gly Thr340 345 350Lys Ala Leu Met Asp Glu Val Val Lys Ala Thr Ser Arg Gly Cys Ile355 360 365Thr Ile Ile Gly Gly Gly Asp Thr Ala Thr Cys Cys Ala Lys Trp Asn370 375 380Thr Glu Asp Lys Val Ser His Val Ser Thr Gly Gly Gly Ala Ser Leu385 390 395 400Glu Leu Leu Glu Gly Lys Val Leu Pro Gly Val Asp Ala Leu Ser Asn405 410 415Ile Leu<210>13<211>332<212>PRT<213>人類(Homo sapiens)<400>13Met Ala Thr Leu Lys Asp Gln Leu Ile Tyr Asn Leu Leu Lys Glu Glu1 5 10 15Gln Thr Pro Gln Asn Lys Ile Thr Val Val Gly Val Gly Ala Val Gly20 25 30Met Ala Cys Ala Ile Ser Ile Leu Met Lys Asp Leu Ala Asp Glu Leu35 40 45Ala Leu Val Asp Val Ile Glu Asp Lys Leu Lys Gly Glu Met Met Asp50 55 60Leu Gln His Gly Ser Leu Phe Leu Arg Thr Pro Lys Ile Val Ser Gly65 70 75 80
Lys Asp Tyr Asn Val Thr Ala Asn Ser Lys Leu Val Ile Ile Thr Ala85 90 95Gly Ala Arg Gln Gln Glu Gly Glu Ser Arg Leu Asn Leu Val Gln Arg100 105 110Asn Val Asn Ile Phe Lys Phe Ile Ile Pro Asn Val Val Lys Tyr Ser115 120 125Pro Asn Cys Lys Leu Leu Ile Val Ser Asn Pro Val Asp Ile Leu Thr130 135 140Tyr Val Ala Trp Lys Ile Ser Gly Phe Pro Lys Asn Arg Val Ile Gly145 150 155 160Ser Gly Cys Asn Leu Asp Ser Ala Arg Phe Arg Tyr Leu Met Gly Glu165 170 175Arg Leu Gly Val His Pro Leu Ser Cys His Gly Trp Val Leu Gly Glu180 185 190His Gly Asp Ser Ser Val Pro Val Trp Ser Gly Met Asn Val Ala Gly195 200 205Val Ser Leu Lys Thr Leu His Pro Asp Leu Gly Thr Asp Lys Asp Lys210 215 220Glu Gln Trp Lys Glu Val His Lys Gln Val Val Glu Ser Ala Tyr Glu225 230 235 240Val Ile Lys Leu Lys Gly Tyr Thr Ser Trp Ala Ile Gly Leu Ser Val245 250 255Ala Asp Leu Ala Glu Ser Ile Met Lys Asn Leu Arg Arg Val His Pro260 265 270Val Ser Thr Met lle Lys Gly Leu Tyr Gly Ile Lys Asp Asp Val Phe275 280 285Leu Ser Val Pro Cys lle Leu Gly Gln Asn Gly Ile Ser Asp Leu Val290295 300Lys Val Thr Leu Thr Ser Glu Glu Glu Ala Arg Leu Lys Lys Ser Ala305 310 315 320Asp Thr Leu Trp Gly Ile Gln Lys Glu Leu Gln Phe325 330<210>14<211>260<212>PRT<213>人類(Homo sapiens)<400>14Met Ser His His Trp Gly Tyr Gly Lys His Asn Gly Pro Glu His Trp1 5 10 15
His Lys Asp Phe Pro Ile Ala Lys Gly Glu Arg Gln Ser Pro Val Asp20 25 30Ile Asp Thr His Thr Ala Lys Tyr Asp Pro Ser Leu Lys Pro Leu Ser35 40 45Val Ser Tyr Asp Gln Ala Thr Ser Leu Arg Ile Leu Asn Asn Gly His50 55 60Ala Phe Asn Val Glu Phe Asp Asp Ser Gln Asp Lys Ala Val Leu Lys65 70 75 80Gly Gly Pro Leu Asp Gly Thr Tyr Arg Leu Ile Gln Phe His Phe His85 90 95Trp Gly Ser Leu Asp Gly Gln Gly Ser Glu His Thr Val Asp Lys Lys100 105 110Lys Tyr Ala Ala Glu Leu His Leu Val His Trp Asn Thr Lys Tyr Gly115 120 125Asp Phe Gly Lys Ala Val Gln Gln Pro Asp Gly Leu Ala Val Leu Gly130 135 140Ile Phe Leu Lys Val Gly Ser Ala Lys Pro Gly Leu Gln Lys Val Val145 150 155 160Asp Val Leu Asp Ser Ile Lys Thr Lys Gly Lys Ser Ala Asp Phe Thr165 170 175Asn Phe Asp Pro Arg Gly Leu Leu Pro Glu Ser Leu Asp Tyr Trp Thr180 185 190Tyr Pro Gly Ser Leu Thr Thr Pro Pro Leu Leu Glu Cys Val Thr Trp195 200 205Ile Val Leu Lys Glu Pro Ile Ser Val Ser Ser Glu Gln Val Leu Lys210 215 220Phe Arg Lys Leu Asn Phe Asn Gly Glu Gly Glu Pro Glu Glu Leu Met225 230 235 240Val Asp Asn Trp Arg Pro Ala Gln Pro Leu Lys Asn Arg Gln Ile Lys245 250 255Ala Ser Phe Lys260<210>15<211>528<212>PRT<213>人類(Homo sapiens)<400>15Met Leu Leu Pro Leu Leu Leu Leu Leu Pro Met Cys Trp Ala Val Glu
1 5 10 15Val Lys Arg Pro Arg Gly Val Ser Leu Thr Asn His His Phe Tyr Asp20 25 30Glu Ser Lys Pro Phe Thr Cys Leu Asp Gly Ser Ala Thr Ile Pro Phe35 40 45Asp Gln Val Asn Asp Asp Tyr Cys Asp Cys Lys Asp Gly Ser Asp Glu50 55 60Pro Gly Thr Ala Ala Cys Pro Asn Gly Ser Phe His Cys Thr Asn Thr65 70 75 80Gly Tyr Lys Pro Leu Tyr Ile Pro Ser Asn Arg Val Asn Asp Gly Val85 90 95Cys Asp Cys Cys Asp Gly Thr Asp Glu Tyr Asn Ser Gly Val Cye Cys100 105 110Glu Asn Thr Cys Lys Glu Lys Gly Arg Lys Glu Arg Glu Ser Leu Gln115 120 125Gln Met Ala Glu Val Thr Arg Glu Gly Phe Arg Leu Lys Lys Ile Leu130135 140Ile Glu Asp Trp Lys Lys Ala Arg Glu Glu Lys Gln Lys Lys Leu Ile145 150 155 160Glu Leu Gln Ala Gly Lys Lys Ser Leu Glu Asp Gln Val Glu Met Leu165 170 175Arg Thr Val Lys Glu Glu Ala Glu Lys Pro Glu Arg Glu Ala Lys Glu180 185 190Gln His Gln Lys Leu Trp Glu Glu Gln Leu Ala Ala Ala Lys Ala Gln195 200 205Gln Glu Gln Glu Leu Ala Mla Asp Mla Phe Lys Glu Leu Asp Asp Asp210 215 220Met Asp Gly Thr Val Ser Val Thr Glu Leu Gln Thr His Pro Glu Leu225 230 235 240Asp Thr Asp Gly Asp Gly Ala Leu Ser Glu Ala Glu Ala Gln Ala Leu245 250 255Leu Ser Gly Asp Thr Gln Thr Asp Ala Thr Ser Phe Tyr Asp Arg Val260 265 270Trp Ala Ala Ile Arg Asp Lys Tyr Arg Ser Glu Ala Leu Pro Thr Asp275 280 285Leu Pro Ala Pro Ser Ala Pro Asp Leu Thr Glu Pro Lys Glu Glu Gln290 295 300Pro Pro Val Pro Ser Ser Pro Thr Glu Glu Glu Glu Glu Glu Glu Glu
305 310 315 320Glu Glu Glu Glu Glu Ala Glu Glu Glu Glu Glu Glu Glu Asp Ser Glu325 330 335Glu Ala Pro Pro Pro Leu Ser Pro Pro Gln Pro Ala Ser Pro Ala Glu340 345 350Glu Asp Lys Met Pro Pro Tyr Asp Glu Gln Thr Gln Ala Phe Ile Asp355 360 365Ala Ala Gln Glu Ala Arg Asn Lys Phe Glu Glu Ala Glu Arg Ser Leu370 375 380Lys Asp Met Glu Glu Ser Ile Arg Asn Leu Glu Gln Glu Ile Ser Phe385 390 395 400Asp Phe Gly Pro Asn Gly Glu Phe Ala Tyr Leu Tyr Ser Gln Cys Tyr405 410 415Glu Leu Thr Thr Asn Glu Tyr Val Tyr Arg Leu Cys Pro Phe Lys Leu420 425 430Val Ser Gln Lys Pro Lys Leu Gly Gly Ser Pro Thr Ser Leu Gly Thr435 440 445Trp Gly Ser Trp Ile Gly Pro Asp His Asp Lys Phe Ser Ala Met Lys450 455 460Tyr Glu Gln Gly Thr Gly Cys Trp Gln Gly Pro Asn Arg Ser Thr Thr465 470 475 480Val Arg Leu Leu Cys Gly Lys Glu Thr Met Val Thr Ser Thr Thr Glu485 490 495Pro Ser Arg Cys Glu Tyr Leu Met Glu Leu Met Thr Pro Ala Ala Cys500 505 510Pro Glu Pro Pro Pro Glu Ala Pro Thr Glu Asp Asp His Asp Glu Leu515 520 525<210>16<211>266<212>PRT<213>人類(Homo sapiens)<400>16Ala Cys Ile Ser Phe Gly Pro Lys Asn Arg Ser lle Gly Ala Ala Ala1 5 10 15Lys Ser Gln Val Ile Ser Asn Ala Lys Asn Thr Val Gln Gly Phe Lys20 25 30Arg Phe His Gly Arg Ala Phe Ser Asp Pro Phe Val Glu Ala Glu Lys
35 40 45Ser Asn Leu Ala Tyr Asp Ile Val Gln Leu Pro Thr Gly Leu Thr Gly50 55 60Ile Lys Val Thr Tyr Met Glu Glu Glu Arg Asn Phe Thr Thr Glu Gln65 70 75 80Val Thr Ala Met Leu Leu Ser Lys Leu Lys Glu Thr Ala Glu Ser Val85 90 95Leu Lys Lys Pro Val Val Asp Cys Val Val Ser Val Pro Cys Phe Tyr100 105 110Thr Asp Ala Glu Arg Arg Ser Val Met Asp Ala Thr Gln Ile Ala Gly115 120 125Leu Asn Cys Leu Arg Leu Met Asn Glu Thr Thr Ala Val Ala Leu Ala130 135 140Tyr Gly Ile Tyr Lys Gln Asp Leu Pro Ala Leu Glu Glu Lys Pro Arg145 150 155 160Asn Val Val Phe Val Asp Met Gly His Ser Ala Tyr Gln Val Ser Val165 170 175Cys Ala Phe Asn Arg Gly Lys Leu Lys Val Leu Ala Thr Ala Phe Asp180 185 190Thr Thr Leu Gly Gly Arg Lys Phe Asp Glu Val Leu Val Asn His Phe195 200 205Cys Glu Glu Phe Gly Lys Lys Tyr Lys Leu Asp Ile Lys Ser Lys Ile210 215 220Arg Ala Leu Leu Arg Leu Ser Gln Glu Cys Glu Lys Leu Lys Lys Leu225 230 235 240Met Ser Ala Asn Ala Ser Asp Leu Pro Leu Ser Ile Glu Cys Phe Met245 250 255Asn Asp Val Asp Val Ser Gly Thr Met Asn260 265<210>17<211>417<212>PRT<213>人類(Homo sapiens)<400>17Met Leu Leu Ser Val Pro Leu Leu Leu Gly Leu Leu Gly Leu Ala Val1 5 10 15Ala Glu Pro Ala Val Tyr Phe Lys Glu Gln Phe Leu Asp Gly Asp Gly20 25 30
Trp Thr Ser Arg Trp Ile Glu Ser Lys His Lys Ser Asp Phe Gly Lys35 40 45Phe Val Leu Ser Ser Gly Lys Phe Tyr Cly Asp Clu Clu Lys Asp Lys50 55 60Gly Leu Gln Thr Ser Gln Asp Ala Arg Phe Tyr Ala Leu Ser Ala Ser65 70 75 80Phe Glu Pro Phe Ser Asn Lys Gly Gln Thr Leu Val Val Gln Phe Thr85 90 95Val Lys His Glu Gln Asn Ile Asp Cys Gly Gly Gly Tyr Val Lys Leu100 105 110Phe Pro Asn Ser Leu Asp Gln Thr Asp Met His Gly Asp Ser Glu Tyr115 120 125Asn Ile Met Phe Gly Pro Asp Ile Cys Gly Pro Gly Thr Lys Lys Val130 135 140His Val Ile Phe Asn Tyr Lys Gly Lys Asn Val Leu Ile Asn Lys Asp145 150 155 160Ile Arg Cys Lys Asp Asp Glu Phe Thr His Leu Tyr Thr Leu Ile Val165 170 175Arg Pro Asp Asn Thr Tyr Glu Val Lys Ile Asp Asn Ser Gln Val Glu180 185 190Ser Gly Ser Leu Glu Asp Asp Trp Asp Phe Leu Pro Pro Lys Lys Ile195 200 205Lys Asp Pro Asp Ala Ser Lys Pro Glu Asp Trp Asp Glu Arg Ala Lys210215 220Ile Asp Asp Pro Thr Asp Ser Lys Pro Glu Asp Trp Asp Lys Pro Glu225 230 235 240His Ile Pro Asp Pro Asp Ala Lys Lys Pro Glu Asp Trp Asp Glu Glu245 250 255Met Asp Gly Glu Trp Glu Pro Pro Val Ile Gln Asn Pro Glu Tyr Lys260 265 270Gly Glu Trp Lys Pro Arg Gln Ile Asp Asn Pro Asp Tyr Lys Gly Thr275 280 285Trp Ile His Pro Glu Ile Asp Asn Pro Glu Tyr Ser Pro Asp Pro Ser290 295 300Ile Tyr Ala Tyr Asp Asn Phe Gly Val Leu Gly Leu Asp Leu Trp Gln305 310 315 320Val Lys Ser Gly Thr Ile Phe Asp Asn Phe Leu Ile Thr Asn Asp Glu325 330 335
Ala Tyr Ala Glu Glu Phe Gly Asn Glu Thr Trp Gly Val Thr Lys Ala340 345 350Ala Glu Lys Gln Met Lys Asp Lys Gln Asp Glu Glu Gln Arg Leu Lys355 360 365Glu Glu Glu Glu Asp Lys Lys Arg Lys Glu Glu Glu Glu Ala Glu Asp370375 380Lys Glu Asp Asp Glu Asp Lys Asp Glu Asp Glu Glu Asp Glu Glu Asp385 390 395 400Lys Glu Glu Asp Glu Glu Glu Asp Val Pro Gly Gln Ala Lys Asp Glu405 410 415Leu<210>18<211>434<212>PRT<213>人類(Homo sapiens)<400>18Met Arg Glu Ile Val Leu Thr Gln Thr Gly Gln Cys Gly Asn Gln Ile1 5 10 15Gly Ala Lys Phe Trp Glu Val Ile Ser Asp Glu His Ala Ile Asp Ser20 25 30Ala Gly Thr Tyr His Gly Asp Ser His Leu Gln Leu Glu Arg Ile Asn35 40 45Val His His His Glu Ala Ser Gly Gly Arg Tyr Val Pro Arg Ala Val50 55 60Leu Val Asp Leu Glu Pro Gly Thr Met Asp Ser Val Arg Ser Gly Pro65 70 75 80Phe Ala Glu Val Phe Arg Pro Asp Asn Phe Ile Ser Arg Gln Cys Gly85 90 95Ala Gly Asn Asn Trp Ala Lys Gly Arg Tyr Thr Glu Gly Ala Glu Leu100 105 110Met Glu Ser Val Met Asp Val Val Arg Lys Glu Ala Glu Ser Cys Asp115 120 125Cys Leu Gln Gly Phe Gln Leu Thr His Ser Leu Gly Gly Gly Thr Gly130 135 140Ser Gly Met Gly Thr Leu Leu Leu Ser Lys Ile Arg Glu Glu Tyr Pro145 150 155 160Asp Arg Ile Ile Asn Thr Phe Ser Ile Leu Pro Ser Pro Lys Val Ser165 170 175
Asp Thr Val Val Glu Pro Tyr Asn Ala Thr Leu Ser Val His Gln Leu180 185 190Ile Glu Asn Ala Asp Glu Thr Phe Cys Ile Asp Asn Glu Ala Leu Tyr195 200 205Asp Ile Cys Ser Arg Thr Leu Lys Leu Pro Thr Pro Thr Tyr Gly Asp210 215 220Leu Asn His Leu Val Ser Ala Thr Val Ser Gly Val Thr Thr Cys Leu225 230 235 240Arg Phe Pro Gly Gln Leu Asn Ala Asp Leu Arg Lys Leu Ala Val Asn245 250 255Met Val Pro Phe Pro Arg Leu His Phe Phe Met Pro Gly Phe Ala Pro260 265 270Leu Thr Ser Gln Gly Ser Gln Gln Tyr Arg Ala Leu Thr Val Ala Glu275 280 285Leu Thr Gln Gln Met Phe Asp Ala Lys Asn Met Met Ala Ala Arg Asp290 295 300Pro Arg His Gly Cys Tyr Leu Thr Ala Ala Ala Ile Phe Arg Gly Arg305 310 315 320Met Pro Met Arg Glu Val Asp Glu Gln Met Phe Asn Ile Gln Asp Lys325 330 335Asn Ser Ser Tyr Phe Ala Asp Trp Leu Pro Asn Asn Ile Lys Thr Ala340 345 350Val Cys Asp Ile Pro Pro Trp Gly Leu Lys Met Ser Val Thr Phe Thr355 360 365Gly Asn Asn Thr Ala Val Gln Glu Leu Lys Arg Val Ser Glu Gln Phe370 375 380Thr Ala Thr Phe Arg Arg Lys Ala Phe Leu His Trp Tyr Thr Gly Glu385 390 395 400Gly Met Asp Glu Met Glu Phe Thr Glu Ala Glu Ser Asn Met Asn Asp405 410 415Leu Val Ser Glu Tyr Gln Gln Tyr Gln Asp Ala Thr Ala Glu Gly Glu420 425 430Gly Val<210>19<211>445<212>PRT<213>人類(Homo sapiens)
<400>19Met Arg Glu Ile Val His Leu Gln Ala Gly Gln Cys Gly Asn Gln Ile1 5 10 15Gly Ala Lys Phe Trp Glu Val Ile Ser Asp Glu His Gly Ile Asp Pro20 25 30Thr Gly Thr Tyr His Gly Asp Ser Asp Leu Gln Leu Glu Arg Ile Asn35 40 45Val Tyr Tyr Asn Glu Ala Thr Gly Gly Lys Tyr Val Pro Arg Ala Val50 55 60Leu Val Asp Leu Glu Pro Gly Thr Met Asp Ser Val Arg Ser Gly Pro65 70 75 80Phe Gly Gln Ile Phe Arg Pro Asp Asn Phe Val Phe Gly Gln Ser Gly85 90 95Ala Gly Asn Asn Trp Ala Lys Gly His Tyr Thr Glu Gly Ala Glu Leu100 105 110Val Asp Ser Val Leu Asp Val Val Arg Lys Glu Ala Glu Ser Cys Asp115 120 125Cys Leu Gln Gly Phe Gln Leu Thr His Ser Leu Gly Gly Gly Thr Gly130 135 140Ser Gly Met Gly Thr Leu Leu Ile Ser Lys Ile Arg Glu Glu Tyr Pro145 150 155 160Asp Arg Ile Met Asn Thr Phe Ser Val Val Pro Ser Pro Lys Val Ser165 170 175Asp Thr Val Val Glu Pro Tyr Asn Ala Thr Leu Ser Val His Gln Leu180 185 190Val Glu Asn Thr Asp Glu Thr Tyr Cys Ile Asp Asn Glu Ala Leu Tyr195 200 205Asp Ile Cys Phe Arg Thr Leu Lys Leu Thr Thr Pro Thr Tyr Gly Asp210 215 220Leu Asn His Leu Val Ser Ala Thr Met Ser Gly Val Thr Thr Cys Leu225 230 235 240Arg Phe Pro Gly Gln Leu Asn Ala Asp Leu Arg Lys Leu Ala Val Asn245 250 255Met Val Pro Phe Pro Arg Leu His Phe Phe Met Pro Gly Phe Ala Pro260 265 270Leu Thr Ser Arg Gly Ser Gln Gln Tyr Arg Ala Leu Thr Val Pro Glu275 280 285Leu Thr Gln Gln Met Phe Asp Ala Lys Asn Met Met Ala Ala Cys Asp
290 295 300Pro Arg His Gly Arg Tyr Leu Thr Val Ala Ala Val Phe Arg Gly Arg305 310 315 320Met Ser Met Lys Glu Val Asp Glu Gln Met Leu Asn Val Gln Asn Lys325 330 335Asn Ser Ser Tyr Phe Val Glu Trp Ile Pro Asn Asn Val Lys Thr Ala340 345 350Val Cys Asp Ile Pro Pro Arg Gly Leu Lys Met Ser Ala Thr Phe Ile355 360 365Gly Asn Ser Thr Ala Ile Gln Glu Leu Phe Lys Arg Ile Ser Glu Gln370 375 380Phe Thr Ala Met Phe Arg Arg Lys Ala Phe Leu His Trp Tyr Thr Gly385 390 395 400Glu Gly Met Asp Glu Met Glu Phe Thr Glu Ala Glu Ser Asn Met Asn405 410 415Asp Leu Val Ser Glu Tyr Gln Gln Tyr Gln Asp Ala Thr Ala Glu Glu420 425 430Glu Gly Glu Phe Glu Glu Glu Ala Glu Glu Glu Val Ala435 440 445<210>20<211>340<212>PRT<213>人類(Homo sapiens)<400>20Met Ser Glu Leu Glu Gln Leu Arg Gln Glu Ala Glu Gln Leu Arg Asn1 5 10 15Gln Ile Gln Asp Ala Arg Lys Ala Cys Asn Asp Ala Thr Leu Val Gln20 25 30Ile Thr Ser Asn Met Asp Ser Val Gly Arg Ile Gln Met Arg Thr Arg35 40 45Arg Thr Leu Arg Gly His Leu Ala Lys Ile Tyr Mla Met His Trp Gly50 55 60Tyr Asp Ser Arg Leu Leu Val Ser Mla Ser Gln Asp Gly Lys Leu Ile65 70 75 80Ile Trp Asp Ser Tyr Thr Thr Asn Lys Met His Ala Ile Pro Leu Arg85 90 95Ser Ser Trp Val Met Thr Cys Ala Tyr Ala Pro Ser Gly Asn Tyr Val100 105 110
Ala Cys Gly Gly Leu Asp Asn Ile Cys Ser Ile Tyr Asn Leu Lys Thr115 120 125Arg Glu Gly Asn Val Arg Val Ser Arg Glu Leu Pro Gly His Thr Gly130 135 140Tyr Leu Ser Cys Cys Arg Phe Leu Asp Asp Ser Gln Ile Val Thr Ser145 150 155 160Ser Gly Asp Thr Thr Cys Ala Leu Trp Asp Ile Glu Thr Ala Gln Gln165 170 175Thr Thr Thr Phe Thr Gly His Ser Gly Asp Val Met Ser Leu Ser Leu180 185 190Ser Pro Asp Met Arg Thr Phe Val Ser Gly Mla Cys Asp Ala Ser Ser195 200 205Lys Leu Trp Asp Ile Arg Asp Gly Met Cys Arg Gln Ser Phe Thr Gly210 215 220His Val Ser Asp Ile Asn Ala Val Ser Phe Phe Pro Asn Gly Tyr Ala225 230 235 240Phe Ala Thr Gly Ser Asp Asp Ala Thr Cys Arg Leu Phe Asp Leu Arg245 250 255Ala Asp Gln Glu Leu Leu Leu Tyr Ser His Asp Asn Ile Ile Cys Gly260 265 270Ile Thr Ser Val Ala Phe Ser Lys Ser Gly Arg Leu Leu Leu Ala Gly275 280 285Tyr Asp Asp Phe Asn Cys Asn Val Trp Asp Thr Leu Lys Gly Asp Arg290 295 300Ala Gly Val Leu Ala Gly His Asp Asn Arg Val Ser Cys Leu Gly Val305 310 315 320Thr Asp Asp Gly Met Ala Val Ala Thr Gly Ser Trp Asp Ser Phe Leu325 330 335Arg Ile Trp Asn340<210>21<211>340<212>PRT<213>人類(Homo sapiens)<400>21Met Ser Glu Leu Asp Gln Leu Arg Gln Glu Ala Glu Gln Leu Lys Asn1 5 10 15Gln Ile Arg Asp Ala Arg Lys Ala Cys Ala Asp Ala Thr Leu Ser Gln20 25 30
Ile Thr Asn Asn Ile Asp Pro Val Gly Arg Ile Gln Met Arg Thr Arg35 40 45Arg Thr Leu Arg Gly His Leu Ala Lys Ile Tyr Ala Met His Trp Gly50 55 60Thr Asp Ser Arg Leu Leu Val Ser Ala Ser Gln Asp Gly Lys Leu Ile65 70 75 80Ile Trp Asp Ser Tyr Thr Thr Asn Lys Val His Ala Ile Pro Leu Arg85 90 95Ser Ser Trp Val Met Thr Cys Ala Tyr Ala Pro Ser Gly Asn Tyr Val100 105 110Ala Cys Gly Gly Leu Asp Asn Ile Cys Ser Ile Tyr Asn Leu Lys Thr115 120 125Arg Glu Gly Asn Val Arg Val Ser Arg Glu Leu Ala Gly His Thr Gly130 135 140Tyr Leu Ser Cys Cys Arg Phe Leu Asp Asp Asn Gln Ile Val Thr Ser145 150 155 160Ser Gly Asp Thr Thr Cys Ala Leu Trp Asp Ile Glu Thr Gly Gln Gln165 170 175Thr Thr Thr Phe Thr Gly His Thr Gly Asp Val Met Ser Leu Ser Leu180 185 190Ala Pro Asp Thr Arg Leu Phe Val Ser Gly Ala Cys Asp Ala Ser Ala195 200 205Lys Leu Trp Asp Val Arg Glu Gly Met Cys Arg Gln Thr Phe Thr Gly210 215 220His Glu Ser Asp l1e Asn Ala Ile Cys Phe Phe Pro Asn Gly Asn Ala225 230 235 240Phe Ala Thr Gly Ser Asp Asp Ala Thr Cys Arg Leu Phe Asp Leu Arg245 250 255Ala Asp Gln Glu Leu Met Thr Tyr Ser His Asp Asn Ile Ile Cys Gly260 265 270Ile Thr Ser Val Ser Phe Ser Lys Ser Gly Arg Leu Leu Leu Ala Gly275 280 285Tyr Asp Asp Phe Asn Cys Asn Val Trp Asp Ala Leu Lys Ala Asp Arg290 295 300Ala Gly Val Leu Ala Gly His Asp Asn Arg Val Ser Cys Leu Gly Val305 310 315 320Thr Asp Asp Gly Met Ala Val Ala Thr Gly Ser Trp Asp Ser Phe Leu325 330 335
Lys Ile Trp Asn340<210>22<211>187<212>PRT<213>人類(Homo sapiens)<400>22Met Pro Val Asp Leu Ser Lys Trp Ser Gly Pro Leu Ser Leu Gln Glu1 5 10 15Val Asp Glu Gln Pro Gln His Pro Leu His Val Thr Tyr Ala Gly Ala20 25 30Ala Val Asp Glu Leu Gly Lys Val Leu Thr Pro Thr Gln Val Lys Asn35 40 45Arg Pro Thr Ser Ile Ser Trp Asp Gly Leu Asp Ser Gly Lys Leu Tyr50 55 60Thr Leu Val Leu Thr Asp Pro Asp Ala Pro Ser Arg Lys Asp Pro Lys65 70 75 80Tyr Arg Glu Trp His His Phe Leu Val Val Asn Met Lys Gly Asn Asp85 90 95Ile Ser Ser Gly Thr Val Leu Ser Asp Tyr Val Gly Ser Gly Pro Pro100 105 110Lys Gly Thr Gly Leu His Arg Tyr Val Trp Leu Val Tyr Glu Gln Asp115 120 125Arg Pro Leu Lys Cys Asp Glu Pro Ile Leu Ser Asn Arg Ser Gly Asp130 135 140His Arg Gly Lys Phe Lys Val Ala Ser Phe Arg Lys Lys Tyr Glu Leu145 150 155 160Arg Ala Pro Val Ala Gly Thr Cys Tyr Gln Ala Glu Trp Asp Asp Tyr165 170 175Val Pro Lys Leu Tyr Glu Gln Leu Ser Gly Lys180 18權利要求
1.用于診斷糖尿病的組合物，其特征是，包括從氨基酸序列SEQ ID NOs1到22描述的蛋白質組成的組中選出的至少一種蛋白質或其片段。
2.用于診斷血管疾病的組合物，其特征是，包括從氨基酸序列SEQ IDNOs1到9和SEQ ID NOs11到22描述的蛋白質組成的組中選出的至少一種蛋白質或其片段。
3.根據(jù)權利要求1或2所述的用于診斷糖尿病或血管疾病的組合物，其中，該組合物包括氨基酸序列SEQ ID NO4描述的蛋白質或其片段。
4.根據(jù)權利要求2所述的用于診斷視網(wǎng)膜血管疾病的組合物，其中，視網(wǎng)膜血管疾病選自由糖尿病性視網(wǎng)膜病、視網(wǎng)膜水腫和老年性黃斑變性組成的組。
5.一種用于診斷糖尿病的試劑盒，包括權利要求1所述的蛋白質或其片段。
6.一種用于診斷血管疾病的試劑盒，包括權利要求2所述的蛋白質或其片段。
7.根據(jù)權利要求5或6所述的試劑盒，其中，該試劑盒進一步包括被標記的抗免疫球蛋白G抗體蛋白。
8.一種對由糖尿病或視網(wǎng)膜血管疾病產(chǎn)生的抗體進行分析的方法，包括權利要求1或2所述的至少一種蛋白質與血液接觸的步驟。
9.根據(jù)權利要求8所述的對由視網(wǎng)膜血管疾病產(chǎn)生的抗體進行分析的方法，其中，該分析抗體的方法進一步包括加入標記的抗免疫球蛋白G抗體蛋白的步驟。
全文摘要
本發(fā)明涉及用于診斷糖尿病和視網(wǎng)膜血管疾病的組合物，用于診斷視網(wǎng)膜血管疾病的試劑盒，其包括蛋白質、編碼該蛋白質的基因，和使用它們來對糖尿病和/或視網(wǎng)膜疾病產(chǎn)生的抗體進行分析的方法。
文檔編號G01N33/543GK1981194SQ200580022808
公開日2007年6月13日 申請日期2005年7月6日 優(yōu)先權日2004年7月6日
發(fā)明者趙良濟, 安寶暎, 俞元一, 權五雄 申請人:愛吉恩公司