專利名稱：與dppiv相關(guān)的新絲氨酸蛋白酶基因的制作方法
技術(shù)領(lǐng)域：
本發(fā)明涉及與二肽酰肽酶IV(DPPIV)相關(guān)的新穎的絲氨酸蛋白酶，以及編碼這些蛋白酶的分離的核酸，它們都可用于開發(fā)新的治療劑，測定蛋白酶活性，和測定針對這些蛋白酶的化合物的抑制活性。
背景技術(shù)：
蛋白酶和肽酶是催化肽酰胺鍵水解的酶。蛋白酶在幾乎每一種生命形式，從細菌到病毒到哺乳動物的生物學活動調(diào)節(jié)中起著重要作用。它們在例如消化、凝血、凋亡、免疫應答激活、酶原激活、病毒成熟、蛋白質(zhì)分泌和蛋白質(zhì)運輸中起著關(guān)鍵作用。它們可以根據(jù)許多特性分類，例如按作用位點、底物傾向性和機制分類。因此例如，氨肽酶優(yōu)先作用于肽的N-末端殘基，而羧肽酶優(yōu)先作用于C-末端，內(nèi)肽酶則作用于兩個末端去除后的位點。在羧肽酶和氨肽酶中，肽酰肽酶從底物切下一個氨基酸殘基，二肽酰肽酶從底物切下一個二肽單元(兩個氨基酸)，三肽酶則從底物切下三個氨基酸。底物優(yōu)先性常常以緊靠切割位點N-末端的氨基酸殘基表示。例如，胰蛋白酶類肽酶優(yōu)先切割緊靠堿性氨基酸(精氨酸或賴氨酸)的肽，即水解的鍵是Arg/Lys-Xaa鍵。作為另一個例子，肽酶的胰凝乳蛋白酶類家族優(yōu)先水解毗鄰芳族殘基的肽。從機制上說，肽酶分類為絲氨酸依賴性、半胱氨酸依賴性、天冬氨酸依賴性或鋅依賴性。
由于肽酶和蛋白酶參與許多生理過程的調(diào)節(jié)，它們是開發(fā)治療劑的誘人目標。蛋白酶和肽酶抑制劑用于治療高血壓、血凝疾病和病毒感染等。
在催化活性中利用絲氨酸的蛋白水解酶是獨特的，在病毒、細菌和真核細胞中都有發(fā)現(xiàn)。已鑒定到超過20個家族(稱為S1-S27)的絲氨酸蛋白酶；根據(jù)結(jié)構(gòu)相似性和其它功能分成6個家族(SA、SB、SC、SE、SF和SG)。已知結(jié)構(gòu)的有四個家族(SA、SB、SC和SE)；它們似乎是完全不相關(guān)的，提示絲氨酸肽酶至少有四種進化起源，可能更多，Rawlings和Barrett，Meth.Enzymol.24419-61(1994)。
脯氨酰寡肽酶家族由許多進化上相關(guān)的肽酶組成，其催化活性似乎是由類似于絲氨酸蛋白酶的胰蛋白酶家族的電荷中繼系統(tǒng)提供的，但是它是通過獨立的同進化而來的。通過實驗顯示一個保守的絲氨酸殘基(在大腸桿菌蛋白酶II和豬和細菌PE中)是催化機制必需的。該絲氨酸是催化三聯(lián)體(Ser、His、Asp)的一部分，通常位于離這些酶(所有蛋白質(zhì)含有約700-800個氨基酸)C末端約150個殘基。
受到最廣泛研究的脯氨酰寡肽酶之一是二肽酰肽酶IV(DPPIV，EC3.414.5)，一種II型糖蛋白，它是唯一的特性已明確的位于胞質(zhì)膜外側(cè)的二肽酰氨肽酶。如上所述，二肽酰氨肽酶的特征是它們能從各種小肽上切下N末端二肽。二肽酰氨肽酶顯示不同的底物專一性和細胞定位，提示肽加工中各活性的不同功能。DPPIV的特征是它能切下含有脯氨酸或丙氨酸作為次末殘基的N-末端二肽。DPPIV基因長約70kb，含有26個外顯子，大小為45bp-1.4kb。cDNA的核苷酸序列(3，465bp)含有編碼766個氨基酸的多肽的開放閱讀框。編碼活性位點序列(G-W-S-Y-G)的核苷酸分隔于2個外顯子之間。這清楚的將脯氨酰寡肽酶家族的基因組組成與經(jīng)典絲氨酸蛋白酶家族區(qū)分開來。
DPPIV廣泛分布在哺乳動物組織中，并大量發(fā)現(xiàn)于腎臟、小腸表皮和胎盤中(Yaron，A.和Naider，F(xiàn).，Critical Reviews in Biochem.Mol.Biol.1993[1]，31)。在人免疫系統(tǒng)中，此酶幾乎只由活化的CD4+型T-淋巴細胞表達，這些細胞中顯示此酶和細胞表面抗原CD26是同義的。雖然DP-IV在人生理學中的確切作用還未被完全了解，近來的研究顯示此酶清楚的在人生理學和病理學中有主要作用。
對于人T細胞，DPPIV表達在胸腺分化中較晚出現(xiàn)，傾向限于CD4+輔助/記憶細胞群，CD26可傳遞強的共刺激T細胞活化信號。DPPIV也稱為T細胞活化抗原CD26，因此通過與CD45酪氨酸磷酸酶的結(jié)合在免疫應答中起到重要作用，并通過其使腺苷脫氨酶(ADA)與T細胞表面結(jié)合的能力，保護T細胞的增殖不受腺苷介導的抑制。另外，CD26/DPPIV對趨化因子功能的調(diào)節(jié)似乎對于淋巴細胞運送和HIV株的感染性是必須的。DPPIV與許多功能有關(guān)，包括參與T細胞活化、細胞粘附、腎臟和小腸中含脯氨酸的肽的消化、HIV感染和凋亡、以及某些黑素瘤細胞中腫瘤原性的調(diào)節(jié)，Pethiyagoda等，Clin.Exp.Metastasis 2000180391-400。DPPIV還參與內(nèi)分泌調(diào)節(jié)和代謝生理學。更具體的，DPPIV切割GLP-1的氨基末端His-Ala二肽，產(chǎn)生GLP-1受體拮抗劑，從而縮短對GLP-1的生理反應。胰高血糖素樣肽-1(GLP-1)是一種誘導葡萄糖依賴性胰島素分泌的腸促胰島素，它被DPPIV迅速降解，并且由于DPPIV切割半衰期比從循環(huán)中除去GLP-1的半衰期短得多，抑制DPP-IV可預期GLP-1生物活性的顯著上升(5-10倍)。目前正在臨床上研究DPPIV的抑制劑，用作2型糖尿病和受損葡萄糖耐受的潛在治療劑。
1993年，知道了各種不同的DPPIV抑制劑。其中之一是自殺抑制劑N-Ala-Pro-O-(硝基苯甲?；?)羥胺。另一種是玉米肽抑制劑e-(4-硝基)苯甲氧基羰基-Lys-Pro，而另一種是多克隆家兔抗豬腎DPPIV免疫球蛋白。其它制劑劑也已被開發(fā)，在美國專利5,939,560、6,110,949、6,011,155和5,462,928中有所描述。
除了，但不依賴于其絲氨酸型催化活性外，DPPIV與作為受體，并據(jù)信介導信號轉(zhuǎn)導的可溶性胞外酶腺苷脫氨酶(ADA)緊密結(jié)合。DPPIV結(jié)構(gòu)的特征是兩個胞外結(jié)構(gòu)域，一個α/β折疊水解酶結(jié)構(gòu)域和7-刃β-螺旋漿結(jié)構(gòu)域，由約50個氨基酸的重復β-片層組成。近來顯示除了通過大小選擇底物，β-螺旋漿結(jié)構(gòu)域含有10-12個高度保守的半胱氨酸殘基，對肽酶結(jié)構(gòu)域的催化有作用。另外，富含半胱氨酸的結(jié)構(gòu)域負責DPPIV與膠原I和胞外ADA結(jié)合。還報道DPPIV在纖連蛋白介導的細胞與胞外基質(zhì)的相互作用中起作用。近來的研究顯示，DPPIV的蛋白酶活性不是其抗侵襲活性所需要的，因為缺乏胞外絲氨酸蛋白酶活性的DPPIV突變體保留了這種活性。
文獻中報道了許多與DPPIV具有相似性的蛋白質(zhì)。這些蛋白質(zhì)中的幾種已被克隆，包括DPP-I、DPP-II、DPP-III、DPP-X和成纖維細胞活化蛋白(FAP)。這些蛋白質(zhì)已被鑒定并通過分子克隆和表達的蛋白質(zhì)的功能研究，或作為組織提取物中的生物化學活性確定了特征。尚未克隆DPPIV-β和其它與DPPIV具有功能相似性的新的肽酶。脯氨酰寡肽酶家族其它成員的鑒定、確定特征和/或合適分類，其生理(特別是病理)作用的闡明，以及這些知識在開發(fā)新治療劑中的應用是重要的挑戰(zhàn)。
發(fā)明簡述本發(fā)明提供了具有脯氨酰寡肽酶(后脯氨酸切割)活性的蛋白質(zhì)，它包括與DPPIV相關(guān)的蛋白質(zhì)家族的三個新成員，包括全長蛋白質(zhì)、其交替剪接形式、亞基和突變體，以及編碼這些成員的核苷酸序列。本發(fā)明還提供了篩選上述蛋白質(zhì)的底物、相互作用的蛋白質(zhì)、激動劑、拮抗劑或抑制劑的方法，和含有蛋白質(zhì)和/或突變體、其衍生物和/或類似物和/或其配體的藥物組合物。
這些具有與DPPIV顯著序列同源性的新穎蛋白質(zhì)稱為二肽酰肽酶IV-相關(guān)蛋白質(zhì)-1、2和3(DPRP-1、DPRP-2和DPRP-3)。SEQ ID NO1、3和5分別提供了DPRP-1、DPRP-2和DPRP-3的氨基酸序列。還公開了編碼這些蛋白質(zhì)的核酸序列(SEQ IDNO2、4和6)。
表1說明了這些新穎蛋白質(zhì)DPRP-1、DPRP-2和DPRP-3和其它已知絲氨酸蛋白酶之間的同源性(即相似性)。
表1-這三種新穎蛋白質(zhì)和DPPIV，以及其它S9家族，SC家族成員和亞家族B成員之間的序列比較
C末端序列中可見DPRP-1、DPRP-2和DPPIV之間最大的同源性。基于與DPPIV(見

圖1)的序列同源性，人們可以預測這些DPRP蛋白質(zhì)具有的功能包括但不限于酶的作用?？寺?、表達、生物化學和分子特征證實了該假說。
DPRP的表達模式和定位于特殊化(specialized)的表皮細胞和漿細胞(睪丸間質(zhì)細胞、前列腺表皮細胞、淋巴細胞、B細胞)與其在分化、增殖和炎癥中的作用相一致。DPRP-1基因在激素敏感性癌癥(乳腺、前列腺、睪丸癌)、睪酮調(diào)節(jié)的組織中的定位和在弱分化癌癥中的大量表達，顯示DPRP-活化或抑制分子將在治療疾病中有許多治療用途，這些疾病的特征是失控的生長、分化和類固醇或多肽激素的合成和降解。本文公開的漿料支持這種假說，即DPRP-1和DPRP-2涉及本領(lǐng)域技術(shù)人員熟知的前列腺和睪丸癌體外模型的增殖調(diào)控。
本文描述的DPRP-1和DPRP-2活性及其表達模式與其通過生物化學調(diào)節(jié)劑(例如肽和趨化因子)的酶修飾，作為免疫和神經(jīng)內(nèi)分泌系統(tǒng)的生理調(diào)節(jié)劑的功能相符。先前對于DPPIV所述的，根據(jù)所使用的抑制劑的許多功能，可能部分是由于其作用和相似蛋白質(zhì)，例如DPRP等的作用。因此，DPPIV、DPRP和其它相關(guān)蛋白酶，例如FAP的選擇性和強抑制劑的發(fā)現(xiàn)，被視為是實現(xiàn)這些酶和任何新鑒定的絲氨酸蛋白酶抑制劑，以及其它能修飾這些蛋白質(zhì)功能的活性化合物的有效和安全藥物用途的中心課題。
本發(fā)明因此提供了新穎的蛋白質(zhì)或多肽，其編碼核酸，被該核酸修飾從而表達這些蛋白質(zhì)的細胞，這些蛋白質(zhì)的抗體，發(fā)現(xiàn)作為這些蛋白質(zhì)活性抑制劑(或作為DPPIV抑制劑而不是這些蛋白質(zhì)的抑制劑)的新治療劑的篩選方法，和用該篩選方法發(fā)現(xiàn)的治療劑。這些新蛋白質(zhì)及其編碼核酸可用于發(fā)現(xiàn)新的治療劑，用于治療某些疾病，例如生殖、炎癥和代謝疾病，和制備具有治療或診斷價值的抗體。
本發(fā)明的一個方面提供了新穎的成熟生物活性蛋白質(zhì)，其主要來自人類。這些蛋白質(zhì)可以從合適的動物(包括人類)組織或生物液中通過標準技術(shù)少量分離出來；然而，可更方便地在基因修飾的從而表達該蛋白質(zhì)的細胞培養(yǎng)物中大量制備。
本發(fā)明的另一個方面提供了編碼本發(fā)明多肽的分離的核酸分子，包括其mRNA、DNA、cDNA和基因組DNA。
本發(fā)明的另一個方面提供了核酸探針，包括具有足夠長度，與本發(fā)明的核酸序列特異性雜交的核酸分子。
本發(fā)明的另一個方面提供了利用重組技術(shù)的方法，產(chǎn)生用于體外科學研究的這些多肽，例如合成DNA和制造DNA載體。產(chǎn)生這些多肽的方法包括在促進這些蛋白質(zhì)表達的條件下，培養(yǎng)被含有核酸序列的DNA載體轉(zhuǎn)染的重組原核和/或真核宿主細胞，所述核酸序列編碼多肽和/或成熟蛋白質(zhì)，然后回收這些蛋白質(zhì)或表達產(chǎn)品的片段。
本發(fā)明的另一個方面提供了使用DPRP多肽和多核苷酸的方法，包括治療感染，例如細菌、真菌、原生動物和病毒感染，特別是HIV-1或HIV-2導致的感染，疼痛、糖尿病、性早熟、不育、肥胖、食欲不振、食欲異?？哼M、帕金森氏病、急性心力衰竭、低血壓、高血壓、尿潴留、骨質(zhì)疏松、心絞痛、心肌梗塞、中風、潰瘍、哮喘、過敏、良性前列腺肥大、癌癥，包括激素敏感性和非雄激素依賴性癌癥，偏頭痛、嘔吐、精神和神經(jīng)性疾病，包括焦慮、精神分裂、狂躁抑郁癥、抑郁、癡呆和嚴重智力遲鈍、和運動障礙，在此統(tǒng)稱為“疾病”。
本發(fā)明的另一個方面提供了一種方法，以利用這些多肽、或編碼這些多肽的多核苷酸，來發(fā)現(xiàn)例如，通過切割N-末端二肽抑制其成熟蛋白質(zhì)的生物活性的化合物，還提供了這類抑制劑。
本發(fā)明的另一個具體方面提供了分離的核酸，其編碼(a)包括SEQ ID NO1、3和5之一的氨基酸序列的多肽，或(b)一種多肽，該多肽的氨基酸序列與其具有至少約70％相似性，并顯示相同的生物功能，或是SEQID NO2、4和6之一的交替剪接變體，或至少含有編碼(a)或(b)的核酸的14個連續(xù)核苷酸的探針，或與上述任一互補的核酸。
本發(fā)明的另一個具體方面提供了一種可任選的糖基化的多肽，它(a)具有SEQID NO1、3和5之一列出的成熟蛋白質(zhì)的氨基酸序列；(b)具有與(a)的成熟蛋白質(zhì)之一至少有70％相似性的成熟蛋白質(zhì)的氨基酸序列，并顯示相同的生物功能；(c)具有成熟蛋白質(zhì)的氨基酸序列，它與SEQ ID NO1、3和5任一的成熟蛋白質(zhì)有至少約90％的相同性；或(d)是(a)的免疫反應性片段。
本發(fā)明的另一個具體方面提供了一種篩選化合物的方法，該化合物能抑制本發(fā)明至少一種成熟蛋白質(zhì)的酶活性，該方法包括在一種或多種測試化合物或其鹽的存在下，培育所述成熟蛋白質(zhì)和合適的底物，測定所述成熟蛋白質(zhì)的酶活性，將所述活性與缺乏測試化合物的情況下測定的相對活性比較，選出能降低酶活性的測試化合物，還提供了一種篩選能抑制DPPIV酶活性的化合物的方法，該化合物不抑制至少一種成熟蛋白質(zhì)，在一種或多種DPPIV抑制劑或其鹽的存在下，培育所述成熟蛋白質(zhì)和合適的底物，測定所述成熟蛋白質(zhì)的酶活性，將所述活性與缺乏DPPIV抑制劑時測定的活性比較，選出不降低所述成熟蛋白質(zhì)活性的化合物。
本領(lǐng)域技術(shù)人員根據(jù)下面的詳述將明白本發(fā)明的這些和其它方面。
附圖簡述圖1A和1B顯示了DPRP-1、DPRP-2、DPRP-3和DPPIV的共線性排列對比，陰影表示特定位置上的相同(黑色)或相似(灰色)的氨基酸殘基。
圖2與圖1相示，顯示了人和小鼠DPRP-2的共線性排列對比。
圖3顯示了各種四肽酰胺抑制劑對二肽酰肽酶酶活性的作用。
圖4A-4C顯示三種抑制劑化合物在不同劑量下對PC3前列腺癌細胞系增殖的作用。
優(yōu)選實施例的詳述本發(fā)明的一個方面提供了分離的核酸序列(多核苷酸)，它編碼具有三種DPRP的推測氨基酸序列(SEQ ID NO1、3和5)的成熟多肽。
本發(fā)明的多肽是用人睪丸cDNA文庫(DPRP-1)、人結(jié)腸文庫(DPRP-2)和人下丘腦cDNA文庫(DPRP-3)發(fā)現(xiàn)的。DPRP-1的分離的核酸含有編碼長約882個氨基酸的蛋白質(zhì)(其與人DPPIV結(jié)構(gòu)相關(guān))的開放閱讀框，顯示與整個人DPPIV蛋白質(zhì)序列有26％相同性和41％相似性。DPRP-2的分離的核酸含有編碼約864個氨基酸的蛋白質(zhì)的開放閱讀框，它與整個DPPIV氨基酸序列具有39％的相似性。用疏水性作圖分析了DPRP-1和DPRP-2的氨基酸一級序列，預計這兩個蛋白質(zhì)不具有跨膜域。盡管有這個事實，可能這些胞內(nèi)絲氨酸蛋白質(zhì)在細胞活化后分泌。靜止性細胞脯氨酸二肽酶(QPP)是一種絲氨酸酶，它靶向與溶酶體不同的胞內(nèi)小泡(Chiravuri M等，J.Immunol.2000 Nov.15；165(10)5695-702)。該假說擴展了涉及趨化因子、細胞因子、肽和多肽翻譯后調(diào)控機制中DPRP-1和DPRP-2作用的可能位點和范圍。全長DPRP-3序列含有796個氨基酸，1-48的信號肽和34-56之間的跨膜域。預測核成熟蛋白質(zhì)是II型膜蛋白，可被切割產(chǎn)生可溶性形式。氨基酸序列列于SEQ ID NO5，是從SEQ ID NO6推測出來的，與DPPIV具有54％的相似性。
這些多肽與脯氨酰寡肽酶亞家族S9B的氨基酸序列排列對比顯示，所有三種DPRP蛋白質(zhì)與DPPIV和FAP具有總體序列和結(jié)構(gòu)同源性。預測DPRP是酶家族SC(絲氨酸親核性)的成員，具有Ser-Asp-His順序的催化性殘基和活性位點序列(G-W-S-Y-G)。
表2 DPRP-1、DPRP-2、DPRP-3和脯氨酰寡肽酶家族S9B酶之間的同源性(即相似性)
DPRP-1、DPRP-2和DPRP-3與經(jīng)典絲氨酸蛋白酶家族，胰凝乳蛋白酶和枯草桿菌蛋白酶的任何成員不顯示序列相似性。催化三聯(lián)體殘基的順序在這三個主要相關(guān)的SC群家族中是不同的胰凝乳蛋白酶是His-Asp-Ser，枯草桿菌蛋白酶是Asp-His-Ser，脯氨酰寡肽酶是Ser-Asp-His。
如表2所示，DPRP-3與DPPVI具有最高同源性(68％同源性和51％相同性)。Wada等從午、大鼠(Wada等，Proc.Natl.Acad.Sci.89197-201(1992))和人(Yokotani等，Hum.Molec.Genet.21037-1039(1993))大腦文庫分離了DPPVI(一種DPPIV-相關(guān)蛋白質(zhì))的cDNA克隆。它們顯示與DPPPIV不同，DPPVI中的催化性三聯(lián)體不具有第一個絲氨酸殘基。在DPRP-3中，絲氨酸蛋白酶家族的特征性催化三聯(lián)體的氨基酸中的二個是保守的。然而，絲氨酸殘基本身被甘氨酸取代。雖然缺乏絲氨酸殘基可能防止蛋白酶該位點的活性，有可能該蛋白質(zhì)的其它功能域介導的多種其它功能仍然是完整的。
如上簡述，DPPIV是多功能分子，根據(jù)表達的細胞和組織，除了其作為肽酶的催化作用外，發(fā)揮了重要功能。DPRP-3和DPPVI也可能保留了多種功能，盡管缺乏完整的催化性三聯(lián)體。例如DPPVI參與了神經(jīng)元可塑性的調(diào)節(jié)。DPPVI在海馬、丘腦、下丘腦和stiatum中高表達。另外，據(jù)信淺白色(rump white)Rw/Rw胚胎的發(fā)育停止和胚胎死亡是由于DPPIV基因的破壞。Rw突變與跨越小鼠染色體5近端部分30cM的染色體倒位有關(guān)。Rw染色體上的DPPVI基因的基因組分析將倒位破裂點置于編碼區(qū)中，導致C末端區(qū)域重要片段的喪失，Hough R.B.等，Proc.Natl.Acad.Sci.9513800-13805(1998)。
預計為32668bp長的人DPRP-1基因具有至少22個外顯子和8個轉(zhuǎn)錄物。圖譜中它位于染色體15(NT_010265)的位置15q21.1-15q22.1。預計的交替剪接變體轉(zhuǎn)錄物長度在602bp-4523bp之間(見SEQ ID NO7-22)。這符合Northern印跡分析所觀察到的多重轉(zhuǎn)錄物(見實施例2)。在許多組織，包括衰老成纖維細胞、T-淋巴細胞、生發(fā)中心B-細胞、胚細胞精原細胞瘤、睪丸、黑素細胞、子宮、卵巢、乳腺、多發(fā)性硬化損傷、胰臟和胎盤中發(fā)現(xiàn)EST代表性該轉(zhuǎn)錄物。
人DPRP-2屬于一種具有至少27個外顯子和9個剪切變體的基因，(見SEQ IDNO23-40)。在3’UTR中觀察到一個SNP(88％(37)C對12％(5)T)。DPRP-2基因作圖在染色體19的19p13.3區(qū)。該位置是許多疾病標態(tài)的宿主，與許多疾病，包括胃酸過少、高血鈣、II型小腦性運動失調(diào)癥、肌肉萎縮癥、痙攣、動脈硬化癥的易感性、牛皮癬、外胚層發(fā)育不良、和急性髓性白血病有關(guān)。與Northern印跡分析(見實施例2)觀察到的mRNA獨特分布一致的是，在檢測EST覆蓋時各種組織(例如在肝臟、脾臟、肌肉、黑素細胞、心臟、肺、胎盤、皮膚、胰臟、胃、大腦、副甲狀腺中表達超過64種EST)表達DPRP-2。
人DPRP-3屬于一種具有至少23個外顯子和兩個剪切變體的基因(見SEQ IDNO41-44)。基因圖位于染色體2(NT_005445)的2q12.3-2q14.1區(qū)域。DPRP-3的轉(zhuǎn)錄物不如DPRP-1和DPRP-2那樣顯示廣泛分布。如實施例2中的Northern印跡分析所示，DPRP-3表達限于大腦和胰臟。代表DPRP-3 mRNA的EST在衍生自多發(fā)性硬化損傷的組織中在下丘腦、全腦和神經(jīng)中是豐富的，在子宮和結(jié)腸中發(fā)現(xiàn)少量轉(zhuǎn)錄物。
用鄰近連接(Neighbor Joining)法(NJ)分析了SC家族，包括DPRP-1、DPRP-2和DPRP-3中人和嚙齒類蛋白酶的關(guān)系，見Saitou和Nei，Mol.Biol.Evol.4，406-525(1987)。系統(tǒng)發(fā)生分析顯示在S9蛋白酶中，DPRP-1和DPRP-2都缺乏跨膜域，它們與DPPIV及其緊密相關(guān)的蛋白質(zhì)FAP不同。然而，在DPPIV和FAP之間，DPRP-3和DPPVI之間顯示了相似性，它們都是II型跨膜蛋白。
數(shù)據(jù)庫檢索其它DPRP相關(guān)基因揭示，存在與DPRP-1相關(guān)的小鼠序列。該小鼠序列與新的人蛋白酶排列對比顯示，mDPRP-1與其人相應物顯示可觀的同源性(圖2)。本領(lǐng)域技術(shù)人員不難理解可用本文公開的序列信息分離新的小鼠蛋白酶基因，并不難將其摻入本領(lǐng)域熟知的常用表達構(gòu)建體之一。本領(lǐng)域技術(shù)人員用該公開的序列產(chǎn)生轉(zhuǎn)基因小鼠模型，將使用基因靶向性載體的開發(fā)，例如，導致小鼠胚胎干細胞同源重組的載體。在進一步分析DPRP基因功能中使用敲除小鼠是有價值的工具。
本發(fā)明的多核苷酸可以是RNA形式或DNA形式；DNA應理解包括cDNA、基因組DNA和合成的DNA。該DNA可以是雙鏈或單鏈，，如果是單鏈，可以是編碼鏈或非編碼(反義)鏈。編碼成熟多肽的編碼序列可以分別與SEQ ID NO2、4和6顯示的編碼序列相同，或可以是編碼同一成熟多肽的不同編碼序列，這是由于基因密碼子或單核苷酸多形性的豐余性或簡并性所致。例如，還可以是RNA轉(zhuǎn)錄物，包括SEQ ID NO2、4和6之一的全長轉(zhuǎn)錄物。
分別編碼SEQ ID NO1、3和5的成熟蛋白質(zhì)的多核苷酸可以包括但不限于該成熟蛋白質(zhì)單獨的編碼序列；成熟蛋白質(zhì)編碼序列加上其它編碼序列，例如前導或分泌序列，或前蛋白序列；和成熟蛋白的編碼序列(和可任選的其它編碼序列)加上非編碼序列，例如內(nèi)含子或成熟蛋白質(zhì)編碼序列的5’和/或3’的非編碼序列。
因此，術(shù)語“編碼多肽的多核苷酸”或術(shù)語“編碼多肽的核酸”應該理解成包括多核苷酸或核酸，它只包括成熟蛋白質(zhì)的編碼序列，也包括含有其它編碼和/或非編碼序列那些序列。術(shù)語多核苷酸和核酸可互換使用。
本發(fā)明還包括多核苷酸，其中成熟蛋白質(zhì)的編碼序列可與多核苷酸序列融合于同一閱讀框中，該多核苷酸序列可幫助多肽表達的從宿主細胞中分泌；例如，還可以融合作為控制多肽從細胞中運出的分泌序列的前導序列。具有這種前導序列的多肽稱作前蛋白或前原蛋白，可由宿主細胞切斷前導序列，形成蛋白質(zhì)的成熟形式。這些多核苷酸可具有5’延伸區(qū)，從而編碼原蛋白，它是成熟蛋白加上N-末端的其它氨基酸殘基。具有這種原序列的表達產(chǎn)物稱為原蛋白，它是成熟蛋白的無活性形式；然而，一旦切開原序列，就保留了成熟蛋白。因此例如，本發(fā)明的多核苷酸可編碼成熟蛋白質(zhì)，或具有原序列的蛋白質(zhì)，或同時具有原序列和前序列(前導序列)的蛋白質(zhì)。
本發(fā)明的多核苷酸還可具有框內(nèi)融合于一標記序列的編碼序列，該標記序列使得我們能純化本發(fā)明的多肽。當使用哺乳動物宿主，例如Cos-1細胞時，標記序列可以是聚組氨酸尾、血凝素(HA)尾、c-myc尾或V5尾。HA尾對應于衍生自流感血凝素蛋白的表位(Wilson等，Cell 37767(1984))，c-myc尾可以是人Myc蛋白的表位(Evan，G.I.等，Mol.Cell.Biol.53610-3616(1985))。
術(shù)語“基因”意味著涉及產(chǎn)生多肽鏈的DNA區(qū)段；它包括前導和后隨編碼區(qū)的區(qū)域(前導序列和后隨序列)以及各個編碼區(qū)段(外顯子)之間的間插序列(內(nèi)含子)。術(shù)語“顯著序列同源性”指至少25％，優(yōu)選至少40％的氨基酸殘基是保守的，非保守殘基中至少40％是保守性取代。
本發(fā)明的全長基因片段可用作cDNA文庫的雜交探針，以分離全長cDNA和分離其它與該基因具有顯著序列相同性，并編碼具有相似生物學活性或功能的蛋白質(zhì)或多肽的其它cDNA。本發(fā)明的“相似的生物活性或功能”意味著切割具有Ala或Pro作為倒數(shù)第二個殘基的N-末端二肽或其它氨基酸的能力。此類型的這種探針具有至少14個堿基(SEQ ID NO2、4或6之一的至少14個連續(xù)核苷酸)，優(yōu)選至少30個堿基，可以含有例如50或更多堿基。這些探針還可用于鑒定對應于全長轉(zhuǎn)錄物的cDNA克隆，和/或基因組克隆或含有完整基因，包括調(diào)節(jié)和啟動子區(qū)域、外顯子和內(nèi)含子的克隆。具有與本發(fā)明基因互補的序列的標記的寡核苷酸用于篩選人cDNA、基因組DNA或mRNA的文庫，以定位探針所雜交的文庫成員。例如，可用已知的DNA序列合成寡核苷酸探針，然后將探針用于篩選文庫，以分離感興趣基因的編碼區(qū)域。
本發(fā)明據(jù)認為還進一步提供了與上述序列雜交的多核苷酸，其中在序列之間具有至少70％，優(yōu)選至少90％，更優(yōu)選至少95％的相同性或相似性。另外，如本領(lǐng)域已知的，當氨基酸序列對于序列中的各殘基含有相同或保守的氨基酸取代，在兩條多肽之間存在“相似性”?？捎眯蛄蟹治鲕浖?例如威斯康星大學生物技術(shù)中心，1710 University Avenue，Madison，WI 53705，遺傳學計算機組的序列分析軟件包)測定同一性和相似性。本發(fā)明特別提供了在嚴謹條件下與上述多核苷酸結(jié)合的這類多核苷酸。本文所用的術(shù)語“嚴謹條件”指允許多核苷酸序列和SEQ IDNO2、4和6的多核苷酸序列雜交的條件，其中有至少約70％相同性。合適的嚴謹條件可通過例如預雜交和雜交溶液中的鹽或甲酰胺濃度，或通過雜交溫度確定，是本領(lǐng)域熟知的。特別是，嚴謹性可以通過減少鹽濃度，通過提高甲酰胺濃度，和/或提高雜交溫度來增加。
例如，高嚴謹性條件下雜交可使用約50％甲酰胺，約37-42℃，而降低的嚴謹條件下雜交可使用約35-25％甲酰胺，約30-35℃。在高嚴謹條件下特定的一組雜交條件使用42℃，50％甲酰胺，5×SSPE，0.3％SDS和200微克/毫升剪切和變性鮭魚精子DNA。對于在降低的嚴謹性下雜交，可使用35％甲酰胺，降低的溫度35℃。對應于特定嚴謹性水平的溫度范圍還可以通過計算感興趣的核酸的嘌呤對嘧啶的比例來進一步縮小，并據(jù)此調(diào)節(jié)溫度。上述范圍和條件的變化是本領(lǐng)域熟知的。優(yōu)選雜交僅在序列之間至少有95％，更優(yōu)選至少97％相同性時進行。與上述優(yōu)選實施例中的多核苷酸雜交的多核苷酸編碼的多肽，顯示至少與SEQ ID NO2、4和6的cDNA之一編碼的成熟蛋白基本相同的生物功能或活性。
如上所述，合適的多核苷酸探針可具有至少14個堿基，優(yōu)選30個堿基，更優(yōu)選至少50個堿基，并可與具有同一性的，可能或不可能保留活性的本發(fā)明的多核苷酸雜交。例如，這些多核苷酸可用作探針，與SEQ ID NO2、4和6的多核苷酸分別雜交，例如，用于回收這些多核苷酸，或作為診斷探針，或PCR引物。因此，本發(fā)明包括分別與編碼SEQ ID NO1、3和5的多肽具有至少70％相同性，優(yōu)選至少90％相同性，更優(yōu)選至少95％相同性的多核苷酸及其片段(這些片段優(yōu)選具有至少30個堿基，更優(yōu)選具有至少50個堿基)以及這些多核苷酸編碼的多肽。
如本領(lǐng)域所知，遺傳密碼有冗余性，因為一些氨基酸由一種以上的核苷酸三聯(lián)體(密碼子)編碼，本發(fā)明包括這些多核苷酸序列，它們用與本文序列中具體舉例的不同密碼子編碼同一氨基酸。這些多核苷酸序列在本文中被稱為“等價”多核苷酸序列。本發(fā)明還包括上述多核苷酸的變體，它們分別編碼該成熟蛋白質(zhì)的片段，例如部分或全部，具有SEQ ID NO1、3和5的推測氨基酸序列的多肽之一的類似物和衍生物。該多核苷酸的變體形式可以是該多核苷酸天然存在的等位基因變體，或該多核苷酸的非天然存在的變體。例如，核酸的變體可能簡單的在氨基酸編碼序列中存在差異，這是由于遺傳密碼的簡并性產(chǎn)生的，或可以是缺失變體、取代變體和添加或插入變體。如本領(lǐng)域所知，等位變體是多核苷酸序列的另一種形式，可以具有一個或多個核苷酸的取代、缺失或添加，而基本不改變該編碼的多肽的生物學功能。
本發(fā)明還包括具有SEQ ID NO1、3和5的推測氨基酸序列的多肽，以及這些多肽的片段、類似物和衍生物。當指SEQ ID NO1、3和5的多肽時，術(shù)語“片段”、“衍生物”和“類似物”指基本上保留了這些多肽相同的生物功能或活性的多肽。類似物可以是例如包括一種原蛋白，它可以通過切割原蛋白部分產(chǎn)生活性成熟蛋白而被活化。本發(fā)明的多肽可以是重組多肽、天然多肽或合成多肽；然而優(yōu)選糖基化或非糖基化的重組多肽。
SEQ ID NO1、3和5各多肽的片段、衍生物或類似物可以是(i)其中一個或多個氨基酸殘基被保守或非保守的氨基酸殘基(優(yōu)選保守氨基酸殘基)取代，這些取代的氨基酸殘基可以或可以不是由遺傳密碼編碼的，或(ii)其中一個或多個氨基酸殘基包含有取代基團，或(iii)其中有附加的氨基酸與成熟蛋白質(zhì)融合，例如前導或分泌序列，或用于純化成熟多肽的序列或原蛋白序列。這些片段、衍生物和類似物被視為在本領(lǐng)域技術(shù)人員能力范圍內(nèi)，在本文知識的基礎(chǔ)上提供。
本發(fā)明的多肽和多核苷酸應該是分離的形式，優(yōu)選純化到基本均一或純凈?；揪灰馕吨辽偌s85％的純度。
術(shù)語“分離的”指從其原來環(huán)境(例如天然環(huán)境，如果它是天然存在的)取出的物質(zhì)。例如，存在于活的動物體內(nèi)的天然多核苷酸或多肽不被視為是分離的，但是當與幾乎所有天然系統(tǒng)中共存的物質(zhì)分開時，同樣的多核苷酸或多肽被視為分離的。對于DNA，該術(shù)語包括例如被摻入到一載體、自主復制質(zhì)?；虿《緝?nèi)，或摻入原核細胞或真核細胞基因組DNA內(nèi)的重組DNA；或作為不依賴于其它序列的單獨分子(例如聚合酶鏈式反應(PCR)或限制性內(nèi)切酶消化產(chǎn)生的cDNA或基因組或cDNA片段)存在。還包括編碼其它多肽序列，例如融合蛋白的雜交基因的一部分的重組DNA，還包括編碼DPRP的交替剪接變體的重組DNA，。各種交替剪接變體的例子見SEQ ID NO10、12、14、16、18、20、22、24、26、28、30、32、34、36、38、40、42、44和46。
本發(fā)明的多肽包括SEQ ID NO1、3和5的多肽(特別是成熟蛋白質(zhì))的任何一種，以及與SEQ ID NO1、3和5多肽之一具有至少70％相似性(例如，優(yōu)選至少60％，更優(yōu)選至少70％相同性)，更優(yōu)選與SEQ ID NO1、3和5多肽之一具有至少90％相似性(例如優(yōu)選至少90％相同性)，和與SEQ ID NO1、3和5多肽之一具有至少95％相似性(例如優(yōu)選至少95％相同性)的多肽。另外，它們宜含有這些多肽的確切部分，含有至少30個氨基酸的序列，更佳含有至少50個氨基酸。
本發(fā)明多肽的片段或一部分可以用作肽合成生產(chǎn)相應全長多肽的中間物。本發(fā)明多核苷酸的片段或一部分還可用于合成本發(fā)明的全長多核苷酸。
本發(fā)明還包括含有這些多核苷酸的載體，用這些載體經(jīng)過基因工程改造的宿主細胞，和用上述材料通過重組技術(shù)產(chǎn)生多肽。用這些載體進行宿主細胞的基因工程改造(轉(zhuǎn)導或轉(zhuǎn)化或轉(zhuǎn)染)，這些載體可以是例如克隆載體或表達載體。該載體可以是例如質(zhì)粒、病毒顆粒、噬菌體等的形式。改造過的宿主細胞可以在經(jīng)過改良，適合激活啟動子，篩選轉(zhuǎn)化株或擴增本發(fā)明基因的常規(guī)營養(yǎng)培養(yǎng)基中培養(yǎng)。培養(yǎng)條件，例如溫度、pH等是本領(lǐng)域普通技術(shù)人員熟知的通常用于篩選表達的宿主細胞的條件。
本發(fā)明的多核苷酸可用于重組技術(shù)產(chǎn)生多肽。因此例如，該多核苷酸可以包含在任何用于表達多肽的各種表達載體之一中。這些載體包括染色體、非染色體和合成的DNA序列，例如SV40的衍生物；細菌質(zhì)粒；噬菌體DNA；桿狀病毒；酵母質(zhì)粒；質(zhì)粒和噬菌體DNA組合產(chǎn)生的質(zhì)粒、病毒DNA，例如牛痘病毒、腺病毒、禽痘病毒和偽狂犬病病毒的DNA。然而，也可使用任何其它載體，只要它們能在宿主中復制并存活。
合適的DNA序列可通過任何方法插入上述載體。一般而言將DNA序列通過本領(lǐng)域熟知的方法插入合適限制性內(nèi)切酶位點，這些方法認為在本領(lǐng)域技術(shù)人員能力范圍內(nèi)。
將表達載體中的DNA序列與合適的表達控制序列(啟動子)操縱性連接，以指導mRNA合成。作為這些啟動子的代表性例子，可能提到LTR或SV40啟動子、大腸桿菌lac或trp、λ噬菌體亞型L啟動子和其它已知在原核或真核細胞，或其病毒中控制基因表達的啟動子。表達載體還應含有翻譯起始的核糖體結(jié)合位點和轉(zhuǎn)錄終止子。此載體還可含有合適的擴增表達序列。另外，表達載體優(yōu)選含有一個或多個可選擇標記基因，以提供選擇轉(zhuǎn)化的宿主細胞的表型性狀，例如對于真核細胞培養(yǎng)，是二氫葉酸還原酶或新霉素抗性，或在大腸桿菌中是四環(huán)素抗性或氨芐青霉素抗性。
本文所述的含有合適DNA序列的載體和合適的啟動子或控制序列，可以用于轉(zhuǎn)化合適的宿主，使宿主表達本發(fā)明的蛋白質(zhì)。作為合適宿主的代表性例子，可以是細菌細胞，例如大腸桿菌、鏈霉菌、鼠傷寒沙門菌(Salmonellatyphimurium)；真菌細胞，例如酵母；昆蟲細胞，例如果蠅S2和夜蛾(Spodoptera)Sf9；動物細胞，例如CHO、COS或Bowes黑素瘤；腺病毒；植物細胞等。合適宿主的選擇認為是本文所述在本領(lǐng)域技術(shù)人員能力范圍內(nèi)。
核酸序列的合成產(chǎn)生是本領(lǐng)域熟知的，例如CLONTECH95/96目錄，215-216頁，CLONTECH，1020 East Meadow Circle，Palo Alto，Calif.94303。因此，本發(fā)明還包括用于產(chǎn)生本發(fā)明蛋白質(zhì)的表達載體。
本發(fā)明還包括重組構(gòu)建物，其含有本文廣泛描述的一條或多條序列。該構(gòu)建物可含有載體，例如質(zhì)粒或病毒載體，其中以正向或反向插入了本發(fā)明的序列。在該實施例的優(yōu)選方面中，該構(gòu)建物還含有調(diào)控序列，包括例如與序列操縱性連接的啟動子。許多合適的載體和啟動子對于本領(lǐng)域技術(shù)人員是已知的，而且是市售的。提供下列載體作為例子細菌pQE70、pQE60、pQE-9(Qiagen)、pBS、pD10、phagescript、psiX174、pbluescript SK、pbsks、pNH8A、pNH16a、pNH18A、pNH46A(Stratagene)、ptrc99a、pKK223-3、pKK233-3、pDR540和pRIT5(Pharmacia)；和真核性pWLNEO、pSV2CAT、pOG44、pXT1、pSG(Stratagene)、pSVK3、pBPV、pMSG和pSVL(Pharmacia)。然而，可使用任何其它合適的質(zhì)?；蜉d體，只要它可以在宿主中復制并存活。
可從任何所需基因用CAT(氯霉素乙酰轉(zhuǎn)移酶)載體或其它具有可選擇標記的載體選擇啟動子區(qū)域。兩個合適的載體是pKK232-8和pCM7。具體命名的細菌啟動子包括lacI、lacZ、T3、T7、gpt、λP.sub.R、P.sub.R、P.sub.L和trp。真核啟動子包括CMV立即早、HSV胸苷激酶、早和晚SV40、反轉(zhuǎn)錄病毒的LTR、和小鼠金屬硫蛋白-T。選擇合適的載體和啟動子在本領(lǐng)域一般技術(shù)人員水平之內(nèi)。
表達載體的成分通?？砂?)新霉素磷酸轉(zhuǎn)移酶(G418)或潮霉素B磷酸轉(zhuǎn)移酶(hyg)基因作為選擇標記，2)大腸桿菌復制起始點，3)T7和SP6噬菌體啟動子序列，4)lac操縱子序列，5)乳糖操縱子抑制基因(lacIq)和6)多個克隆位點接頭區(qū)。復制起始點(oriC)可衍生自pUC19(LTI，Gaithersburg，Md.)。
根據(jù)下文實施例1所述的PCR方案，對于DPRP-I用具有KpnI(作為5’引物)和NotI或SacI(作為3’引物)，或?qū)τ贒PRP-2用HindIII(作為5’引物)和NotI或BamIII(作為3’引物)的限制性位點的PCR引物，產(chǎn)生編碼具有合適限制性位點的SEQ ID NO2、4和6多肽之一的核苷酸序列。PCR插入物是凝膠純化的并用相容性限制性酶消化。插入物和載體根據(jù)標準方法連接。
在另一個實施例中，本發(fā)明提供了含有上述構(gòu)建物的宿主細胞。宿主細胞可以是高等真核細胞，例如哺乳動物細胞，或低等真核細胞，例如酵母細胞，或宿主細胞可以是原核細胞，例如細菌細胞?？赏ㄟ^磷酸鈣轉(zhuǎn)染、DEAE-葡聚糖介導的轉(zhuǎn)染、脂質(zhì)轉(zhuǎn)染或電穿孔將該構(gòu)建物引入宿主細胞(Davis，L.，Dibner，M.，Battey，I.，Basic Methods in Molecular Biology(1986))。
宿主細胞中的這些構(gòu)建物優(yōu)選以常規(guī)方式用于制備以上重組序列編碼的基因產(chǎn)物。另外，本發(fā)明的多肽可用常規(guī)肽合成儀合成產(chǎn)生，或化學連接如此制備的合適片段產(chǎn)生。
成熟蛋白質(zhì)可以在哺乳動物細胞、酵母、細菌或其它細胞中，在合適啟動子的控制下表達。還可用無細胞翻譯系統(tǒng)，用本發(fā)明的DNA構(gòu)建物衍生的RNA產(chǎn)生這些蛋白質(zhì)。用于原核和真核宿主的合適的克隆和表達載體如Sambrook等，Molecular CloningA laboratory Manual，第2版，Cold Spring Harbor，N.Y.(1989)所述。
通過在載體中插入增強子序列，提高了高等真核細胞對編碼本發(fā)明多肽的DNA的轉(zhuǎn)錄。增強子包括DNA的順式作用元件，通常約10-300bp，它作用于啟動子，以提高其轉(zhuǎn)錄。例子包括在復制起始點晚期一側(cè)bp100-270的SV40增強子，巨細胞病毒早啟動子增強子、在復制起始點晚期一側(cè)的多瘤病毒增強子、和腺病毒增強子。
通常重組表達載體將包含復制起始點和允許宿主細胞轉(zhuǎn)化的可選擇標記，例如大腸桿菌的氨芐青霉素抗性基因和釀酒酵母TRP1基因，和衍生自高度表達基因的啟動子，以指導下游結(jié)構(gòu)序列的轉(zhuǎn)錄。這些啟動子可衍生自編碼糖酵解酶，例如磷酸甘油酸激酶(PGK)，α-因子、酸性磷酸酶或熱休克蛋白等的操縱子。該異源結(jié)構(gòu)序列可在合適時期內(nèi)，與翻譯起始和終止序列，優(yōu)選能指導翻譯的蛋白質(zhì)分泌到周質(zhì)空間或胞外基質(zhì)中的前導序列裝配。可任選的，該異源序列可編碼融合蛋白，其含有N-末端識別肽，賦予所需特征，例如穩(wěn)定表達的重組產(chǎn)物或簡化其純化。
細菌的有用表達載體是通過將編碼所需蛋白質(zhì)的結(jié)構(gòu)DNA序列和合適的翻譯起始和終止信號，與功能性啟動子插入可操縱閱讀位置構(gòu)建的。此載體可含有一個或多個表型可選擇標記和復制起始點，以確保此載體的維持，如需要，則提供在宿主內(nèi)擴增。轉(zhuǎn)化用的合適的原核宿主包括大腸桿菌，枯草芽胞桿菌，雖然其他細菌也可選擇使用。鼠傷寒沙門菌和各種假單胞菌屬中的菌種，鏈霉菌和葡萄球菌等。
作為代表性而非限制性的例子，用于細菌用途的有用的表達載體可含有衍生自市售質(zhì)粒的可選擇性標記和細菌復制起始點，這些質(zhì)粒含有熟知的克隆載體pBR322(ATCC37017)的基因元件。這些市售載體包括例如pKK223-3(Pharmacia FineChemicals，Uppsala，Sweden)和GEM1(Promega Biotec，Madison，Wis.U.S.A.)。將這些pBR322“骨架”區(qū)段與合適的啟動子以及要表達的結(jié)構(gòu)序列相聯(lián)合。
在轉(zhuǎn)化合適的宿主菌株，并使宿主菌株生長到合適細胞密度后，通過合適的方法(例如溫度變化或化學誘導)誘導所選啟動子，再培養(yǎng)細胞一段時間。通常離心收集細胞，然后以物理或化學方法破碎，保留得到的粗提取物用于進一步純化?？捎萌魏伪憷姆椒?，包括凍融循環(huán)，超聲，機械破碎和使用細胞裂解劑破碎用于表達蛋白質(zhì)的微生物細胞；這些方法是本領(lǐng)域技術(shù)人員熟知的。
還可用各種哺乳動物細胞培養(yǎng)物系統(tǒng)表達重組蛋白質(zhì)。哺乳動物表達系統(tǒng)的例子包括猴腎成纖維細胞的COS-7株系，如Gluzman，Cell 23175(1981)所述。能表達相容性載體的其它細胞系包括例如C127、3T3、CHO、HeLa和BHK細胞系。哺乳動物表達載體通常含有復制起始點、合適的啟動子和增強子，還有任何必需的核糖體結(jié)合位點、聚腺苷酸位點、剪切供體和受體位點、轉(zhuǎn)錄終止序列和5’旁側(cè)非翻譯序列。衍生自SV40剪切子的DNA序列和聚腺苷酸位點可用于提供所需的非轉(zhuǎn)錄基因元件。
可以從重組細胞培養(yǎng)物中，用包括硫酸銨或乙醇沉淀、酸提取、陰離子或陽離子交換層析、磷酸纖維素層析、疏水反應層析、親和層析、羥基磷灰石層析和植物凝血素層析等方法，回收和純化多肽。如果多肽在細胞表面表達，可促進回收，但不是必需的?；厥諏τ诟L形式的多肽在表達后切的切割產(chǎn)物也可能是理想的。如需要，可使用本領(lǐng)域已知的蛋白質(zhì)重折疊步驟來完成成熟蛋白的構(gòu)型。高效液相層析(HPLC)可用于最終純化步驟。
本發(fā)明的多肽可以是純化的天然產(chǎn)物，或由重組技術(shù)從原核或真核宿主(例如培養(yǎng)的細菌、酵母、高等植物、昆蟲或哺乳動物細胞)產(chǎn)生。根據(jù)在重組生產(chǎn)過程中使用的宿主，本發(fā)明的多肽可以是糖基化的，或可以是非糖基化的。本發(fā)明的多肽還可以包括一個起始甲硫氨酸殘基。
在優(yōu)選實施例中，分離和純化本發(fā)明的蛋白質(zhì)，從而基本沒有其它蛋白質(zhì)的污染。例如，本發(fā)明的蛋白質(zhì)應該占樣品中存在的總蛋白質(zhì)的至少80％以上重量，較佳至少90％，更佳至少95％，最佳至少占總蛋白質(zhì)的98％重量。
這些蛋白質(zhì)可以是溶于水、其它合適溶劑(例如二甲亞砜(DMSO)或乙醇)或合適溶劑混合物的形式。溶劑混合物的例子包括10％(重量)乙醇水溶液和2％(重量)DMSO水溶液。溶液還可含有鹽、緩沖劑、破膜試劑、去污劑、防腐劑等。另外，蛋白質(zhì)可以是固體形式，例如凍干粉末或晶狀態(tài)固體，還可以含有殘余溶劑、鹽等。本文所用的術(shù)語“抗體”包括多克隆抗體、親和純化的多克隆抗體、單克隆抗體和抗原結(jié)合性片段，例如F(ab’)2和Fab’蛋白水解片段。還包括基因工程改造的完整抗體或片段，例如嵌合抗體、Fv片段、單鏈抗體等和合成的抗原結(jié)合性肽和多肽。通過將非人CDR植入人框架和恒定區(qū)，或通過摻入整個非人可變區(qū)(可任選的通過置換接觸殘基，用類似人的表面“包裹”它們，結(jié)果是“裝飾”的抗體)，來人源化非人抗體。在一些情況下，人源化抗體可以在人可變區(qū)閱讀框結(jié)構(gòu)域中保留非人殘基，以增強正確結(jié)合性質(zhì)。通過人源化抗體，可增加生物半衰期，并減少在對人類給藥后產(chǎn)生不良免疫反應的可能性。
本文所用的產(chǎn)生或選擇抗體的其它技術(shù)包括淋巴細胞體外接觸人激素源DPRP蛋白質(zhì)或其肽，并選擇噬菌體或類似載體中的抗體展示文庫(例如，通過使用固定化或標記的人DPRP蛋白質(zhì)或多肽)?？赏ㄟ^在噬菌體(噬菌體顯示)或在細菌，例大腸桿菌上展示的肽文庫的隨機篩選獲得編碼具有可能的人DPRP多肽結(jié)構(gòu)域的多肽的基因?？捎迷S多本領(lǐng)域熟知的方法獲得編碼這些多肽的核苷酸序列。
如對于本領(lǐng)域普通技術(shù)人員，明顯的，可用人DPRP多肽或其片段接種各種溫血動物，例如馬、牛、山羊、綿羊、犬、雞、家兔、小鼠和大鼠，產(chǎn)生多克隆抗體。可通過使用佐劑，例如明礬(氫氧化鋁)或弗氏完全或不完全佐劑，或表面活性物質(zhì)，例如溶血卵磷脂、質(zhì)子化多元醇、聚陰離子、肽、油乳液、KLH或二硝基苯酚，提高人原激素DPRP多肽的免疫原性。在人用佐劑中，BCG(bacilliCalmette-Guerin)和短小棒狀桿菌(Corynebacterium parvum)是尤其優(yōu)選的。用于免疫接種的多肽還包括融合多肽，例如DPRP或其一部分與免疫球蛋白多肽或與麥芽糖結(jié)合蛋白的融合蛋白，多肽免疫原可以是蛋白的全長分子或其一部分。如果多肽部分是“半抗原樣的”，該部分的優(yōu)點是可以與大分子載體，例如匙孔血藍蛋白(KLH)、牛血清清蛋白(BSA)或破傷風類毒素連接用于免疫接種。針對DPRP的抗體還可以用本領(lǐng)域熟知的方法產(chǎn)生。這些抗體可包括但不限于多克隆、單克隆、嵌合和單鏈抗體、Fab片段和Fab表達文庫產(chǎn)生的片段。特別優(yōu)選中和性抗體(即能封閉或修飾活性位點上的相互作用)用于治療。
對于與DPRP特異性結(jié)合的抗體、結(jié)合性蛋白質(zhì)或肽的產(chǎn)生，可篩選單鏈抗體、Fab片段、其它抗體片段、非抗體蛋白質(zhì)結(jié)構(gòu)域或肽的文庫。該文庫可用噬菌體顯示法和其它重組DNA方法或肽合成產(chǎn)生(Vaughan，T.J.等，NatureBiotechnology 14398-314(1966))。這些文庫通常用本領(lǐng)域熟知的方法篩選的來鑒定顯示與DPRP特異性結(jié)合的序列。
優(yōu)選用于誘導DPRP抗體的寡肽、肽或片段具有由5個氨基酸組成的，更佳至少約10個氨基酸組成的氨基酸序列。還優(yōu)選這些寡肽、肽或片段與該天然蛋白質(zhì)的氨基酸序列的一部分是相同的。也可將DPRP氨基酸的短延展段與其它蛋白質(zhì)，例如KLH融合，可產(chǎn)生針對嵌合分子的抗體。
可用任何熟知技術(shù)制備抗DPRP的單克隆抗體，這些技術(shù)提供了通過連續(xù)細胞系培養(yǎng)產(chǎn)生的抗體分子。這些技術(shù)包括但不限于雜交瘤技術(shù)、人B細胞雜交瘤技術(shù)和EBV-雜交瘤技術(shù)，雖然雜交瘤細胞產(chǎn)生的單克隆抗體是優(yōu)選的。
另外，可使用為了生產(chǎn)“嵌合抗體”開發(fā)的技術(shù)，例如將小鼠抗體基因剪接到人抗體基因上，以獲得具有合適的抗原特異性和生物活性的分子，見Neuberger，M.S.等，Nature 312604-608(1984)。另外，可用本領(lǐng)域已知的方法改造生產(chǎn)單鏈抗體的技術(shù)，來產(chǎn)生DPRP-特異性單鏈抗體?？赏ㄟ^從隨機組合性免疫球蛋白文庫進行鏈改組，產(chǎn)生具有相關(guān)特異性，但具有不同獨特型組成的抗體(Burton，D.R.，Proc.Natl.Acad.Sci.8811120-11123(1991))。
還可如文獻中所述，通過誘導體內(nèi)淋巴細胞群產(chǎn)生，或通過篩選免疫球蛋白文庫或一系列高特異性結(jié)合試劑來產(chǎn)生抗體(Orlandi，R.等，Proc.Natl.Acad.Sci.863833-3837(1989))。
還可產(chǎn)生含有DPRP特異性結(jié)合位點的抗體片段。例如，這些片段包括但不限于胃蛋白酶消化抗體分子產(chǎn)生的F(ab’)2片段，和還原F(ab’)2片段的二硫鍵產(chǎn)生的Fab片段。另外，可構(gòu)建Fab表達文庫，來快速方便的鑒定具有所需特異性的單克隆Fab片段(Huse，W.D.等，Science 2541275-1281(1989))。
可用各種免疫試驗鑒定具有所需特異性的抗體。采用已確定特異性的多克隆或單克隆抗體的競爭性結(jié)合試驗或免疫放射測定試驗的許多方案是本領(lǐng)域熟知的。這些免疫試驗通常涉及測定DPRP與其特異性抗體之間的復合物形成。采用與兩個非相干DPRP表位反應的單克隆抗體進行的雙位點、單克隆抗體免疫試驗是優(yōu)選的，但是也可使用競爭性結(jié)合試驗。
如上所述，DPRP可用于治療疾病。適用于本發(fā)明該方面的藥物組合物包括含有有效量的活性成分的組合物，，以實現(xiàn)與某一疾病相關(guān)的目的。確定治療有效量在本領(lǐng)域技術(shù)人員的能力范圍內(nèi)，可以在細胞培養(yǎng)試驗，例如腫瘤細胞或在動物模型，通常是小鼠、大鼠、家兔、犬或豬中初步估計。動物模型還可用于確定給藥的合適濃度范圍和途徑，這些信息然后通常被用于確定人類給藥的有用劑量和途徑。
治療有效量指活性成分，例如DPRP或其片段、DPRP的抗體、或DPRP的激動劑、拮抗劑或抑制劑的量，此量能改善疾病的具體癥狀或病況。例如，給藥的量可在接觸后有效切割所需靶底物。治療效力和毒性也可以用標準藥物學方法在細胞培養(yǎng)物或?qū)嶒瀯游镏写_定，例如通過計算ED50(在50％群體中治療有效的劑量)或LD50(群體50％的致死劑量)統(tǒng)計學確定。毒性對療效的劑量比是治療指數(shù)，可以表達成LD50/ED50比率。顯示大的治療指數(shù)的藥物組合物是優(yōu)選的。從細胞培養(yǎng)實驗和動物研究獲得的數(shù)據(jù)用于配制一定范圍的人用劑量。此種組合物中所含的劑量宜在循環(huán)血液濃度范圍內(nèi)，該濃度包括ED50和極小或無毒性。在該范圍內(nèi)劑量應根據(jù)所使用的劑型、病人的敏感度和給藥途徑而不同。
通常由醫(yī)生根據(jù)與需要治療的患者相關(guān)的諸種因素確定確切劑量，調(diào)節(jié)劑量和給藥以提供充足水平的活性成分，或維持所需效果。要考慮的因素包括病情的嚴重程度、患者的總體健康狀況、年齡、體重和患者的性別、飲食、給藥的時間和頻率、藥物組合、反應敏感度和對治療的耐受/反應。長效藥物組合物可每3-4天、每周、或甚至每兩周給藥一次，由具體制劑的半衰期和清除速率決定。
本發(fā)明的另一個方面提供了多核苷酸分子，它具有與DPRP1、DPRP2和DPRP-3多核苷酸的mRNA轉(zhuǎn)錄物反義的序列。施用反義多核苷酸分子可阻止DPRP-1、DPRP-2或DPRP-3編碼的蛋白質(zhì)的產(chǎn)生。用于制備反義多核苷酸分子和施用這些分子的技術(shù)是本領(lǐng)域已知的。例如，反義多核苷酸分子可包裹在脂質(zhì)體中，與細胞融合。
具體說，DPRP-1、DPRP-2和DPRP-3在特殊表皮細胞、免疫細胞(淋巴細胞和B細胞)、星形細胞腫瘤和各種激素敏感性癌癥中的表達提供了其在癌癥、組織轉(zhuǎn)化和轉(zhuǎn)移中的病理學中有潛在作用的證據(jù)。因此在另一個方面，本發(fā)明涉及檢測與不合當DPRP活性或表達水平相關(guān)疾病的診斷試驗。與DPRP特異性結(jié)合的抗體可用于診斷以DPRP表達為特征的疾病，或用于監(jiān)測用DPRP或DPRP的激動劑或拮抗劑(抑制劑)治療的病人的試驗。用于診斷目的的抗體可以用上述用于治療的抗體的相同方式制備。DPRP的診斷試驗包括采用抗體和標記，來檢測人體液或細胞或組織提取物中的DPRP的方法?？刹捎媒?jīng)或不經(jīng)過修飾的抗體，可通過與報道分子共價或非共價連接標記抗體。各種報道分子是本領(lǐng)域已知的。經(jīng)修飾，從而無催化活性的重組DPRP蛋白質(zhì)也可用作顯性失活抑制劑。這些修飾包括例如活性位點的突變。
各種測定DPRP的方法，包括ELISA、RIA和FACS是本領(lǐng)域已知的，提供了診斷改變的或異常的DPRP表達水平的基礎(chǔ)。通過將取自正常哺乳動物個體(優(yōu)選人)的體液或細胞提取物與抗DPRP抗體在適合形成復合物的條件下混合，確定值正常值或標準DPRP表達的。用于檢測生物樣品中DPRP的方法包括以下步驟a)提供生物樣品；b)將生物樣品與抗DPRP抗體在適合在DPRP和抗體之間形成復合物的條件下混合；和c)檢測DPRP和抗體之間形成的復合物，從而確定生物樣品中DPRP的存在。然后可用各種方法，優(yōu)選光度測定法定量檢測復合物形成的量。將患者、對照和活檢組織的疾病樣品中表達的DPRP量與標準值進行比較。標準值和患者值之間的偏差確定了診斷疾病的參數(shù)。
在本發(fā)明的另一個實施例中，編碼DPRP的多核苷酸被用于診斷目的，其中多核苷酸可包括寡核苷酸序列、互補RNA和DNA分子和PNA。這些多核苷酸可用于檢測和定量活檢組織中的DPRP基因表達，這種表達可能與某一疾病互相關(guān)聯(lián)。診斷試驗可用于區(qū)別DPRP表達的缺乏、存在和過量，和監(jiān)測治療干預中DPRP水平的調(diào)節(jié)。另外，可用DPRP基因的藥物基因組學、單個苷酸的多態(tài)性(SNP)分析作為篩選突變的方法，該突變表明了疾病的傾向性或?qū)λ幬锔淖兊姆磻?br> 可采用DPRP多核苷酸和多肽序列、其片段、DPRP抗體和DPRP的激動劑、拮抗劑或抑制劑作為開發(fā)工具，來鑒定分子識別活動和與DPRP蛋白質(zhì)相互作用的蛋白質(zhì)、多肽和肽。具體例子是噬菌體展示肽文庫，此文庫中可在一輪淘選中篩選出108種以上的肽序列。這些方法和其它方法是本領(lǐng)域已知的，可用于鑒定能抑制或增強DPRP-1、DPRP-2或DPRP-3活性的化合物。偶聯(lián)連接提供的功能性相互作用，例如與DPRP相互作用的復合物或通路和，蛋白質(zhì)可以通過酵母雙雜交系統(tǒng)、蛋白組學(差異性2D凝膠分析和質(zhì)譜)，以及基因組學(以微陣列檢測差異性基因表達或基因表達SAGE的系列分析)來鑒定。鑒定到與DPRP功能性連接的蛋白質(zhì)和相互作用的過程形成了篩選這些DPRP蛋白質(zhì)相互作用的抑制劑、激動劑和拮抗劑的方法的基礎(chǔ)。
本文所用的術(shù)語“拮抗劑”指一種抑制劑分子，它與DPRP結(jié)合時能降低DPRP的量或生物或免疫學活性作用的持續(xù)時間，例如降低肽酶切割N-末端二肽的酶活性。拮抗劑可包括蛋白質(zhì)、核酸、糖類、抗體或能降低DPRP的效果的任何其它分子，；例如它們可以包括小分子化合物和有機化合物，它們與DPRP結(jié)合，并通過競爭性或非競爭性機制滅活DPRP。DPRP四肽肽酶活性抑制劑的具體例子如實施例6和7所述。抑制劑可以是例如DPRP蛋白酶活性的抑制劑，或其它DPRP與與其相互作用的蛋白質(zhì)的結(jié)合能力的抑制劑。這些抑制劑的具體例子可包括例如抗-DPRP抗體、肽、蛋白質(zhì)片段或小的肽基蛋白酶抑制劑、或小的非肽有機分子抑制劑，可將它們配制在能夠引入所需細胞類型的介質(zhì)中。另外，這些抑制劑可以與靶向配體結(jié)合，通過細胞介導的胞吞作用和其它受體介導活動引入細胞。下文進一步描述了這些方法，考慮到本文所述的DPRP核苷酸和氨基酸序列，可由本領(lǐng)域技術(shù)人員實施。
DPRP的另一種用途是篩選潛在的拮抗劑，用作治療劑，例如用于抑制與DPRP的結(jié)合，和用作激動劑的篩選。DPRP、其免疫原性片段、或其寡肽可在各種藥物篩選技術(shù)之一中，用作篩選可能的激動劑或拮抗劑的化合物文庫。用于這類篩選的片段可以游離在溶液中，附著在固相載體上，攜帶于細胞表面，或位于胞內(nèi)。然后測定DPRP與所測試制劑之間結(jié)合復合物的形成。用于發(fā)現(xiàn)能抑制DPRP的拮抗劑的其它試驗可參見美國專利6,011,155、6,107,317、6,110,949、6,124,305和6,166,063所公開的內(nèi)容，它們描述了DPPIV的抑制劑。這些DPRP的另一種有價值的用途是篩選DPPIV的抑制劑，以顯示它們沒有抑制一種或多種DPRP的不良副作用。
提供了一種篩選小分子文庫，以鑒定結(jié)合DPRP的分子的方法，一般包括a)提供一種小分子文庫；b)將小分子文庫與SEQ ID NO1、3或5的多肽、或其片段，在適合復合物形成的條件下混合；和c)檢測復合物形成，其中這種復合物的存在鑒定了與DPRP結(jié)合的小分子。
一種鑒定拮抗劑的方法包括將結(jié)合DPRP的小分子和染色體底物(例如Ala-Pro-AFC或Ala-Pro-AMC)在正常發(fā)生切割的條件下，傳遞到用表達DPRP的載體轉(zhuǎn)化的細胞的提取物中，然后通過分光光度計監(jiān)測熒光、紫外光吸收的變化，檢測酶切割的抑制，來鑒定抑制切割的分子。在該分子存在下，反應速率的下降或熒光或紫外光吸收總量的減少，確定了該小分子是降低DPRP催化/酶活性的拮抗劑。一旦鑒定了這類分子，可施用它們來減少或抑制DPRP的切割。
本文所用的術(shù)語“激動劑”指一種分子，當其與DPRP結(jié)合時，能提高或延長DPRP作用的持續(xù)時間。激動劑可包括蛋白質(zhì)、核酸、糖類或任何與DPRP結(jié)合并改變其效力的分子。雖然不大可能證明小分子是有效的DPRP激動劑，一種鑒定這類作為激動劑與DPRP結(jié)合的小分子的方法包括將結(jié)合DPRP的小分子的生色形式輸送到用表達DPRP的載體轉(zhuǎn)化的細胞中，并通過分光光度計測定熒光或紫外光吸收的變化。紫外光或熒光吸收的量增加將確定該小分子是提高DPRP活性的激動劑。
可使用的另一種藥物篩選技術(shù)提供高通量篩選對感興趣的蛋白質(zhì)具有合適結(jié)合親和力的化合物，如出版的PCT申請WO84/03564所述。在該方法中，在固相載體，例如塑料針或其它表面上合成大量不同的小測試化合物。使這些測試化合物與DPRP或其片段反應，然后洗滌。然后用本領(lǐng)域熟知的方法檢測結(jié)合的DPRP。還可將純化的DPRP直接包被在平板上，用于上述的藥物篩選技術(shù)。另外，可使用非中和性抗體來捕獲肽并將其固定在固相載體上。
在另一個實施例中，可以用競爭性藥物篩選試驗，其中能與DPRP特異性結(jié)合的中和性抗體與測試化合物競爭結(jié)合DPRP。在該方法中，可用抗體檢測是否存在與DPRP共享一個或多個抗原性決定簇的肽。
如上所述，通過調(diào)查結(jié)合位點，可設計配體，例如比天然配體與DPRP的相互作用更強的配體。這些拮抗性配體將以高親和力結(jié)合DPRP，因此可作為競爭性配體。另外，可設計天然DPRP的配體結(jié)合位點的同源物或類似物的合成或重組蛋白質(zhì)，也可設計其它與DPRP具有高親和力的分子。這些分子也應該能夠頂替DPRP，并提供保護性作用。
如上所述，DPRP結(jié)構(gòu)的知識使得能夠設計合成性結(jié)合位點同源物或類似物。這些分子可大大促進利用這種結(jié)合性能來導向可能的治療劑，并且還可用于篩選可能的治療劑。另外，它們可在生產(chǎn)單克隆抗體中用作免疫原，抗體本身可用于本文所述的診斷和/或治療。
考慮到脯氨酰寡肽酶S9B家族幾個成員的獨特表達，因細胞中作為靶的DPPIV、DPRP-1、DPRP-2、DPRP-3、FAP和DPPVI基因的破壞而建立的裸表型(無表面標志)細胞系，將有很大價值有助于篩選選擇性和強效化合物。因此，本發(fā)明提供了這類用Lox-Neo IRES tk盒和GFP-Neo敲入/敲除盒DNA元件工程改造的細胞系，以構(gòu)建體基因靶向載體。
實施例1用哺乳動物表達系統(tǒng)克隆和表達DPRP基因用對應于該基因5’和3’序列的PCR寡核苷酸引物，即SEQ ID NO45和46擴增了編碼全長多肽DPRP-1的DNA片段。另外，用對應于該基因5’和3’序列的PCR寡核苷酸引物，即SEQ ID NO50和51擴增了編碼全長多肽DPRP-2的DNA片段。另外，用對應于該基因5’和3’序列的PCR寡核苷酸引物，即SEQ ID NO55和56擴增了編碼全長多肽DPRP-3的DNA片段。
用商品試劑盒(GFX PCR DNA和凝膠條帶純化試劑盒，Amersham PharmaciaBiotech Inc.，Piscataway NJ，USA)從0.7％瓊脂糖凝膠中分別分離了以上三種擴增的序列。然后將片段連接入克隆載體pGEM-7Zf(-)(Promega Corporation，Madison WI，USA)并測序。對應的克隆構(gòu)建體分別命名為pGEM7-DPRP1、pGEM7-DPRP2和pGEM7-DPRP3。用pGEM7-DPRP1、pGEM7-DPRP2或pGEM7-DPRP3作為模板和PCR寡核苷酸引物，擴增了編碼截短的DPRP-1或DPRP-2或DPRP-3的DNA序列。SEQ ID NO45和47用于DPRP-1；SEQ ID NO50和52用于DPRP-2；SEQ ID NO57和58用于DPRP-3。用同一純化試劑盒從0.7％瓊脂糖凝膠分離了擴增的序列，并亞克隆入pGEM-7Zf(-)。得到的構(gòu)建物命名為pGEM7-DPRP1f、pGEM7-DPRP2f和pGEM7-DPRP3f。
為了制備DPRP-1哺乳動物表達構(gòu)建物，用限制性酶KpnI和NotI消化pGEM7-DPRP1，釋放出全長DPRP-1基因。攜帶DPRP-1基因的DNA片段用上述試劑盒凝進行膠條帶純化，然后插入表達載體pcDNA3(Invitrogen，Carlsbad CA，USA)，制備了天然DPRP-1表達構(gòu)建物，命名為pcDNA-DPRP1。用限制性酶XbaI和HindIII消化PGEM7-DPRP1f，釋放出截短的DPRP-1f基因。攜帶DPRP-1f基因的DNA片段用上述試劑盒進行凝膠條帶純化，然后插入表達載體pcDNA3.1(-)/myc-HisA(Invitrogen，Carlsbad CA，USA)以制備帶標記的DPRP-1表達構(gòu)建物pcDNA-MycHis-DPRP1。
為了制備DPRP-2哺乳動物表達構(gòu)建物，用限制性酶HindIII和BamHI消化pGEM7-DPRP2，釋放出全長DPRP-2基因。攜帶DPRP-2基因的DNA片段用上述試劑盒進行凝膠條帶純化，然后插入表達載體pcDNA3(Invitrogen，Carlsbad CA，USA)，制備了天然DPRP-2表達構(gòu)建物，命名為pcDNA-DPRP2。用限制性酶EcoRI和BamHI消化pGEM7-DPRP2f，釋放出截短的DPRP-2f基因。攜帶DPRP-2f基因的DNA片段用上述試劑盒進行凝膠條帶純化，然后插入表達載體pcDNA3.1(-)/myc-HisB(Invitrogen，Carlsbad CA，USA)制備了帶標記的DPRP-2表達構(gòu)建物pcDNA-MycHis-DPRP2。
為了制備DPRP-3哺乳動物表達構(gòu)建物，用限制性酶EcoRI和XhoI消化pGEM7-DPRP3，釋放出全長DPRP-3基因。攜帶DPRP-3基因的DNA片段用上述試劑盒進行凝膠條帶純化，然后插入表達載體pcDNA3(Invitrogen，Carlsbad CA，USA)，制備了天然DPRP-3表達構(gòu)建物，命名為pcDNA-DPRP3。用限制性酶NheI和ApaI消化PGEM7-DPRP3f，釋放出截短的DPRP-3f基因。攜帶DPRP-3f基因的DNA片段用上述試劑盒進行凝膠條帶純化，然后插入表達載體pcDNA3.1(-)/myc-HisB(Invitrogen，Carlsbad CA，USA)制備了帶標記的DPRP-3表達構(gòu)建物pcDNA-MycHis-DPRP3。
實施例2DPRP基因在人組織中的表達模式進行定量PCR分析，以檢測本發(fā)明多肽的mRNA在人組織中的表達水平。還對于許多人細胞系，包括但不限于前列腺癌細胞(LNCaP、PC3、DU145)、MLTC-1系(小鼠睪丸)和MDA-MB231細胞(乳腺癌)進行了RT-PCR。DPRP-1、DPRP-2和DPPIV的預期大小的條帶在各種癌細胞系中都有表達，而FAP也以非常低的水平表達。
Northern印跡分析用DPRP探針對從8種不同組織分離到的2微克poly(A)+RNA進行了Northern印跡分析。具體說，在32PdCTP的存在時通過隨機引導(A.P.Feinberg等，Anal.Biochem.132，6(1983))，用放射性標記的1kb N-末端片段探測了人多種組織的Northen(MTN)印跡(Clontech，Palo Alto，Calif.)。在ExpressHyb(tm)雜交溶液(Clontech，Plao Alto，Calif.)中68℃過夜進行雜交。印跡先以2×SSC和0.05％SDS室溫洗滌，然后在60℃(DPRP-1和DPRP-2)和50℃(DPRP-3)下，以0.1×SSC和0.1％SDS洗滌。
Northern印跡分析顯示DPRP-1在幾種組織中表達，其中在睪丸、前列腺、肌肉和大腦中有最豐富的信號。睪丸顯示3種大約7.5、4.5和2.5kb長的轉(zhuǎn)錄物。較短的mRNA品種在睪丸中非常豐富，但是在其它被測試的組織中幾乎可忽略不計。DPRP-2在每一種組織中普遍表達，在肝臟和肌肉中水平最高，主要是5kb的轉(zhuǎn)錄物。DPRP-3表達限于大腦和胰臟。對于具體的大腦區(qū)域(小腦、皮層、髓質(zhì)、脊索、后葉、前葉、側(cè)葉和豆狀核)中的三種蛋白酶進行了進一步的分析。DPRP-1在所有區(qū)域中表達，在脊索中水平低，而DPRP-2在所有測試的大腦區(qū)域中表達。
用寡核苷酸引物SEQ ID NO48和49進行DPRP-1定量PCR，而用寡核苷酸引物SEQ ID NO53和54進行DPRP-2定量PCR。人多種組織cDNA(MTC(tm))組I和組II(Clontech，Palo Alto CA，USA)被用作標準化的cDNA模板。0.5ng各cDNA被用于25微升PCR反應，各引物最終濃度為300nM。用SYBR Green PCR核心試劑試劑盒(Applied Biosystems，F(xiàn)oster City CA，USA)進行了PCR反應，并用Applied Biosystems GeneAmp5700序列檢測系統(tǒng)進行檢測。采用廠商推薦的熱循環(huán)參數(shù)，例如50℃2分鐘，95℃10分鐘然后是95℃15秒鐘和60℃1分鐘，40輪循環(huán)。獲得的數(shù)據(jù)顯示DPRP-1和DPRP-2在胰臟、卵巢和睪丸中都有相對高的表達率，DPRP-2在肝臟中有特別高的表達率。
實施例3-DPRP多克隆抗體的產(chǎn)生和蛋白質(zhì)印跡用DNASTAR軟件(DNASTAR，Inc.)分析了從編碼DPRP-1的cDNA中推測出的氨基酸序列，以確定高免疫原性區(qū)，合成相應的寡肽，并用于產(chǎn)生抗-DPRP-1抗體。對于DPRP-2和DPRP-3重復該過程。選擇合適的肽序列和抗體產(chǎn)生的技術(shù)是本領(lǐng)域技術(shù)人員熟知的方法。選擇合適的表位，例如靠近親水區(qū)C-末端的那些表位是本領(lǐng)域熟知的。
通常，用Applied Biosystems肽合成儀431A型合成了長約15-20個殘基的寡肽，例如DPRP-1的SEQ ID NO59、DPRP-2的SEQ ID NO60和DPRP-3的SEQ IDNO61。采用Fmoc-化學試劑，通過與N-馬來亞酰亞胺苯甲酸-N-羥基琥珀酰亞胺酯(MBS)反應，將19-或15-個殘基的肽分別與匙孔血藍蛋白(KLH，Sigma，St.Louis，MO)偶聯(lián)。用寡肽-KLH復合物的完全弗氏佐劑免疫家兔。測試得到的抗血清的抗肽活性，例如通過將肽與塑料板結(jié)合，用1％BSA封閉，與家兔抗血清反應，洗滌，并與放射性碘化的山羊抗兔IgG反應。
用從Clontech獲得的正常人蛋白質(zhì)樣品(protein Medley)(約36微克總蛋白)進行了蛋白質(zhì)印跡分析。將蛋白質(zhì)級分通過10％SDS-聚丙烯酰胺凝膠，并轉(zhuǎn)移到0.45mm硝基纖維素膜上。用Tris-緩沖鹽水(TBS)和0.05％Tween20和1％BSA封閉膜。用抗DPRP-1或DPRP-2特異性抗體作為一抗，并用含0.05％Tween20的Tris緩沖鹽水(TBST)稀釋5000倍。使用前用同一緩沖液1∶5000稀釋堿性磷酸酶(AP)偶聯(lián)的羊抗兔IgG(Promega)。通過將薄膜在Western Blue固定化底物(Promega)中溫育，直到感興趣的條帶達到所需的密度，觀察AP的陽性反應。在大腦、肌肉、腎、前列腺、睪丸和卵巢組織中檢測到DPRP-1和DPRP-2蛋白。分別合成了約101kDa和100kDa形式的DPRP-1和DPRP-2，它們與其一級結(jié)構(gòu)估計的分子量良好吻合，如表3所示。
表3預計的分子量、可能的N-連接糖基化位點(Asn殘基)數(shù)目和預測的DPRP-1、DPRP-2和DPRP-3的pI值，根據(jù)用Hopp和Woods，Proc.Natl.Acad.Sci.783824-3828(1981)開發(fā)的方法作的序列分析。
觀察到幾個分子量相似的其它條帶。據(jù)信這是由于存在這些蛋白質(zhì)的翻譯后糖基化。表3還顯示了DPRP蛋白質(zhì)的可能N-糖基化位點數(shù)目。用衣霉素，一種寡糖合成的抑制劑評估這些蛋白質(zhì)的糖基化和非糖基化形式的存在。顯然較小的形式是非糖基化形式。DPRP-1的mRNA(Northern分析)和蛋白質(zhì)質(zhì)量(Western分析)之間的相互關(guān)聯(lián)如表4所示。
表4 人組織中DPRP-1的mRNA和蛋白質(zhì)表達的相互關(guān)聯(lián)
實施例4人組織中DPRP蛋白質(zhì)的免疫組織化學定位制備了許多不同的福爾馬林固定、石蠟包埋的人組織的4微米切片。組織切片通過二甲苯浸泡5分鐘，4次脫蠟，然后通過系列稀釋的乙醇蒸發(fā)除去水。用幾種不同的SHIER溶液以兩種不同濃度的酶或不用酶消化組織，進行蒸氣加熱誘導的表位恢復(SHIER)(Ladner等，Cancer Res.；60，p3493-3503，2000)。所用的處理和抗體稀釋液如下1.封閉試劑15分鐘(正常山羊血清)。
2.一抗25、60分鐘或保溫過夜3.二抗25分鐘(生物素化的山羊-抗兔IgG)4.內(nèi)源性過氧化物酶封閉3×1.5分鐘5.ABC(親和素-生物素復合物)/辣根過氧化物酶25分鐘6.DAB色原3×5分鐘(棕色反應產(chǎn)物)7.淡蘇木精反染1分鐘制作陽性對照，以確保檢測化學物質(zhì)和抗原預處理是正確工作的。用家兔IgG作為陰性對照。用基于親和素-生物素的組織染色系統(tǒng)檢測DPRP-1抗體。用辣根過氧化物酶作為報道酶，DAB作為色原。染色后，通過系列乙醇-純乙醇對載玻片進行脫水，然后用二甲苯漂洗。載玻片用蓋玻片永久封蓋。用Olympus攝像機拍攝暗棕色色原(DAB-HRP反應產(chǎn)物)表示陽性染色的代表性染色的數(shù)碼照片。蘇木精反染提供了藍色的核染色，以評估細胞和組織形態(tài)。
DPRP-1家兔多克隆抗體標記福爾馬林固定、石蠟包埋的人組織，包括正常睪丸、前列腺、子宮內(nèi)膜腺體、扁桃腺和胰臟。還存在于正常卵巢、膀胱和腎臟的內(nèi)皮細胞中。染色位于表皮細胞和一些間質(zhì)細胞，例如成纖維細胞、內(nèi)皮細胞和淋巴細胞的胞質(zhì)中。令人感興趣的是在用DPRP-1抗體檢測的正常睪丸中也有，在睪丸間質(zhì)細胞和間隙組織(圍繞輸精管的空隙)的多核化巨噬細胞中有明顯表達。扁桃腺B細胞被DPRP-1抗體染色。
實施例5DPRP蛋白質(zhì)的哺乳動物和昆蟲細胞表達和純化用廠商推薦的LipofectAmine(Life Technologies，Gaithersburg MD，USA)方法將pcDNA-DPRP1、pcDNA-MycHis-DPRP1、pcDNA-DPRP2或pcDNA-MycHis-DPRP2的質(zhì)粒DNA轉(zhuǎn)染入PEAK(EdgeBioSystems，Gaithersburg MD，USA)或COS-1(ATCCCRL-1650)中。轉(zhuǎn)染的細胞37℃維持在含有5％FBS的DMEM中，在5％CO2下48小時。然后收集細胞，用于重組蛋白質(zhì)抽提。轉(zhuǎn)染48小時后收集細胞，勻漿然后18,000xg旋轉(zhuǎn)40分鐘。收集上清液作為細胞溶解組分。將該組分加到TALON旋轉(zhuǎn)柱(Clontech)上，用50mM PBS、150mM咪唑，pH7洗脫His加尾的蛋白質(zhì)。然后用抗myc抗體蛋白質(zhì)印跡分析檢測重組蛋白質(zhì)，并用ProtoBlot II AP系統(tǒng)(Promega)觀察。用蛋白質(zhì)印跡檢測DPRP-1和DPRP-2的重組親和純化的融合物，合成了預計的112kDa和109kDa形式的DPRP-1和DPRP-2。
用DPRP-1、DPRP-2或DPRP-3的特異性抗體，通過免疫親和層析基本純化了天然或重組的DPRP蛋白質(zhì)。通過共價偶聯(lián)DPRP抗體和活化的層析樹脂，例如CNBr-活化的Sepharose(Pharmacia & Upjohn)構(gòu)建了免疫親和柱。偶聯(lián)后，根據(jù)廠商說明書封閉樹脂并洗滌。
培養(yǎng)基或含有DPRP蛋白質(zhì)的細胞提取物通過免疫親和柱，在允許優(yōu)先DPRP吸附的條件下(例如在去污劑存在下的高離子強度緩沖液)洗滌此柱。在破壞抗體/DPRP結(jié)合(例如pH2-3的緩沖液或高濃度的破膜試劑，例如脲或硫氰酸根離子)的條件下洗脫柱，收集純化的DPRP。
實施例6
DPRP蛋白質(zhì)的酶活性和篩選抑制劑的方法用連續(xù)熒光測定試驗測定了重組DPRP-1和DPRP-2的動力學性質(zhì)。緩沖液、pH和溫度依賴性優(yōu)化得到下列試驗條件在50mM PBS，pH7.4下進行酶試驗，將50微升(50微克/毫升)純化的酶與1微升不同濃度的Ala-Pro-AMC(Enzyme Systems)混合。然后37℃保溫平板30分鐘，用Wallac1420熒光計以λex40355和λem535檢測熒光。DPRP-1和DPRP-2的Km值相似(分別為208和161μM)。
進一步確定生物化學特征揭示，DPRP-1和DPRP-2具有與DPPIV相似的分布圖。預先將兩種純化的蛋白酶和DPPIV在室溫下與抑制劑溫育30分鐘。然后加入底物Ala-Pro-AMC(100μM)，在60分鐘內(nèi)記錄熒光強度成為60個讀數(shù)。不可逆絲氨酸蛋白酶抑制劑AEBSF是顯示強抑制的所有三種酶中測試的唯一抑制劑(表5)。這證實了結(jié)構(gòu)和功能域分析的預測，即這些酶屬于絲氨酸蛋白酶超家族。
表5 蛋白酶抑制劑對DPRP-1和DPRP-2的抑制
除Ala-Pro-AMC外，其它測試的底物也證實了DPRP-1和DPRP-2是二肽酰肽酶。通過測定30分鐘溫育底物(125M)和酶后熒光的變化，產(chǎn)生了數(shù)據(jù)，是為在Ala-Pro-AMC時測定的熒光百分率，Gly-Pro-AMC是測試的底物中唯一的良好底物。
測試了其它天然和非天然氨基酸二、三和四肽，以尋找最佳底物，用于測試當與DPPIV一起溫育時會顯示活性下降的各種DPRP蛋白質(zhì)。
本文所述的酶試驗是許多方法之一，可用于篩選DPRP酶的肽和非肽抑制劑。測試了四肽文庫，以發(fā)現(xiàn)酶活性的抑制劑。制備了候選抑制劑以DMSO配成的儲存液，儲藏在-20℃。用試驗緩沖液進行稀釋。通過將受到抑制的酶的熒光改變與對照(載體)酶的熒光改變比較，確定抑制。100-(樣品的fl單位/對照的fl單位×100)得到抑制百分數(shù)值。通過抑制百分數(shù)對抑制劑濃度的對數(shù)值作圖，確立了抑制百分數(shù)和50％酶被抑制的抑制劑濃度(IC50)。如圖3所示，幾種四肽酰胺抑制了酶活性，其中數(shù)據(jù)表達為在單有運載體(0.02％DMSO)存在下的活性百分數(shù)。以1mM加入化合物。最令人感興趣的是，幾種四肽對DPRP-1和DPRP-2的活性與對DPPIV的活性相比明顯不同。雖然三種酶都受到肽-1抑制，只有DPRP-1和DPRP-2受到肽4和肽5的顯示抑制。這證明了純化的酶的選擇性抑制是可實現(xiàn)的。
該實施例中所述的試驗還可用于篩選其它合成的或天然存在的化合物文庫，包括大分子中的抑制或增強DPRP活性的藥物。在該試驗中使用的DPRP-1和DPRP-2多肽可通過例如體外翻譯、重組表達(見實施例5)或生物化學方法獲得。還可用除了本文描述的其它方法篩選和鑒定抑制DPRP-1、DPRP-2或DPRP-3的化合物，這些方法可以包括例如結(jié)合試驗，例如ELISA和RIA。
實施例7DPRP抑制劑對體外人癌癥細胞增殖的作用嘗試評估了影響DPRP-1和DPRP-2活性的幾種抑制劑對人癌細胞增殖的作用，將LNCap、PC3和Du145、小鼠睪丸細胞系MLTC-1和MDA-MB231乳腺癌細胞接種(104/孔)在96孔組織培養(yǎng)板中，使其生CO2培養(yǎng)箱37℃生長和附著24小時。然后將各種稀釋度的化合物(最終稀釋度0.1nM-10μM)加到孔中，培養(yǎng)24-96小時每天更換新鮮化合物，單獨加入稀釋的DMSO作為對照。在與這些化合物一式三份培養(yǎng)后，用XTT細胞增殖試驗試劑盒(Roche 1-465-015)測定細胞的增殖。加入XTT混合物5小時后，在490和650nm閱讀平板。用三種抑制劑在相當于0.1、1、10和100×IC50的濃度下觀察細胞增殖的增加，結(jié)果如圖4A、4B和4C對于PC3細胞所示。
總的說，DPRP在各種組織中表達，如mRNA擴增、蛋白質(zhì)印跡和免疫組織化學證明的那樣。Northern和Western印跡檢測DPRP-1在睪丸中最豐富。大量表達的睪丸cDNA來源的序列標記(EST)與DPRP-1同源，也證實DPRP-1在睪丸中的豐富表達。實施例4描述了人睪丸中用特異性DPRP-1抗體進行DPRP-1蛋白質(zhì)的免疫組織化學定位。DPRP-1在上皮樣睪丸間質(zhì)細胞中強表達，睪丸間質(zhì)細胞是雄性哺乳動物中睪丸雄激素(雄性類固醇激素)的主要來源。在睪丸間質(zhì)中，睪丸間質(zhì)細胞和巨噬細胞通過睪丸間質(zhì)細胞延伸到巨噬細胞表面的“指狀物”而密切相連。緊鄰睪丸間質(zhì)細胞的多核細胞也被DPRP-1抗體染色，提示該蛋白酶也在巨噬細胞中表達，而睪丸中的巨噬細胞在睪丸間質(zhì)細胞的旁分泌調(diào)節(jié)中起著重要作用。睪丸巨噬細胞分泌的細胞因子對睪丸間質(zhì)細胞具有有絲分裂作用，在間充質(zhì)祖細胞分化成成熟睪丸間質(zhì)細胞中起著重要作用。對睪丸成熟中蛋白質(zhì)和通路的更清楚了解對于發(fā)現(xiàn)新的性早熟治療方法是重要的。另外，睪丸間質(zhì)細胞導致腫瘤，例如由于性類固醇產(chǎn)生(主要是睪酮)的生殖索-間質(zhì)腫瘤。睪酮與幾種腫瘤和疾病有關(guān)，例如乳腺癌和子宮癌、卵巢癌和雄性脫發(fā)(脫發(fā))。對于DPRP蛋白質(zhì)在機體產(chǎn)生睪酮和其它雄性激素的其他腺體(例如腎上腺)中定位的進一步檢測目前正在調(diào)查中。正在調(diào)查DPRP-1與類固醇和多肽激素生物合成通路功能的可能關(guān)系，實施例7是關(guān)于了解體外細胞模型中DPRP蛋白質(zhì)在前列腺、睪丸和乳腺中的作用。
免疫組織化學分析也將DPRP-1定位于子宮內(nèi)膜腺體、胰腺腺泡、腎小球、膀胱中的漿細胞、扁桃腺中的B細胞亞組、前列腺中的柱狀表皮細胞，分化類的前列腺鱗狀化生、Gleason4級前列腺癌和良性前列腺增生中的增生腺體中。在乳癌和精原細胞瘤和前列腺鱗狀化生中陽性染色，提示DPRP-1與激素敏感組織，特別是變得分化差的細胞中有普遍的連系。DPRP-1在特殊化表皮細胞中和在炎癥漿細胞(淋巴細胞)中的存在也是令人感興趣的。炎癥性乳癌具有豐富的滲透性淋巴細胞和完全不良預后。DPRP-1和其它DPRP蛋白質(zhì)出現(xiàn)在髓質(zhì)癌中，此癌通常在腫瘤周圍有穩(wěn)定的滲透性淋巴漿細胞組分，據(jù)信這代表宿主組織對腫瘤的反應。大多數(shù)淋巴細胞是T細胞，而大多數(shù)漿細胞是產(chǎn)生IgG類型的細胞。幾種抗原在B細胞、乳癌細胞的一個亞類和其它表皮癌細胞中是豐富的，這些抗原是一類新的治療性單克隆抗體的目標，對于針對B細胞特異性抗原CD20的人源化單克隆抗體已經(jīng)獲得了一些引人注目的進展。因此，針對DPRP蛋白質(zhì)的單克隆抗體將被用于診斷和治療它們所涉及的疾病，包括癌癥。
DPRP-1在許多組織中的特殊表皮細胞中的表達提示了DPRP-1和其它DPRP蛋白質(zhì)可能涉及此種表皮細胞的生長和分化。用實施例6所述的抑制劑在前列腺癌和睪丸癌(實施例7)的體外模型中測試，顯示在如圖4A-4C所示nM濃度下DPRP-1/DPRP-2抑制劑導致PC3細胞增殖增加了50-60％。
雖然根據(jù)構(gòu)成發(fā)明人目前所知的最佳模式的優(yōu)選例描述了本發(fā)明，應理解對于本領(lǐng)域技術(shù)人員來說可明顯的進行改變和修改，而不違背權(quán)利要求中所列出的范圍。例如，雖然在某些情況下公開的內(nèi)容集中在DPRP-1和DPRP-2，但DPRP-3及其片段也被視為具有相似用途，其編碼核酸也有相似用途。本發(fā)明的具體特征如以下權(quán)利要求所述。
序列表<110> S.戚(QI，Steve)K.埃金桑亞(AKINSANYA，Karen)P.里弗(RIVIERE，Pierre)J.-L.朱尼英(JUNIEN，Jean-Louis)<120> 與DPPIV相關(guān)的新絲氨酸蛋白酶基因<130> 70669<150> US 60/240,117<151> 2000-10-12<160> 61<170> Patent In version 3.1<210> 1<211> 882<212> PRT<213> 智人(Homo sapiens)<400> 1Met Ala Ala Ala Met Glu Thr Glu Gln Leu Gly Val Glu Ile Phe Glu1 5 10 15Thr Ala Asp Cys Glu Glu Asn Ile Glu Ser Gln Asp Arg Pro Lys Leu20 25 30Glu Pro Phe Tyr Val Glu Arg Tyr Ser Trp Ser Gln Leu Lys Lys Leu35 40 45Leu Ala Asp Thr Arg Lys Tyr His Gly Tyr Met Met Ala Lys Ala Pro50 55 60His Asp Phe Met Phe Val Lys Arg Asn Asp Pro Asp Gly Pro His Ser65 70 75 80Asp Arg Ile Tyr Tyr Leu Ala Met Ser Gly Glu Asn Arg Glu Asn Thr85 90 95Leu Phe Tyr Ser Glu Ile Pro Lys Thr Ile Asn Arg Ala Ala Val Leu100 105 110Met Leu Ser Trp Lys Pro Leu Leu Asp Leu Phe Gln Ala Thr Leu Asp115 120 125Tyr Gly Met Tyr Ser Arg Glu Glu Glu Leu Leu Arg Glu Arg Lys Arg130 135 140Ile Gly Thr Val Gly Ile Ala Ser Tyr Asp Tyr His Gln Gly Ser Gly145 150 155 160Thr Phe Leu Phe Gln Ala Gly Ser Gly Ile Tyr His Val Lys Asp Gly165 170 175Gly Pro Gln Gly Phe Thr Gln Gln Pro Leu Arg Pro Asn Leu Val Glu180 185 190Thr Ser Cys Pro Asn Ile Arg Met Asp Pro Lys Leu Cys Pro Ala Asp195 200 205Pro Asp Trp Ile Ala Phe Ile His Ser Asn Asp Ile Trp Ile Ser Asn210 215 220Ile Val Thr Arg Glu Glu Arg Arg Leu Thr Tyr Val His Asn Glu Leu225 230 235 240Ala Asn Met Glu Glu Asp Ala Arg Ser Ala Gly Val Ala Thr Phe Val245 250 255
Leu Gln Glu Glu Phe Asp Arg Tyr Ser Gly Tyr Trp Trp Cys Pro Lys260 265 270Ala Glu Thr Thr Pro Ser Gly Gly Lys Ile Leu Arg Ile Leu Tyr Glu275 280 285Glu Asn Asp Glu Ser Glu Val Glu Ile Ile His Val Thr Ser Pro Met290 295 300Leu Glu Thr Arg Arg Ala Asp Ser Phe Arg Tyr Pro Lys Thr Gly Thr305 310 315 320Ala Asn Pro Lys Val Thr Phe Lys Met Ser Glu Ile Met Ile Asp Ala325 330 335Glu Gly Arg Ile Ile Asp Val Ile Asp Lys Glu Leu Ile Gln Pro Phe340 345 350Glu Ile Leu Phe Glu Gly Val Glu Tyr Ile Ala Arg Ala Gly Trp Thr355 360 365Pro Glu Gly Lys Tyr Ala Trp Ser Ile Leu Leu Asp Arg Ser Gln Thr370 375 380Arg Leu Gln Ile Val Leu Ile Ser Pro Glu Leu Phe Ile Pro Val Glu385 390 395 400Asp Asp Val Met Glu Arg Gln Arg Leu Ile Glu Ser Val Pro Asp Ser405 410 415Val Thr Pro Leu Ile Ile Tyr Glu Glu Thr Thr Asp Ile Trp Ile Asn420 425 430Ile His Asp Ile Phe His Val Phe Pro Gln Ser His Glu Glu Glu Ile435 440 445Glu Phe Ile Phe Ala Ser Glu Cys Lys Thr Gly Phe Arg His Leu Tyr450 455 460Lys Ile Thr Ser Ile Leu Lys Glu Ser Lys Tyr Lys Arg Ser Ser Gly465 470 475 480Gly Leu Pro Ala Pro Ser Asp Phe Lys Cys Pro Ile Lys Glu Glu Ile485 490 495Ala Ile Thr Ser Gly Glu Trp Glu Val Leu Gly Arg His Gly Ser Asn500 505 510Ile Gln Val Asp Glu Val Arg Arg Leu Val Tyr Phe Glu Gly Thr Lys515 520 525Asp Ser Pro Leu Glu His His Leu Tyr Val Val Ser Tyr Val Asn Pro530 535 540Gly Glu Val Thr Arg Leu Thr Asp Arg Gly Tyr Ser His Ser Cys Cys545 550 555 560Ile Ser Gln His Cys Asp Phe Phe Ile Ser Lys Tyr Ser Asn Gln Lys565 570 575Asn Pro His Cys Val Ser Leu Tyr Lys Leu Ser Ser Pro Glu Asp Asp580 585 590Pro Thr Cys Lys Thr Lys Glu Phe Trp Ala Thr Ile Leu Asp Ser Ala595 600 605Gly Pro Leu Pro Asp Tyr Thr Pro Pro Glu Ile Phe Ser Phe Glu Ser610 615 620Thr Thr Gly Phe Thr Leu Tyr Gly Met Leu Tyr Lys Pro His Asp Leu625 630 635 640Gln Pro Gly Lys Lys Tyr Pro Thr Val Leu Phe Ile Tyr Gly Gly Pro645 650 655Gln Val Gln Leu Val Asn Asn Arg Phe Lys Gly Val Lys Tyr Phe Arg660 665 670Leu Asn Thr Leu Ala Ser Leu Gly Tyr Val Val Val Val Ile Asp Asn675 680 685Arg Gly Ser Cys His Arg Gly Leu Lys Phe Glu Gly Ala Phe Lys Tyr690 695 700Lys Met Gly Gln Ile Glu Ile Asp Asp Gln Val Glu Gly Leu Gln Tyr705 710 715 720
Leu Ala Ser Arg Tyr Asp Phe Ile Asp Leu Asp Arg Val Gly Ile His725 730 735Gly Trp Ser Tyr Gly Gly Tyr Leu Ser Leu Met Ala Leu Met Gln Arg740 745 750Ser Asp Ile Phe Arg Val Ala Ile Ala Gly Ala Pro Val Thr Leu Trp755 760 765Ile Phe Tyr Asp Thr Gly Tyr Thr Glu Arg Tyr Met Gly His Pro Asp770 775 780Gln Asn Glu Gln Gly Tyr Tyr Leu Gly Ser Val Ala Met Gln Ala Glu785 790 795 800Lys Phe Pro Ser Glu Pro Asn Arg Leu Leu Leu Leu His Gly Phe Leu805 810 815Asp Glu Asn Val His Phe Ala His Thr Ser Ile Leu Leu Ser Phe Leu820 825 830Val Arg Ala Gly Lys Pro Tyr Asp Leu Gln Ile Tyr Pro Gln Glu Arg835 840 845His Ser Ile Arg Val Pro Glu Ser Gly Glu His Tyr Glu Leu His Leu850 855 860Leu His Tyr Leu Gln Glu Asn Leu Gly Ser Arg Ile Ala Ala Leu Lys865 870 875 880Val Ile<210>2<211>2671<212>DNA<213>智人(Homo sapiens)<400>2cggtaccatg gcagcagcaa tggaaacaga acagctgggt gttgagatat ttgaaactgc 60ggactgtgag gagaatattg aatcacagga tcggcctaaa ttggagcctt tttatgttga120gcggtattcc tggagtcagc ttaaaaagct gcttgccgat accagaaaat atcatggcta180catgatggct aaggcaccac atgatttcat gtttgtgaag aggaatgatc cagatggacc240tcattcagac agaatctatt accttgccat gtctggtgag aacagagaaa atacactgtt300ttattctgaa attcccaaaa ctatcaatag agcagcagtc ttaatgctct cttggaagcc360tcttttggat ctttttcagg caacactgga ctatggaatg tattctcgag aagaagaact420attaagagaa agaaaacgca ttggaacagt cggaattgct tcttacgatt atcaccaagg480aagtggaaca tttctgtttc aagccggtag tggaatttat cacgtaaaag atggagggcc540acaaggattt acgcaacaac ctttaaggcc caatctagtg gaaactagtt gtcccaacat600acggatggat ccaaaattat gccctgctga tccagactgg attgctttta tacatagcaa660cgatatttgg atatctaaca tcgtaaccag agaagaaagg agactcactt atgtgcacaa720tgagctagcc aacatggaag aagatgccag atcagctgga gtcgctacct ttgttctcca780agaagaattt gatagatatt ctggctattg gtggtgtcca aaagctgaaa caactcccag840tggtggtaaa attcttagaa ttctatatga agaaaatgat gaatctgagg tggaaattat900tcatgttaca tcccctatgt tggaaacaag gagggcagat tcattccgtt atcctaaaac960aggtacagca aatcctaaag tcacttttaa gatgtcagaa ataatgattg atgctgaagg 1020aaggatcata gatgtcatag ataaggaact aattcaacct tttgagattc tatttgaagg 1080agttgaatat attgccagag ctggatggac tcctgaggga aaatatgctt ggtccatcct 1140actagatcgc tcccagactc gcctgcagat agtgttgatc tcacctgaat tatttatccc 1200agtagaagat gatgttatgg aaaggcagag actcattgag tcagtgcctg attctgtgac 1260gccactaatt atctatgaag aaacaacaga catctggata aatatccatg acatctttca 1320tgtttttccc caaagtcacg aagaggaaat tgagtttatt tttgcctctg aatgcaaaac 1380aggtttccgt catttataca aaattacatc tattttaaag gaaagcaaat ataaacgatc 1440cagtggtggg ctgcctgctc caagtgattt caagtgtcct atcaaagagg agatagcaat 1500taccagtggt gaatgggaag ttcttggccg gcatggatct aatatccaag ttgatgaagt 1560cagaaggctg gtatattttg aaggcaccaa agactcccct ttagagcatc acctgtacgt 1620agtcagttac gtaaatcctg gagaggtgac aaggctgact gaccgtggct actcacattc 1680ttgctgcatc agtcagcact gtgacttctt tataagtaag tatagtaacc agaagaatcc 1740acactgtgtg tccctttaca agctatcaag tcctgaagat gacccaactt gcaaaacaaa 1800ggaattttgg gccaccattt tggattcagc aggtcctctt cctgactata ctcctccaga 1860aattttctct tttgaaagta ctactggatt tacattgtat gggatgctct acaagcctca 1920
tgatctacag cctggaaaga aatatcctac tgtgctgttc atatatggtg gtcctcaggt 1980gcagttggtg aataatcgat ttaaaggagt caagtatttc cgcttgaata ccctagcctc 2040tctaggttat gtggttgtag tgatagacaa caggggatcc tgtcaccgag ggcttaaatt 2100tgaaggcgcc tttaaatata aaatgggtca aatagaaatt gacgatcagg tggaaggact 2160ccaatatcta gcttctcgat atgatttcat tgacttagat cgtgtgggca tccacggctg 2220gtcctatgga ggatacctct ccctgatggc attaatgcag aggtcagata tcttcagggt 2280tgctattgct ggggccccag tcactctgtg gatcttctat gatacaggat acacggaacg 2340ttatatgggt caccctgacc agaatgaaca gggctattac ttaggatctg tggccatgca 2400agcagaaaag ttcccctctg aaccaaatcg tttactgctc ttacatggtt tcctggatga 2460gaatgtccat tttgcacata ccagtatatt actgagtttt ttagtgaggg ctggaaagcc 2520atatgattta cagatctatc ctcaggagag acacagcata agagttcctg aatcgggaga 2580acattatgaa ctgcatcttt tgcactacct tcaagaaaac cttggatcac gtattgctgc 2640tctaaaagtg atatgagcgg ccgcgagctc c 2671<210>3<211>863<212>PRT<213>智人(Homo sapiens)<400>3Met Ala Thr Thr Gly Thr Pro Thr Ala Asp Arg Gly Asp Ala Ala Ala1 5 10 15Thr Asp Asp Pro Ala Ala Arg Phe Gln Val Gln Lys His Ser Trp Asp20 25 30Gly Leu Arg Ser Ile Ile His Gly Ser Arg Lys Tyr Ser Gly Leu Ile35 40 45Val Asn Lys Ala Pro His Asp Phe Gln Phe Val Gln Lys Thr Asp Glu50 55 60Ser Gly Pro His Ser His Arg Leu Tyr Tyr Leu Gly Met Pro Tyr Gly65 70 75 80Ser Arg Glu Asn Ser Leu Leu Tyr Ser Glu Ile Pro Lys Lys Val Arg85 90 95Lys Glu Ala Leu Leu Leu Leu Ser Trp Lys Gln Met Leu Asp His Phe100 105 110Gln Ala Thr Pro His His Gly Val Tyr Ser Arg Glu Glu Glu Leu Leu115 120 125Arg Glu Arg Lys Arg Leu Gly Val Phe Gly Ile Thr Ser Tyr Asp Phe130 135 140His Ser Glu Ser Gly Leu Phe Leu Phe Gln Ala Ser Asn Ser Leu Phe145 150 155 160His Cys Arg Asp Gly Gly Lys Asn Gly Phe Met Val Ser Pro Met Lys165 170 175Pro Leu Glu Ile Lys Thr Gln Cys Ser Gly Pro Arg Met Asp Pro Lys180 185 190Ile Cys Pro Ala Asp Pro Ala Phe Phe Ser Phe Ile Asn Asn Ser Asp195 200 205Leu Trp Val Ala Asn Ile Glu Thr Gly Glu Glu Arg Arg Leu Thr Phe210 215 220Cys His Gln Gly Leu Ser Asn Val Leu Asp Asp Pro Lys Ser Ala Gly225 230 235 240Val Ala Thr Phe Val Ile Gln Glu Glu Phe Asp Arg Phe Thr Gly Tyr245 250 255Trp Trp Cys Pro Thr Ala Ser Trp Glu Gly Ser Glu Gly Leu Lys Thr260 265 270Leu Arg Ile Leu Tyr Glu Glu Val Asp Glu Ser Glu Val Glu Val Ile275 280 285His Val Pro Ser Pro Ala Leu Glu Glu Arg Lys Thr Asp Ser Tyr Arg290 295 300Tyr Pro Arg Thr Gly Ser Lys Asn Pro Lys Ile Ala Leu Lys Leu Ala305 310 315 320
Glu Phe Gln Thr Asp Ser Gln Gly Lys Ile Val Ser Thr Gln Glu Lys325 330 335Glu Leu Val Gln Pro Phe Ser Ser Leu Phe Pro Lys Val Glu Tyr Ile340 345 350Ala Arg Ala Gly Trp Thr Arg Asp Gly Lys Tyr Ala Trp Ala Met Phe355 360 365Leu Asp Arg Pro Gln Gln Trp Leu Gln Leu Val Leu Leu Pro Pro Ala370 375 380Leu Phe Ile Pro Ser Thr Glu Asn Glu Glu Gln Arg Leu Ala Ser Ala385 390 395 400Arg Ala Val Pro Arg Asn Val Gln Pro Tyr Val Val Tyr Glu Glu Val405 410 415Thr Asn Val Trp Ile Asn Val His Asp Ile Phe Tyr Pro Phe Pro Gln420 425 430Ser Glu Gly Glu Asp Glu Leu Cys Phe Leu Arg Ala Asn Glu Cys Lys435 440 445Thr Gly Phe Cys His Leu Tyr Lys Val Thr Ala Val Leu Lys Ser Gln450 455 460Gly Tyr Asp Trp Ser Glu Pro Phe Ser Pro Gly Glu Asp Glu Phe Lys465 470 475 480Cys Pro Ile Lys Glu Glu Ile Ala Leu Thr Ser Gly Glu Trp Glu Val485 490 495Leu Ala Arg His Gly Ser Lys Ile Trp Val Asn Glu Glu Thr Lys Leu500 505 510Val Tyr Phe Gln Gly Thr Lys Asp Thr Pro Leu Glu His His Leu Tyr515 520 525Val Val Ser Tyr Glu Ala Ala Gly Glu Ile Val Arg Leu Thr Thr Pro530 535 540Gly Phe Ser His Ser Cys Ser Met Ser Gln Asn Phe Asp Met Phe Val545 550 555 560Ser His Tyr Ser Ser Val Ser Thr Pro Pro Cys Val His Val Tyr Lys565 570 575Leu Ser Gly Pro Asp Asp Asp Pro Leu His Lys Gln Pro Arg Phe Trp580 585 590Ala Ser Met Met Glu Ala Ala Ser Cys Pro Pro Asp Tyr Val Pro Pro595 600 605Glu Ile Phe His Phe His Thr Arg Ser Asp Val Arg Leu Tyr Gly Met610 615 620Ile Tyr Lys Pro His Ala Leu Gln Pro Gly Lys Lys His Pro Thr Val625 630 635 640Leu Phe Val Tyr Gly Gly Pro Gln Val Gln Leu Val Asn Asn Ser Phe645 650 655Lys Gly Ile Lys Tyr Leu Arg Leu Asn Thr Leu Ala Ser Leu Gly Tyr660 665 670Ala Val Val Val Ile Asp Gly Arg Gly Ser Cys Gln Arg Gly Leu Arg675 680 685Phe Glu Gly Ala Leu Lys Asn Gln Met Gly Gln Val Glu Ile Glu Asp690 695 700Gln Val Glu Gly Leu Gln Phe Val Ala Glu Lys Tyr Gly Phe Ile Asp705 710 715 720Leu Ser Arg Val Ala Ile His Gly Trp Ser Tyr Gly Gly Phe Leu Ser725 730 735Leu Met Gly Leu Ile His Lys Pro Gln Val Phe Lys Val Ala Ile Ala740 745 750Gly Ala Pro Val Thr Val Trp Met Ala Tyr Asp Thr Gly Tyr Thr Glu755 760 765
Arg Tyr Met Asp Val Pro Glu Asn Asn Gln His Gly Tyr Glu Ala Gly770 775 780Ser Val Ala Leu His Val Glu Lys Leu Pro Asn Glu Pro Asn Arg Leu785 790 795 800Leu Ile Leu His Gly Phe Leu Asp Glu Asn Val His Phe Phe His Thr805 810 815Asn Phe Leu Val Ser Gln Leu Ile Arg Ala Gly Lys Pro Tyr Gln Leu820 825 830Gln Ile Tyr Pro Asn Glu Arg His Ser Ile Arg Cys Pro Glu Ser Gly835 840 845Glu His Tyr Glu Val Thr Leu Leu His Phe Leu Gln Glu Tyr Leu850 855 860<210>4<211>2617<212>DNA<213>智人(Homo sapiens)<400>4caagcttacc atggccacca ccgggacccc aacggccgac cgaggcgacg cagccgccac 60agatgacccg gccgcccgct tccaggtgca gaagcactcg tgggacgggc tccggagcat120catccacggc agccgcaagt actcgggcct cattgtcaac aaggcgcccc acgacttcca180gtttgtgcag aagacggatg agtctgggcc ccactcccac cgcctctact acctgggaat240gccatatggc agccgagaga actccctcct ctactctgag attcccaaga aggtccggaa300agaggctctg ctgctcctgt cctggaagca gatgctggat catttccagg ccacgcccca360ccatggggtc tactctcggg aggaggagct gctgagggag cggaaacgcc tgggggtctt420cggcatcacc tcctacgact tccacagcga gagtggcctc ttcctcttcc aggccagcaa480cagcctcttc cactgtcgcg acggcggcaa gaacggcttc atggtgtccc ctatgaaacc540gctggaaatc aagacccagt gctcagggcc ccggatggac cccaaaatct gccctgccga600ccctgccttc ttctccttca tcaataacag cgacctgtgg gtggccaaca tcgagacagg660cgaggagcgg cggctgacct tctgccacca aggtttatcc aatgtcctgg atgaccccaa720gtctgcgggt gtggccacct tcgtcataca ggaagagttc gaccgcttca ctgggtactg780gtggtgcccc acagcctcct gggaaggttc agagggcctc aagacgctgc gaatcctgta840tgaggaagtc gatgagtccg aggtggaggt cattcacgtc ccctctcctg cgctagaaga900aaggaagacg gactcgtatc ggtaccccag gacaggcagc aagaatccca agattgcctt960gaaactggct gagttccaga ctgacagcca gggcaagatc gtctcgaccc aggagaagga 1020gctggtgcag cccttcagct cgctgttccc gaaggtggag tacatcgcca gggccgggtg 1080gacccgggat ggcaaatacg cctgggccat gttcctggac cggccccagc agtggctcca 1140gctcgtcctc ctccccccgg ccctgttcat cccgagcaca gagaatgagg agcagcggct 1200agcctctgcc agagctgtcc ccaggaatgt ccagccgtat gtggtgtacg aggaggtcac 1260caacgtctgg atcaatgttc atgacatctt ctatcccttc ccccaatcag agggagagga 1320cgagctctgc tttctccgcg ccaatgaatg caagaccggc ttctgccatt tgtacaaagt 1380caccgccgtt ttaaaatccc agggctacga ttggagtgag cccttcagcc ccggggaaga 1440tgaatttaag tgccccatta aggaagagat tgctctgacc agcggtgaat gggaggtttt 1500ggcgaggcac ggctccaaga tctgggtcaa tgaggagacc aagctggtgt acttccaggg 1560caccaaggac acgccgctgg agcaccacct ctacgtggtc agctatgagg cggccggcga 1620gatcgtacgc ctcaccacgc ccggcttctc ccatagctgc tccatgagcc agaacttcga 1680catgttcgtc agccactaca gcagcgtgag cacgccgccc tgcgtgcacg tctacaagct 1740gagcggcccc gacgacgacc ccctgcacaa gcagccccgc ttctgggcta gcatgatgga 1800ggcagccagc tgccccccgg attatgttcc tccagagatc ttccatttcc acacgcgctc 1860ggatgtgcgg ctctacggca tgatctacaa gccccacgcc ttgcagccag ggaagaagca 1920ccccaccgtc ctctttgtat atggaggccc ccaggtgcag ctggtgaata actccttcaa 1980aggcatcaag tacttgcggc tcaacacact ggcctccctg ggctacgccg tggttgtgat 2040tgacggcagg ggctcctgtc agcgagggct tcggttcgaa ggggccctga aaaaccaaat 2100gggccaggtg gagatcgagg accaggtgga gggcctgcag ttcgtggccg agaagtatgg 2160cttcatcgac ctgagccgag ttgccatcca tggctggtcc tacgggggct tcctctcgct 2220catggggcta atccacaagc cccaggtgtt caaggtggcc atcgcgggtg ccccggtcac 2280cgtctggatg gcctacgaca cagggtacac tgagcgctac atggacgtcc ctgagaacaa 2340ccagcacggc tatgaggcgg gttccgtggc cctgcacgtg gagaagctgc ccaatgagcc 2400caaccgcttg cttatcctcc acggcttcct ggacgaaaac gtgcactttt tccacacaaa 2460
cttcctcgtc tcccaactga tccgagcagg gaaaccttac cagctccaga tctaccccaa 2520cgagagacac agtattcgct gccccgagtc gggcgagcac tatgaagtca cgttgctgca 2580ctttctacag gaatacctct gagcggccgc ggatccg2617<210>5<211>796<212>PRT<213>智人(Homo sapiens)<400>5Met Asn Gln Thr Ala Ser Val Ser His His Ile Lys Cys Gln Pro Ser1 5 10 15Lys Thr Ile Lys Glu Leu Gly Ser Asn Ser Pro Pro Gln Arg Asn Trp20 25 30Lye Gly Ile Ala Ile Ala Leu Leu Val Ile Leu Val Val Cys Ser Leu35 40 45Ile Thr Met Ser Val Ile Leu Leu Ser Pro Asp Glu Leu Thr Asn Ser50 55 60Ser Glu Thr Arg Leu Ser Leu Glu Asp Leu Phe Arg Lys Asp Phe Val65 70 75 80Leu His Asp Pro Glu Ala Arg Trp Ile Asn Asp Thr Asp Val Val Tyr85 90 95Lys Ser Glu Asn Gly His Val Ile Lys Leu Asn Ile Glu Thr Asn Ala100 105 110Thr Thr Leu Leu Leu Glu Asn Thr Thr Phe Val Thr Phe Lys Ala Ser115 120 125Arg His Ser Val Ser Pro Asp Leu Lys Tyr Val Leu Leu Ala Tyr Asp130 135 140Val Lys Gln Ile Phe His Tyr Ser Tyr Thr Ala Ser Tyr Val Ile Tyr145 150 155 160Asn Ile His Thr Arg Glu Val Trp Glu Leu Asn Pro Pro Glu Val Glu165 170 175Asp Ser Val Leu Gln Tyr Ala Ala Trp Gly Val Gln Gly Gln Gln Leu180 185 190Ile Tyr Ile Phe Glu Asn Asn Ile Tyr Tyr Gln Pro Asp Ile Lys Ser195 200 205Ser Ser Leu Arg Leu Thr Ser Ser Gly Lys Glu Glu Ile Ile Phe Asn210 215 220Gly Ile Ala Asp Trp Leu Tyr Glu Glu Glu Leu Leu His Ser His Ile225 230 235 240Ala His Trp Trp Ser Pro Asp Gly Glu Arg Leu Ala Phe Leu Met Ile245 250 255Asn Asp Ser Leu Val Pro Thr Met Val Ile Pro Arg Phe Thr Gly Ala260 265 270Leu Tyr Pro Lys Gly Lys Gln Tyr Pro Tyr Pro Lys Ala Gly Gln Val275 280 285Asn Pro Thr Ile Lys Leu Tyr Val Val Asn Leu Tyr Gly Pro Thr His290 295 300Thr Leu Glu Leu Met Pro Pro Asp Ser Phe Lys Ser Arg Glu Tyr Tyr305 310 315 320Ile Thr Met Val Lys Trp Val Ser Asn Thr Lys Thr Val Val Arg Trp325 330 335Leu Asn Arg Pro Gln Asn Ile Ser Ile Leu Thr Val Cys Glu Thr Thr340 345 350Thr Gly Ala Cys Ser Lys Lys Tyr Glu Met Thr Ser Asp Thr Trp Leu355 360 365Ser Gln Gln Asn Glu Glu Pro Val Phe Ser Arg Asp Gly Ser Lys Phe370 375 380Phe Met Thr Val Pro Val Lys Gln Gly Gly Arg Gly Glu Phe His His385 390 395 400
Ile Ala Met Phe Leu Ile Gln Ser Lys Ser Glu Gln Ile Thr Val Arg405 410 415His Leu Thr Ser Gly Asn Trp Glu Val Ile Lys Ile Leu Ala Tyr Asp420 425 430Glu Thr Thr Gln Lys Ile Tyr Phe Leu Ser Thr Glu Ser Ser Pro Arg435 440 445Gly Arg Gln Leu Tyr Ser Ala Ser Thr Glu Gly Leu Leu Asn Arg Gln450 455 460Cys Ile Ser Cys Asn Phe Met Lys Glu Gln Cys Thr Tyr Phe Asp Ala465 470 475 480Ser Phe Ser Pro Met Asn Gln His Phe Leu Leu Phe Cys Glu Gly Pro485 490 495Arg Val Pro Val Val Ser Leu His Ser Thr Asp Asn Pro Ala Lys Tyr500 505 510Phe Ile Leu Glu Ser Asn Ser Met Leu Lys Glu Ala Ile Leu Lys Lys515 520 525Lys Ile Gly Lys Pro Glu Ile Lys Ile Leu His Ile Asp Asp Tyr Glu530 535 540Leu Pro Leu Gln Leu Ser Leu Pro Lys Asp Phe Met Asp Arg Asn Gln545 550 555 560Tyr Ala Leu Leu Leu Ile Met Asp Glu Glu Pro Gly Gly Gln Leu Val565 570 575Thr Asp Lys Phe His Ile Asp Trp Asp Ser Val Leu Ile Asp Met Asp580 585 590Asn Val Ile Val Ala Arg Phe Asp Gly Arg Gly Ser Gly Phe Gln Gly595 600 605Leu Lys Ile Leu Gln Glu Ile His Arg Arg Leu Gly Ser Val Glu Val610 615 620Lys Asp Gln Ile Thr Ala Val Lys Phe Leu Leu Lys Leu Pro Tyr Ile625 630 635 640Asp Ser Lys Arg Leu Ser Ile Phe Gly Lys Gly Tyr Gly Gly Tyr Ile645 650 655Ala Ser Met Ile Leu Lys Ser Asp Glu Lys Leu Phe Lys Cys Gly Ser660 665 670Val Val Ala Pro Ile Thr Asp Leu Lys Leu Tyr Ala Ser Ala Phe Ser675 680 685Glu Arg Tyr Leu Gly Met Pro Ser Lys Glu Glu Ser Thr Tyr Gln Ala690 695 700Ala Ser Val Leu His Asn Val His Gly Leu Lys Glu Glu Asn Ile Leu705 710 715 720Ile Ile His Gly Thr Ala Asp Thr Lys Val His Phe Gln His Ser Ala725 730 735Glu Leu Ile Lys His Leu Ile Lys Ala Gly Val Asn Tyr Thr Met Gln740 745 750Val Tyr Pro Asp Glu Gly His Asn Val Ser Glu Lys Ser Lys Tyr His755 760 765Leu Tyr Ser Thr Ile Leu Lys Phe Phe Ser Asp Cys Leu Lys Glu Glu770 775 780Ile Ser Val Leu Pro Gln Glu Pro Glu Glu Asp Glu785 790 795<210>6<211>2583<212>DNA<213>智人(Homo sapiens)<400>6gcctgggatt gtgcactgtc cagggtcctg aaacatgaac caaactgcca gcgtgtccca 60tcacatcaag tgtcaaccct caaaaacaat caaggaactg ggaagtaaca gccctccaca120gagaaactgg aagggaattg ctattgctct gctggtgatt ttagttgtat gctcactcat180
cactatgtca gtcatcctct taagcccaga tgaactcaca aattcgtcag aaaccagatt240gtctttggaa gacctcttta ggaaagactt tgtgcttcac gatccagagg ctcggtggat300caatgataca gatgtggtgt ataaaagcga gaatggacat gtcattaaac tgaatataga360aacaaatgct accacattat tattggaaaa cacaactttt gtaaccttca aagcatcaag420acattcagtt tcaccagatt taaaatatgt ccttctggca tatgatgtca aacagatttt480tcattattcg tatactgctt catatgtgat ttacaacata cacactaggg aagtttggga540gttaaatcct ccagaagtag aggactccgt cttgcagtac gcggcctggg gtgtccaagg600gcagcagctg atttatattt ttgaaaataa tatctactat caacctgata taaagagcag660ttcattgcga ctgacatctt ctggaaaaga agaaataatt tttaatggga ttgctgactg720gttatatgaa gaggaactcc tgcattctca catcgcccac tggtggtcac cagatggaga780aagacttgcc ttcctgatga taaatgactc tttggtaccc accatggtta tccctcggtt840tactggagcg ttgtatccca aaggaaagca gtatccgtat cctaaggcag gtcaagtgaa900cccaacaata aaattatatg ttgtaaacct gtatggacca actcacactt tggagctcat960gccacctgac agctttaaat caagagaata ctatatcact atggttaaat gggtaagcaa 1020taccaagact gtggtaagat ggttaaaccg acctcagaac atctccatcc tcacagtctg 1080tgagaccact acaggtgctt gtagtaaaaa atatgagatg acatcagata cgtggctctc 1140tcagcagaat gaggagcccg tgttttctag agacggcagc aaattcttta tgacagtgcc 1200tgttaagcaa gggggacgtg gagaatttca ccacatagct atgttcctca tccagagtaa 1260aagtgagcaa attaccgtgc ggcatctgac atcaggaaac tgggaagtga taaagatctt 1320ggcatacgat gaaactactc aaaaaattta ctttctgagc actgaatctt ctcccagagg 1380aaggcagctg tacagtgctt ctactgaagg attattgaat cgccaatgca tttcatgtaa 1440tttcatgaaa gaacaatgta catattttga tgccagtttt agtcccatga atcaacattt 1500cttattattc tgtgaaggtc caagggtccc agtggtcagc ctacatagta cggacaaccc 1560agcaaaatat tttatattgg aaagcaattc tatgctgaag gaagctatcc tgaagaagaa 1620gataggaaag ccagaaatta aaatccttca tattgacgac tatgaacttc ctttacagtt 1680gtcccttccc aaagatttta tggaccgaaa ccagtatgct cttctgttaa taatggatga 1740agaaccagga ggccagctgg ttacagataa gttccatatt gactgggatt ccgtactcat 1800tgacatggat aatgtcattg tagcaagatt tgatggcaga ggaagtggat tccagggtct 1860gaaaattttg caggagattc atcgaagatt aggttcagta gaagtaaagg accaaataac 1920agctgtgaaa tttttgctga aactgcctta cattgactcc aaaagattaa gcatttttgg 1980aaagggttat ggtggctata ttgcatcaat gatcttaaaa tcagatgaaa agctttttaa 2040atgtggatcc gtggttgcac ctatcacaga cttgaaattg tatgcctcag ctttctctga 2100aagatacctt gggatgccat ctaaggaaga aagcacttac caggcagcca gtgtgctaca 2160taatgttcat ggcttgaaag aagaaaatat attaataatt catggaactg ctgacacaaa 2220agttcatttc caacactcag cagaattaat caagcaccta ataaaagctg gagtgaatta 2280tactatgcag gtctacccag atgaaggtca taacgtatct gagaagagca agtatcatct 2340ctacagcaca atcctcaaat tcttcagtga ttgtttgaag gaagaaatat ctgtgctacc 2400acaggaacca gaagaagatg aataatggac cgtatttata cagaactgaa gggaatattg 2460aggctcaatg aaacctgaca aagagactgt aatattgtag ttgctccaga atgtcaaggg 2520cagcttacgg agatgtcact ggagcagcac gctcagagac agtgaactag catttgaata 2580cac 2583<210>7<211>690<212>PRT<213>智人(Homo sapiens)<400>7Met Ala Ala Ala Met Glu Thr Glu Gln Leu Gly Val Glu Ile Phe Glu1 5 10 15Thr Ala Asp Cys Glu Glu Asn Ile Glu Ser Gln Asp Arg Pro Lys Leu20 25 30Glu Pro Phe Tyr Val Glu Arg Tyr Ser Trp Ser Gln Leu Lys Lys Leu35 40 45Leu Ala Asp Thr Arg Lys Tyr His Gly Tyr Met Met Ala Lys Ala Pro50 55 60His Asp Phe Met Phe Val Lys Arg Asn Asp Pro Asp Gly Pro His Ser65 70 75 80Asp Arg Ile Tyr Tyr Leu Ala Met Ser Gly Glu Asn Arg Glu Asn Thr85 90 95
Leu Phe Tyr Ser Glu Ile Pro Lys Thr Ile Asn Arg Ala Ala Val Leu100 105 110Met Leu Ser Trp Lys Pro Leu Leu Asp Leu Phe Gln Ala Thr Leu Asp115 120 125Tyr Gly Met Tyr Ser Arg Glu Glu Glu Leu Leu Arg Glu Arg Lys Arg130 135 140Ile Gly Thr Val Gly Ile Ala Ser Tyr Asp Tyr His Gln Gly Ser Gly145 150 155 160Thr Phe Leu Phe Gln Ala Gly Ser Gly Ile Tyr His Val Lys Asp Gly165 170 175Gly Pro Gln Gly Phe Thr Gln Gln Pro Leu Arg Pro Asn Leu Val Glu180 185 190Thr Ser Cys Pro Asn Ile Arg Met Asp Pro Lys Leu Cys Pro Ala Asp195 200 205Pro Asp Trp Ile Ala Phe Ile His Ser Asn Asp Ile Trp Ile Ser Asn210 215 220Ile Val Thr Arg Glu Glu Arg Arg Leu Thr Tyr Val His Asn Glu Leu225 230 235 240Ala Asn Met Glu Glu Asp Ala Arg Ser Ala Gly Val Ala Thr Phe Val245 250 255Leu Gln Glu Glu Phe Asp Arg Tyr Ser Gly Tyr Trp Trp Cys Pro Lys260 265 270Ala Glu Thr Thr Pro Ser Gly Gly Lys Ile Leu Arg Ile Leu Tyr Glu275 280 285Glu Asn Asp Glu Ser Glu Val Glu Ile Ile His Val Thr Ser Pro Met290 295 300Leu Glu Thr Arg Arg Ala Asp Ser Phe Arg Tyr Pro Lys Thr Gly Thr305 310 315 320Ala Asn Pro Lys Val Thr Phe Lys Met Ser Glu Ile Met Ile Asp Ala325 330 335Glu Gly Arg Ile Ile Asp Val Ile Asp Lys Glu Leu Ile Gln Pro Phe340 345 350Glu Ile Leu Phe Glu Gly Val Glu Tyr Ile Ala Arg Ala Gly Trp Thr355 360 365Pro Glu Gly Lys Tyr Ala Trp Ser Ile Leu Leu Asp Arg Ser Gln Thr370 375 380Arg Leu Gln Ile Val Leu Ile Ser Pro Glu Leu Phe Ile Pro Val Glu385 390 395 400Asp Asp Val Met Glu Arg Gln Arg Leu Ile Glu Ser Val Pro Asp Ser405 410 415Val Thr Pro Leu Ile Ile Tyr Glu Glu Thr Thr Asp Ile Trp Ile Asn420 425 430Ile His Asp Ile Phe His Val Phe Pro Gln Ser His Glu Glu Glu Ile435 440 445Glu Phe Ile Phe Ala Ser Glu Cys Lys Thr Gly Phe Arg His Leu Tyr450 455 460Lys Ile Thr Ser Ile Leu Lys Glu Ser Lys Tyr Lys Arg Ser Ser Gly465 470 475 480Gly Leu Pro Ala Pro Ser Asp Phe Lys Cys Pro Ile Lys Glu Glu Ile485 490 495Ala Ile Thr Ser Gly Glu Trp Glu Val Leu Gly Arg His Gly Ser Asn500 505 510Ile Gln Val Asp Glu Val Arg Arg Leu Val Tyr Phe Glu Gly Thr Lys515 520 525Asp Ser Pro Leu Glu His His Leu Tyr Val Val Ser Tyr Val Asn Pro530 535 540Gly Glu Val Thr Arg Leu Thr Asp Arg Gly Tyr Ser His Ser Cys Cys545 550 555 560Ile Ser Gln His Cys Asp Phe Phe Ile Ser Lys Tyr Ser Asn Gln Lys565 570 575
Asn Pro His Cys Val Ser Leu Tyr Lys Leu Ser Ser Pro Glu Asp Asp580 585 590Pro Thr Cys Lys Thr Lys Glu Phe Trp Ala Thr Ile Leu Asp Ser Ala595 600 605Gly Pro Leu Pro Asp Tyr Thr Pro Pro Glu Ile Phe Ser Phe Glu Ser610 615 620Thr Thr Gly Phe Thr Leu Tyr Gly Met Leu Tyr Lys Pro His Asp Leu625 630 635 640Gin Pro Gly Lys Lys Tyr Pro Thr Val Leu Phe Ile Tyr Gly Gly Arg645 650 655Leu Leu Leu Leu Gly Pro Gln Ser Leu Cys Gly Ser Ser Met Ile Gln660 665 670Asp Thr Arg Asn Val Ile Trp Val Thr Leu Thr Arg Met Asn Arg Ala675 680 685Ile Thr690<210>8<211>4523<212>DNA<213>智人(Homo sapiens)<400>8aagtgctaaa gcctccgagg ccaaggccgc tgctactgcc gccgctgctt cttagtgccg 60cgttcgccgc ctgggttgtc accggcgccg ccgccgagga agccactgca accaggaccg120gagtggaggc ggcgcagcat gaagcggcgc aggcccgctc catagcgcac gtcgggacgg180tccgggcggg gccgggggga aggaaaatgc aacatggcag cagcaatgga aacagaacag240ctgggtgttg agatatttga aactgcggac tgtgaggaga atattgaatc acaggatcgg300cctaaattgg agccttttta tgttgagcgg tattcctgga gtcagcttaa aaagctgctt360gccgatacca gaaaatatca tggctacatg atggctaagg caccacatga tttcatgttt420gtgaagagga atgatccaga tggacctcat tcagacagaa tctattacct tgccatgtct480ggtgagaaca gagaaaatac actgttttat tctgaaattc ccaaaactat caatagagca540gcagtcttaa tgctctcttg gaagcctctt ttggatcttt ttcaggcaac actggactat600ggaatgtatt ctcgagaaga agaactatta agagaaagaa aacgcattgg aacagtcgga660attgcttctt acgattatca ccaaggaagt ggaacatttc tgtttcaagc cggtagtgga720atttatcacg taaaagatgg agggccacaa ggatttacgc aacaaccttt aaggcccaat780ctagtggaaa ctagttgtcc caacatacgg atggatccaa aattatgccc tgctgatcca840gactggattg cttttataca tagcaacgat atttggatat ctaacatcgt aaccagagaa900gaaaggagac tcacttatgt gcacaatgag ctagccaaca tggaagaaga tgccagatca960gctggagtcg ctacctttgt tctccaagaa gaatttgata gatattctgg ctattggtgg 1020tgtccaaaag ctgaaacaac tcccagtggt ggtaaaattc ttagaattct atatgaagaa 1080aatgatgaat ctgaggtgga aattattcat gttacatccc ctatgttgga aacaaggagg 1140gcagattcat tccgttatcc taaaacaggt acagcaaatc ctaaagtcac ttttaagatg 1200tcagaaataa tgattgatgc tgaaggaagg atcatagatg tcatagataa ggaactaatt 1260caaccttttg agattctatt tgaaggagtt gaatatattg ccagagctgg atggactcct 1320gagggaaaat atgcttggtc catcctacta gatcgctccc agactcgcct acagatagtg 1380ttgatctcac ctgaattatt tatcccagta gaagatgatg ttatggaaag gcagagactc 1440attgagtcag tgcctgattc tgtgacgcca ctaattatct atgaagaaac aacagacatc 1500tggataaata tccatgacat ctttcatgtt tttccccaaa gtcacgaaga ggaaattgag 1560tttatttttg cctctgaatg caaaacaggt ttccgtcatt tatacaaaat tacatctatt 1620ttaaaggaaa gcaaatataa acgatccagt ggtgggctgc ctgctccaag tgatttcaag 1680tgtcctatca aagaggagat agcaattacc agtggtgaat gggaagttct tggccggcat 1740ggatctaata tccaagttga tgaagtcaga aggctggtat attttgaagg caccaaagac 1800tcccctttag agcatcacct gtacgtagtc agttacgtaa atcctggaga ggtgacaagg 1860ctgactgacc gtggctactc acattcttgc tgcatcagtc agcactgtga cttctttata 1920agtaagtata gtaaccagaa gaatccacac tgtgtgtccc tttacaagct atcaagtcct 1980gaagatgacc caacttgcaa aacaaaggaa ttttgggcca ccattttgga ttcagcaggt 2040cctcttcctg actatactcc tccagaaatt ttctcttttg aaagtactac tggatttaca 2100ttgtatggga tgctctacaa gcctcatgat ctacagcctg gaaagaaata tcctactgtg 2160
ctgttcatat atggtggtcg gttgctattg ctggggcccc agtcactctg tggatcttct 2220atgatacagg atacacggaa cgttatatgg gtcaccctga ccagaatgaa cagggctatt 2280acttaggatc tgtggccatg caagcagaaa agttcccctc tgaaccaaat cgtttactgc 2340tcttacatgg tttcctggat gagaatgtcc attttgcaca taccagtata ttactgagtt 2400ttttagtgag ggctggaaag ccatatgatt tacagatcta tcctcaggag agacacagca 2460taagagttcc tgaatcggga gaacattatg aactgcatct tttgcactac cttcaagaaa 2520accttggatc acgtattgct gctctaaaag tgatataatt ttgacctgtg tagaactctc 2580tggtatacac tggctattta accaaatgag gaggtttaat caacagaaaa cacagaattg 2640atcatcacat tttgatacct gccatgtaac atctactcct gaaaataaat gtggtgccat 2700gcaggggtct acggtttgtg gtagtaatct aataccttaa ccccacatgc tcaaaatcaa 2760atgatacata ttcctgagag acccagcaat accataagaa ttactaaaaa aaaaaaaaaa 2820aaaaagacat tagcaccatg tattcatact accctatttt cacttttaat agtattataa 2880acttcatgaa cttaattagt gtatttttac agtatacttt tgagtttgtt aaaatatgat 2940gatattagtg attggtttgg ttcagttcca gaatctttga ctagttacag atttgatagc 3000acttaaatgt aattgaatag cttatgcttc attgcttggg catatccagc atgttatgaa 3060ctaataacta ttaaacttga cttaaccagt cattcattaa taatttttca aggataactt 3120agtggcctcc taaagacact tgttttggca ctgaccagtt tttagccaat ttaatctgta 3180tctagtataa ataattctca tttttctttg atgatattaa cagagtgggc ttttcctttt 3240gcataaaggc tagtaactgt atatgtagca tggatttaat tagtcatgat attgataatt 3300acaggcagaa aatttttaat caaatgatta gagcttaaat atttgcaggc aagttttttt 3360ttttccttta agaaaaggaa aaagtacaca ttcactagaa ttcttcagaa aatttagtgg 3420tgccagtttc catttggtat ttccttatta aaatattcta gaattttaag gagattgaag 3480ggaatcacag tggggtgggg agacctgggt ttggggaatg acagagagaa gaggtggtga 3540gggcctgatt aaaaactaag cagaagtagt tttaacaaaa atactcatga aaatgtttgg 3600aaactgaaat ttaaacaact gtaatattaa ggaaaccaga atcaataaat cactgtcttg 3660ccagcacagc tacagagtaa catgattcag gggaggaaaa gttccttaga gttactttta 3720taattctttt tttttttcct cttaggttta gaaatcttac aaatttaaac tttatccttt 3780taaaattatt tgaacataat ttagatattg taagcttaaa atacaaatgt ttatagataa 3840cctctttacc ataaactaat ccctggcaag ccatggctct cttttttttt ttggtgttta 3900aagcctgtaa acagtttttc tgaatgatca tgaacttttc ttggtttagc actaggattt 3960agctatgaag agagctcata ggctttcagg tgctaattga gatctgccct gttagagtct 4020tggggtgcta gattggtcac attgacacca gtggcaggga aggcatctat gagtttgatg 4080ctttttatca cacacttcag tgtttagaaa gttattacca atacttttaa acaacactcc 4140aagaaaattt gctatatttc tttctcatca ctacagagag agtagatttc cccatagaga 4200gcacagcctc cattagtaag gttggtgact attggtaaga ggtggacttc attgacacca 4260agtgggaggt agggaaagcc cagaaatggc aggatgatat ggtggttctg tcgttgggaa 4320aggtattggg ttttgctgtt tgtatttata ctgtataata gataccacgc tttttcttat 4380tatctgtata tgtattgctt ttcatgtttg atattttccc atgccaagat ttgtttatat 4440atattttcaa tgttaaatta aattgatttg ggtaactttc ttccccaaga aagtattttc 4500ccccttaagt ataaatctga ctg 4523<210>9<211>241<212>PRT<213>智人(Homo sapiens)<400>9Met Ala Ala Ala Met Glu Thr Glu Gln Leu Gly Val Glu Ile Phe Glu1 5 10 15Thr Ala Asp Cys Glu Glu Asn Ile Glu Ser Gln Asp Arg Pro Lys Leu20 25 30Glu Pro Phe Tyr Val Glu Arg Tyr Ser Trp Ser Gln Leu Lys Lys Leu35 40 45Leu Ala Asp Thr Arg Lys Tyr His Gly Tyr Met Met Ala Lys Ala Pro50 55 60His Asp Phe Met Phe Val Lys Arg Asn Asp Pro Asp Gly Pro His Ser65 70 75 80Asp Arg Ile Tyr Tyr Leu Ala Met Ser Gly Glu Asn Arg Glu Asn Thr85 90 95Leu Phe Tyr Ser Glu Ile Pro Lys Thr Ile Asn Arg Ala Ala Val Leu
100 105 110Met Leu Ser Trp Lys Pro Leu Leu Asp Leu Phe Gln Ala Thr Leu Asp115 120 125Tyr Gly Met Tyr Ser Arg Glu Glu Glu Leu Leu Arg Glu Arg Lys Arg130 135 140Ile Gly Thr Val Gly Ile Ala Ser Tyr Asp Tyr His Gln Gly Ser Gly145 150 155 160Thr Phe Leu Phe Gln Ala Gly Ser Gly Ile Tyr His Val Lys Asp Gly165 170 175Gly Pro Gln Gly Phe Thr Gln Gln Pro Leu Arg Pro Asn Leu Val Glu180 185 190Thr Ser Cys Pro Asn Ile Arg Met Asp Pro Lys Leu Cys Pro Ala Asp195 200 205Pro Asp Trp Ile Ala Phe Ile His Ser Asn Asp Ile Trp Ile Ser Asn210 215 220Ile Val Thr Arg Glu Glu Arg Arg Leu Thr Tyr Val His Asn Gly Lys225 230 235 240Ala<210>10<211>1356<212>DNA<213>智人(Homo sapiens)<400>10aagtgctaaa gcctccgagg ccaaggccgc tgctactgcc gccgctgctt cttagtgccg 60cgttcgccgc ctgggttgtc accggcgccg ccgccgagga agccactgca accaggaccg120gagtggaggc ggcgcagcat gaagcggcgc aggcccgctc catagcgcac gtcgggacgg180tccgggcggg gccgggggga aggaaaatgc aacatggcag cagcaatgga aacagaacag240ctgggtgttg agatatttga aactgcggac tgtgaggaga atattgaatc acaggatcgg300cctaaattgg agccttttta tgttgagcgg tattcctgga gtcagcttaa aaagctgctt360gccgatacca gaaaatatca tggctacatg atggctaagg caccacatga tttcatgttt420gtgaagagga atgatccaga tggacctcat tcagacagaa tctattacct tgccatgtct480ggtgagaaca gagaaaatac actgttttat tctgaaattc ccaaaactat caatagagca540gcagtcttaa tgctctcttg gaagcctctt ttggatcttt ttcaggcaac actggactat600ggaatgtatt ctcgagaaga agaactatta agagaaagaa aacgcattgg aacagtcgga660attgcttctt acgattatca ccaaggaagt ggaacatttc tgtttcaagc cggtagtgga720atttatcacg taaaagatgg agggccacaa ggatttacgc aacaaccttt aaggcccaat780ctagtggaaa ctagttgtcc caacatacgg atggatccaa aattatgccc tgctgatcca840gactggattg cttttataca tagcaacgat atttggatat ctaacatcgt aaccagagaa900gaaaggagac tcacttatgt gcacaatggt aaggcgtagt tcttcagatt tacttttctg960aacagtattt tttgaagtat aatttgctgc ttgcattttg aaattagatt accacgttgg 1020gtgatcttta tatttgaaat tcaagtcttt aaaattttta aaaaatggag aaaagtacag 1080aggataactt gtatgtacca catgtataat attcatttta atgttttaat gttcattttc 1140aaacagtgaa acaaaagaac ctctgacatg attgttcttt tagcttgcta agactgccag 1200aattttccca aaactgttct tattaaaata aaattttagg ctaggcatgg tggctcatgc 1260ctgtaatcct agcactctgg gaggctgagg caggcagatt gtttgagccc agaagttcaa 1320gatcaggatg ggcaacatgg tgacacctcg tttgac 1356<210>11<211>661<212>PRT<213>智人(Homo sapiens)<400>11Met Ala Ala Ala Met Glu Thr Glu Gln Leu Gly Val Glu Ile Phe Glu1 5 10 15Thr Ala Asp Cys Glu Glu Asn Ile Glu Sar Gln Asp Arg Pro Lys Leu20 25 30Glu Pro Phe Tyr Val Glu Arg Tyr Ser Trp Ser Gln Leu Lys Lys Leu
35 40 45Leu Ala Asp Thr Arg Lys Tyr His Gly Tyr Met Met Ala Lys Ala Pro50 55 60His Asp Phe Met Phe Val Lys Arg Asn Asp Pro Asp Gly Pro His Ser65 70 75 80Asp Arg Ile Tyr Tyr Leu Ala Met Ser Gly Glu Asn Arg Glu Asn Thr85 90 95Leu Phe Tyr Ser Glu Ile Pro Lys Thr Ile Asn Arg Ala Ala Val Leu100 105 110Met Leu Ser Trp Lys Pro Leu Leu Asp Leu Phe Gln Ala Thr Leu Asp115 120 125Tyr Gly Met Tyr Ser Arg Glu Glu Glu Leu Leu Arg Glu Arg Lys Arg130 135 140Ile Gly Thr Val Gly Ile Ala Ser Tyr Asp Tyr His Gln Gly Ser Gly145 150 155 160Thr Phe Leu Phe Gln Ala Gly Ser Gly Ile Tyr His Val Lys Asp Gly165 170 175Gly Pro Gln Gly Phe Thr Gln Gln Pro Leu Arg Pro Asn Leu Val Glu180 185 190Thr Ser Cys Pro Asn Ile Arg Met Asp Pro Lys Leu Cys Pro Ala Asp195 200 205Pro Asp Trp Ile Ala Phe Ile His Ser Asn Asp Ile Trp Ile Ser Asn210 215 220Ile Val Thr Arg Glu Glu Arg Arg Leu Thr Tyr Val His Asn Glu Leu225 230 235 240Ala Asn Met Glu Glu Asp Ala Arg Ser Ala Gly Val Ala Thr Phe Val245 250 255Leu Gln Glu Glu Phe Asp Arg Tyr Ser Gly Tyr Trp Trp Cys Pro Lys260 265 270Ala Glu Thr Thr Pro Ser Gly Gly Lys Ile Leu Arg Ile Leu Tyr Glu275 280 285Glu Asn Asp Glu Sar Glu Val Glu Ile Ile His Val Thr Ser Pro Met290 295 300Leu Glu Thr Arg Arg Ala Asp Ser Phe Arg Tyr Pro Lys Thr Gly Thr305 310 315 320Ala Asn Pro Lys Val Thr Phe Lys Met Ser Glu Ile Met Ile Asp Ala325 330 335Glu Gly Arg Ile Ile Asp Val Ile Asp Lys Glu Leu Ile Gln Pro Phe340 345 350Glu Ile Leu Phe Glu Gly Val Glu Tyr Ile Ala Arg Ala Gly Trp Thr355 360 365Pro Glu Gly Lys Tyr Ala Trp Ser Ile Leu Leu Asp Arg Ser Gln Thr370 375 380Arg Leu Gln Ile Val Leu Ile Ser Pro Glu Leu Phe Ile Pro Val Glu385 390 395 400Asp Asp Val Met Glu Arg Gln Arg Leu Ile Glu Ser Val Pro Asp Ser405 410 415Val Thr Pro Leu Ile Ile Tyr Glu Glu Thr Thr Asp Ile Trp Ile Asn420 425 430Ile His Asp Ile Phe His Val Phe Pro Gln Ser His Glu Glu Glu Ile435 440 445Glu Phe Ile Phe Ala Ser Glu Cys Lys Thr Gly Phe Arg His Leu Tyr450 455 460Lys Ile Thr Ser Ile Leu Lys Glu Ser Lys Tyr Lys Arg Ser Ser Gly465 470 475 480Gly Leu Pro Ala Pro Ser Asp Phe Lys Cys Pro Ile Lys Glu Glu Ile485 490 495Ala Ile Thr Ser Gly Glu Trp Glu Val Leu Gly Arg His Gly Ser Asn500 505 510Ile Gln Val Asp Glu Val Arg Arg Leu Val Tyr Phe Glu Gly Thr Lys
515 520 525Asp Ser Pro Leu Glu His His Leu Tyr Val Val Ser Tyr Val Asn Pro530 535 540Gly Glu Val Thr Arg Leu Thr Asp Arg Gly Tyr Ser His Ser Cys Cys545 550 555 560Ile Ser Gln His Cys Asp Phe Phe Ile Ser Lys Tyr Ser Asn Gln Lys565 570 575Asn Pro His Cys Val Ser Leu Tyr Lys Leu Ser Ser Pro Glu Asp Asp580 585 590Pro Thr Cys Lys Thr Lys Glu Phe Trp Ala Thr Ile Leu Asp Ser Ala595 600 605Gly Pro Leu Pro Asp Tyr Thr Pro Pro Glu Ile Phe Ser Phe Glu Ser610 615 620Thr Thr Gly Phe Thr Leu Tyr Gly Met Leu Tyr Lys Pro His Asp Leu625 630 635 640Gln Pro Gly Lys Lys Tyr Pro Thr Val Leu Phe Ile Tyr Gly Gly Leu645 650 655Leu Arg Cys Ser Trp660<210>12<211>4829<212>DNA<213>智人(Homo sapiens)<400>12aagtgctaaa gcctccgagg ccaaggccgc tgctactgcc gccgctgctt cttagtgccg 60cgttcgccgc ctgggttgtc accggcgccg ccgccgagga agccactgca accaggaccg120gagtggaggc ggcgcagcat gaagcggcgc aggcccgctc catagcgcac gtcgggacgg180tccgggcggg gccgggggga aggaaaatgc aacatggcag cagcaatgga aacagaacag240ctgggtgttg agatatttga aactgcggac tgtgaggaga atattgaatc acaggatcgg300cctaaattgg agccttttta tgttgagcgg tattcctgga gtcagcttaa aaagctgctt360gccgatacca gaaaatatca tggctacatg atggctaagg caccacatga tttcatgttt420gtgaagagga atgatccaga tggacctcat tcagacagaa tctattacct tgccatgtct480ggtgagaaca gagaaaatac actgttttat tctgaaattc ccaaaactat caatagagca540gcagtcttaa tgctctcttg gaagcctctt ttggatcttt ttcaggcaac actggactat600ggaatgtatt ctcgagaaga agaactatta agagaaagaa aacgcattgg aacagtcgga660attgcttctt acgattatca ccaaggaagt ggaacatttc tgtttcaagc cggtagtgga720atttatcacg taaaagatgg agggccacaa ggatttacgc aacaaccttt aaggcccaat780ctagtggaaa ctagttgtcc caacatacgg atggatccaa aattatgccc tgctgatcca840gactggattg cttttataca tagcaacgat atttggatat ctaacatcgt aaccagagaa900gaaaggagac tcacttatgt gcacaatgag ctagccaaca tggaagaaga tgccagatca960gctggagtcg ctacctttgt tctccaagaa gaatttgata gatattctgg ctattggtgg 1020tgtccaaaag ctgaaacaac tcccagtggt ggtaaaattc ttagaattct atatgaagaa 1080aatgatgaat ctgaggtgga aattattcat gttacatccc ctatgttgga aacaaggagg 1140gcagattcat tccgttatcc taaaacaggt acagcaaatc ctaaagtcac ttttaagatg 1200tcagaaataa tgattgatgc tgaaggaagg atcatagatg tcatagataa ggaactaatt 1260caaccttttg agattctatt tgaaggagtt gaatatattg ccagagctgg atggactcct 1320gagggaaaat atgcttggtc catcctacta gatcgctccc agactcgcct acagatagtg 1380ttgatctcac ctgaattatt tatcccagta gaagatgatg ttatggaaag gcagagactc 1440attgagtcag tgcctgattc tgtgacgcca ctaattatct atgaagaaac aacagacatc 1500tggataaata tccatgacat ctttcatgtt tttccccaaa gtcacgaaga ggaaattgag 1560tttatttttg cctctgaatg caaaacaggt ttccgtcatt tatacaaaat tacatctatt 1620ttaaaggaaa gcaaatataa acgatccagt ggtgggctgc ctgctccaag tgatttcaag 1680tgtcctatca aagaggagat agcaattacc agtggtgaat gggaagttct tggccggcat 1740ggatctaata tccaagttga tgaagtcaga aggctggtat attttgaagg caccaaagac 1800tcccctttag agcatcacct gtacgtagtc agttacgtaa atcctggaga ggtgacaagg 1860ctgactgacc gtggctactc acattcttgc tgcatcagtc agcactgtga cttctttata 1920agtaagtata gtaaccagaa gaatccacac tgtgtgtccc tttacaagct atcaagtcct 1980gaagatgacc caacttgcaa aacaaaggaa ttttgggcca ccattttgga ttcagcaggt 2040
cctcttcctg actatactcc tccagaaatt ttctcttttg aaagtactac tggatttaca 2100ttgtatggga tgctctacaa gcctcatgat ctacagcctg gaaagaaata tcctactgtg 2160ctgttcatat atggtggtct cctcaggtgc agttggtgaa taatcggttt aaaggagtca 2220agtatttccg cttgaatacc ctagcctctc taggttatgt ggttgtagtg atagacaaca 2280ggggatcctg tcaccgaggg cttaaatttg aaggcgcctt taaatataaa atgggtcaaa 2340tagaaattga cgatcaggtg gaaggactcc aatatctagc ttctcgatat gatttcattg 2400acttagatcg tgtgggcatc cacggctggt cctatggagg atacctctcc ctgatggcat 2460taatgcagag gtcagatatc ttcagggttg ctattgctgg ggccccagtc actctgtgga 2520tcttctatga tacaggatac acggaacgtt atatgggtca ccctgaccag aatgaacagg 2580gctattactt aggatctgtg gccatgcaag cagaaaagtt cccctctgaa ccaaatcgtt 2640tactgctctt acatggtttc ctggatgaga atgtccattt tgcacatacc agtatattac 2700tgagtttttt agtgagggct ggaaagccat atgatttaca gatctatcct caggagagac 2760acagcataag agttcctgaa tcgggagaac attatgaact gcatcttttg cactaccttc 2820aagaaaacct tggatcacgt attgctgctc taaaagtgat ataattttga cctgtgtaga 2880actctctggt atacactggc tatttaacca aatgaggagg tttaatcaac agaaaacaca 2940gaattgatca tcacattttg atacctgcca tgtaacatct actcctgaaa ataaatgtgg 3000tgccatgcag gggtctacgg tttgtggtag taatctaata ccttaacccc acatgctcaa 3060aatcaaatga tacatattcc tgagagaccc agcaatacca taagaattac taaaaaaaaa 3120aaaaaaaaaa agacattagc accatgtatt catactaccc tattttcact tttaatagta 3180ttataaactt catgaactta attagtgtat ttttacagta tacttttgag tttgttaaaa 3240tatgatgata ttagtgattg gtttggttca gttccagaat ctttgactag ttacagattt 3300gatagcactt aaatgtaatt gaatagctta tgcttcattg cttgggcata tccagcatgt 3360tatgaactaa taactattaa acttgactta accagtcatt cattaataat ttttcaagga 3420taacttagtg gcctcctaaa gacacttgtt ttggcactga ccagttttta gccaatttaa 3480tctgtatcta gtataaataa ttctcatttt tctttgatga tattaacaga gtgggctttt 3540ccttttgcat aaaggctagt aactgtatat gtagcatgga tttaattagt catgatattg 3600ataattacag gcagaaaatt tttaatcaaa tgattagagc ttaaatattt gcaggcaagt 3660tttttttttt cctttaagaa aaggaaaaag tacacattca ctagaattct tcagaaaatt 3720tagtggtgcc agtttccatt tggtatttcc ttattaaaat attctagaat tttaaggaga 3780ttgaagggaa tcacagtggg gtggggagac ctgggtttgg ggaatgacag agagaagagg 3840tggtgagggc ctgattaaaa actaagcaga agtagtttta acaaaaatac tcatgaaaat 3900gtttggaaac tgaaatttaa acaactgtaa tattaaggaa accagaatca ataaatcact 3960gtcttgccag cacagctaca gagtaacatg attcagggga ggaaaagttc cttagagtta 4020cttttataat tctttttttt tttcctctta ggtttagaaa tcttacaaat ttaaacttta 4080tccttttaaa attatttgaa cataatttag atattgtaag cttaaaatac aaatgtttat 4140agataacctc tttaccataa actaatccct ggcaagccat ggctctcttt ttttttttgg 4200tgtttaaagc ctgtaaacag tttttctgaa tgatcatgaa cttttcttgg tttagcacta 4260ggatttagct atgaagagag ctcataggct ttcaggtgct aattgagatc tgccctgtta 4320gagtcttggg gtgctagatt ggtcacattg acaccagtgg cagggaaggc atctatgagt 4360ttgatgcttt ttatcacaca cttcagtgtt tagaaagtta ttaccaatac ttttaaacaa 4440cactccaaga aaatttgcta tatttctttc tcatcactac agagagagta gatttcccca 4500tagagagcac agcctccatt agtaaggttg gtgactattg gtaagaggtg gacttcattg 4560acaccaagtg ggaggtaggg aaagcccaga aatggcagga tgatatggtg gttctgtcgt 4620tgggaaaggt attgggtttt gctgtttgta tttatactgt ataatagata ccacgctttt 4680tcttattatc tgtatatgta ttgcttttca tgtttgatat tttcccatgc caagatttgt 4740ttatatatat tttcaatgtt aaattaaatt gatttgggta actttcttcc ccaagaaagt 4800attttccccc ttaagtataa atctgactg 4829<210>13<211>358<212>PRT<213>智人(Homo sapiens)<400>13Met Ala Ala Ala Met Glu Thr Glu Gln Leu Gly Val Glu Ile Phe Glu1 5 10 15Thr Ala Asp Cys Glu Glu Asn Ile Glu Ser Gln Asp Arg Pro Lys Leu20 25 30Glu Pro Phe Tyr Val Glu Arg Tyr Ser Trp Ser Gln Leu Lys Lys Leu35 40 45
Leu Ala Asp Thr Arg Lys Tyr His Gly Tyr Met Met Ala Lys Ala Pro50 55 60His Asp Phe Met Phe Val Lys Arg Asn Asp Pro Asp Gly Pro His Ser65 70 75 80Asp Arg Ile Tyr Tyr Leu Ala Met Ser Gly Glu Asn Arg Glu Asn Thr85 90 95Leu Phe Tyr Ser Glu Ile Pro Lys Thr Ile Asn Arg Ala Ala Val Leu100 105 110Met Leu Ser Trp Lys Pro Leu Leu Asp Leu Phe Gln Ala Thr Leu Asp115 120 125Tyr Gly Met Tyr Ser Arg Glu Glu Glu Leu Leu Arg Glu Arg Lys Arg130 135 140Ile Gly Thr Val Gly Ile Ala Ser Tyr Asp Tyr His Gln Gly Ser Gly145 150 155 160Thr Phe Leu Phe Gln Ala Gly Ser Gly Ile Tyr His Val Lys Asp Gly165 170 175Gly Pro Gln Gly Phe Thr Gln Gln Pro Leu Arg Pro Asn Leu Val Glu180 185 190Thr Ser Cys Pro Asn Ile Arg Met Asp Pro Lys Leu Cys Pro Ala Asp195 200 205Pro Asp Trp Ile Ala Phe Ile His Ser Asn Asp Ile Trp Ile Ser Asn210 215 220Ile Val Thr Arg Glu Glu Arg Arg Leu Thr Tyr Val His Asn Glu Leu225 230 235 240Ala Asn Met Glu Glu Asp Ala Arg Ser Ala Gly Val Ala Thr Phe Val245 250 255Leu Gln Glu Glu Phe Asp Arg Tyr Ser Gly Tyr Trp Trp Cys Pro Lys260 265 270Ala Glu Thr Thr Pro Ser Gly Gly Lys Ile Leu Arg Ile Leu Tyr Glu275 280 285Glu Asn Asp Glu Ser Glu Val Glu Ile Ile His Val Thr Ser Pro Met290 295 300Leu Glu Thr Arg Arg Ala Asp Ser Phe Arg Tyr Pro Lys Thr Gly Thr305 310 315 320Ala Asn Pro Lys Val Thr Phe Lys Met Ser Glu Ile Met Ile Asp Ala325 330 335Glu Gly Arg Ser Lys Leu Met Lys Ser Glu Gly Trp Tyr Ile Leu Lys340 345 350Ala Pro Lys Thr Pro Leu355<210>14<211>4309<212>DNA<213>智人(Homo sapiens)<400>14aagtgctaaa gcctccgagg ccaaggccgc tgctactgcc gccgctgctt cttagtgccg 60cgttcgccgc ctgggttgtc accggcgccg ccgccgagga agccactgca accaggaccg120gagtggaggc ggcgcagcat gaagcggcgc aggcccgctc catagcgcac gtcgggacgg180tccgggcggg gccgggggga aggaaaatgc aacatggcag cagcaatgga aacagaacag240ctgggtgttg agatatttga aactgcggac tgtgaggaga atattgaatc acaggatcgg300cctaaattgg agccttttta tgttgagcgg tattcctgga gtcagcttaa aaagctgctt360gccgatacca gaaaatatca tggctacatg atggctaagg caccacatga tttcatgttt420gtgaagagga atgatccaga tggacctcat tcagacagaa tctattacct tgccatgtct480ggtgagaaca gagaaaatac actgttttat tctgaaattc ccaaaactat caatagagca540gcagtcttaa tgctctcttg gaagcctctt ttggatcttt ttcaggcaac actggactat600ggaatgtatt ctcgagaaga agaactatta agagaaagaa aacgcattgg aacagtcgga660attgcttctt acgattatca ccaaggaagt ggaacatttc tgtttcaagc cggtagtgga720atttatcacg taaaagatgg agggccacaa ggatttacgc aacaaccttt aaggcccaat780
ctagtggaaa ctagttgtcc caacatacgg atggatccaa aattatgccc tgctgatcca840gactggattg cttttataca tagcaacgat atttggatat ctaacatcgt aaccagagaa900gaaaggagac tcacttatgt gcacaatgag ctagccaaca tggaagaaga tgccagatca960gctggagtcg ctacctttgt tctccaagaa gaatttgata gatattctgg ctattggtgg 1020tgtccaaaag ctgaaacaac tcccagtggt ggtaaaattc ttagaattct atatgaagaa 1080aatgatgaat ctgaggtgga aattattcat gttacatccc ctatgttgga aacaaggagg 1140gcagattcat tccgttatcc taaaacaggt acagcaaatc ctaaagtcac ttttaagatg 1200tcagaaataa tgattgatgc tgaaggaaga tccaagttga tgaagtcaga aggctggtat 1260attttgaagg caccaaagac tcccctttag agcatcacct gtacgtagtc agttacgtaa 1320atcctggaga ggtgacaagg ctgactgacc gtggctactc acattcttgc tgcatcagtc 1380agcactgtga cttctttata agtaagtata gtaaccagaa gaatccacac tgtgtgtccc 1440tttacaagct atcaagtcct gaagatgacc caacttgcaa aacaaaggaa ttttgggcca 1500ccattttgga ttcagcaggt cctcttcctg actatactcc tccagaaatt ttctcttttg 1560aaagtactac tggatttaca ttgtatggga tgctctacaa gcctcatgat ctacagcctg 1620gaaagaaata tcctactgtg ctgttcatat atggtggtct cctcaggtgc agttggtgaa 1680taatcggttt aaaggagtca agtatttccg cttgaatacc ctagcctctc taggttatgt 1740ggttgtagtg atagacaaca ggggatcctg tcaccgaggg cttaaatttg aaggcgcctt 1800taaatataaa atgggtcaaa tagaaattga cgatcaggtg gaaggactcc aatatctagc 1860ttctcgatat gatttcattg acttagatcg tgtgggcatc cacggctggt cctatggagg 1920atacctctcc ctgatggcat taatgcagag gtcagatatc ttcagggttg ctattgctgg 1980ggccccagtc actctgtgga tcttctatga tacaggatac acggaacgtt atatgggtca 2040ccctgaccag aatgaacagg gctattactt aggatctgtg gccatgcaag cagaaaagtt 2100cccctctgaa ccaaatcgtt tactgctctt acatggtttc ctggatgaga atgtccattt 2160tgcacatacc agtatattac tgagtttttt agtgagggct ggaaagccat atgatttaca 2220gatctatcct caggagagac acagcataag agttcctgaa tcgggagaac attatgaact 2280gcatcttttg cactaccttc aagaaaacct tggatcacgt attgctgctc taaaagtgat 2340ataattttga cctgtgtaga actctctggt atacactggc tatttaacca aatgaggagg 2400tttaatcaac agaaaacaca gaattgatca tcacattttg atacctgcca tgtaacatct 2460actcctgaaa ataaatgtgg tgccatgcag gggtctacgg tttgtggtag taatctaata 2520ccttaacccc acatgctcaa aatcaaatga tacatattcc tgagagaccc agcaatacca 2580taagaattac taaaaaaaaa aaaaaaaaaa agacattagc accatgtatt catactaccc 2640tattttcact tttaatagta ttataaactt catgaactta attagtgtat ttttacagta 2700tacttttgag tttgttaaaa tatgatgata ttagtgattg gtttggttca gttccagaat 2760ctttgactag ttacagattt gatagcactt aaatgtaatt gaatagctta tgcttcattg 2820cttgggcata tccagcatgt tatgaactaa taactattaa acttgactta accagtcatt 2880cattaataat ttttcaagga taacttagtg gcctcctaaa gacacttgtt ttggcactga 2940ccagttttta gccaatttaa tctgtatcta gtataaataa ttctcatttt tctttgatga 3000tattaacaga gtgggctttt ccttttgcat aaaggctagt aactgtatat gtagcatgga 3060tttaattagt catgatattg ataattacag gcagaaaatt tttaatcaaa tgattagagc 3120ttaaatattt gcaggcaagt tttttttttt cctttaagaa aaggaaaaag tacacattca 3180ctagaattct tcagaaaatt tagtggtgcc agtttccatt tggtatttcc ttattaaaat 3240attctagaat tttaaggaga ttgaagggaa tcacagtggg gtggggagac ctgggtttgg 3300ggaatgacag agagaagagg tggtgagggc ctgattaaaa actaagcaga agtagtttta 3360acaaaaatac tcatgaaaat gtttggaaac tgaaatttaa acaactgtaa tattaaggaa 3420accagaatca ataaatcact gtcttgccag cacagctaca gagtaacatg attcagggga 3480ggaaaagttc cttagagtta cttttataat tctttttttt tttcctctta ggtttagaaa 3540tcttacaaat ttaaacttta tccttttaaa attatttgaa cataatttag atattgtaag 3600cttaaaatac aaatgtttat agataacctc tttaccataa actaatccct ggcaagccat 3660ggctctcttt ttttttttgg tgtttaaagc ctgtaaacag tttttctgaa tgatcatgaa 3720cttttcttgg tttagcacta ggatttagct atgaagagag ctcataggct ttcaggtgct 3780aattgagatc tgccctgtta gagtcttggg gtgctagatt ggtcacattg acaccagtgg 3840cagggaaggc atctatgagt ttgatgcttt ttatcacaca cttcagtgtt tagaaagtta 3900ttaccaatac ttttaaacaa cactccaaga aaatttgcta tatttctttc tcatcactac 3960agagagagta gatttcccca tagagagcac agcctccatt agtaaggttg gtgactattg 4020gtaagaggtg gacttcattg acaccaagtg ggaggtaggg aaagcccaga aatggcagga 4080tgatatggtg gttctgtcgt tgggaaaggt attgggtttt gctgtttgta tttatactgt 4140ataatagata ccacgctttt tcttattatc tgtatatgta ttgcttttca tgtttgatat 4200tttcccatgc caagatttgt ttatatatat tttcaatgtt aaattaaatt gatttgggta 4260actttcttcc ccaagaaagt attttccccc ttaagtataa atctgactg 4309
<210>15<211>108<212>PRT<213>智人(Homo sapiens)<400>15Met Ala Ala Ala Met Glu Thr Glu Gln Leu Gly Val Glu Ile Phe Glu1 5 10 15Thr Ala Asp Cys Glu Glu Asn Ile Glu Ser Gln Asp Arg Pro Lys Leu20 25 30Glu Pro Phe Tyr Val Glu Arg Tyr Ser Trp Ser Gln Leu Lys Lys Leu35 40 45Leu Ala Asp Thr Arg Lys Tyr His Gly Tyr Met Met Ala Lye Ala Pro50 55 60His Asp Phe Met Phe Val Lys Arg Asn Asp Pro Asp Gly Pro His Ser65 70 75 80Asp Arg Ile Tyr Tyr Leu Gly Asn Lys Ser Leu Ile Asp His Asp Arg85 90 95Phe Ser Lys Ser Lys Met Pro Glu Ile Ala Ser Ser100 105<210>16<211>620<212>DNA<213>智人(Homo sapiens)<400>16aagtgctaaa gcctccgagg ccaaggccgc tgctactgcc gccgctgctt cttagtgccg 60cgttcgccgc ctgggttgtc accggcgccg ccgccgagga agccactgca accaggaccg120gagtggaggc ggcgcagcat gaagcggcgc aggcccgctc catagcgcac gtcgggacgg180tccgggcggg gccgggggga aggaaaatgc aacatggcag cagcaatgga aacagaacag240ctgggtgttg agatatttga aactgcggac tgtgaggaga atattgaatc acaggatcgg300cctaaattgg agccttttta tgttgagcgg tattcctgga gtcagcttaa aaagctgctt360gccgatacca gaaaatatca tggctacatg atggctaagg caccacatga tttcatgttt420gtgaagagga atgatccaga tggacctcat tcagacagaa tctattacct tggtaacaag480tcattaattg atcatgatcg tttttcaaaa tcgaagatgc cagaaattgc ttcttcctaa540agctagcttg aaatgccttt ctttagatgg tctgattagg aaaacaaaca ataaaaccat600tagtttgttc ccactcaaca620<210>17<211>194<212>PRT<213>智人(Homo sapiens)<400>17
Met Ala Ala Ala Met Glu Thr Glu Gln Leu Gly Val Glu Ile Phe Glul 5 10 15Thr Ala Asp Cys Glu Glu Asn Ile Glu Ser Gln Asp Arg Pro Lys Leu20 25 30Glu Pro Phe Tyr Val Glu Arg Tyr Ser Trp Ser Gln Leu Lys Lys Leu35 40 45Leu Ala Asp Thr Arg Lys Tyr His Gly Tyr Met Met Ala Lys Ala Pro50 55 60His Asp Phe Met Phe Val Lys Arg Asn Asp Pro Asp Gly Pro His Ser65 70 75 80Asp Arg Ile Tyr Tyr Leu Ala Met Ser Gly Glu Asn Arg Glu Asn Thr85 90 95Leu Phe Tyr Ser Glu Ile Pro Lys Thr Ile Asn Arg Ala Ala Val Leu100 105 110Met Leu Ser Trp Lys Pro Leu Leu Asp Leu Phe Gln Ala Thr Leu Asp115 120 125Tyr Gly Met Tyr Ser Arg Glu Glu Glu Leu Leu Arg Glu Arg Lys Arg130 135 140Ile Gly Thr Val Gly Ile Ala Ser Tyr Asp Tyr His Gln Gly Ser Gly145 150 155 160Thr Phe Leu Phe Gln Ala Gly Ser Gly Ile Tyr His Val Lys Asp Gly165 170 175Gly Pro Gln Gly Phe Thr Gln Pro Leu Arg Pro Asn Leu Val Glu Thr180 185 190Cys Ala<210>18<211>832<212>DNA<213>智人(Homo sapiens)<400>18aagtgctaaa gcctccgagg ccaaggccgc tgctactgcc gccgctgctt cttagtgccg 60cgttcgccgc ctgggttgtc accggcgccg ccgccgagga agccactgca accaggaccg120gagtggaggc ggcgcagcat gaagcggcgc aggcccgctc catagcgcac gtcgggacgg180tccgggcggg gccgggggga aggaaaatgc aacatggcag cagcaatgga aacagaacag240ctgggtgttg agatatttga aactgcggac tgtgaggaga atattgaatc acaggatcgg300cctaaattgg agccttttta tgttgagcgg tattcctgga gtcagcttaa aaagctgctt360gccgatacca gaaaatatca tggctacatg atggctaagg caccacatga tttcatgttt420gtgaagagga atgatccaga tggacctcat tcagacagaa tctattacct tgccatgtct480ggtgagaaca gagaaaatac actgttttat tctgaaattc ccaaaactat caatagagca540gcagtcttaa tgctctcttg gaagcctctt ttggatcttt ttcaggcaac actggactat600ggaatgtatt ctcgagaaga agaactatta agagaaagaa aacgcattgg aacagtcgga660attgcttctt acgattatca ccaaggaagt ggaacatttc tgtttcaagc cggtagtgga720atttatcacg taaaagatgg agggccacaa ggatttacgc wacaaccttt aaggcccaat780ctagtggaaa ctasttgtsc caracytgca tgacccaatc agatcctgta ga832<210>19<211>658<212>PRT<213>智人(Homo sapiens)<400>19Met Ala Ala Ala Met Glu Thr Glu Gln Leu Gly Val Glu Ile Phe Glu1 5 10 15Thr Ala Asp Cys Glu Glu Asn Ile Glu Ser Gln Asp Arg Pro Lys Leu20 25 30Glu Pro Phe Tyr Val Glu Arg Tyr Ser Trp Ser Gln Leu Lys Lys Leu35 40 45Leu Ala Asp Thr Arg Lys Tyr His Gly Tyr Met Met Ala Lys Ala Pro
50 55 60His Asp Phe Met Phe Val Lys Arg Asn Asp Pro Asp Gly Pro His Ser65 70 75 80Asp Arg Ile Tyr Tyr Leu Ala Met Ser Gly Glu Asn Arg Glu Asn Thr85 90 95Leu Phe Tyr Ser Glu Ile Pro Lys Thr Ile Asn Arg Ala Ala Val Leu100 105 110Met Leu Ser Trp Lys Pro Leu Leu Asp Leu Phe Gln Ala Thr Leu Asp115 120 125Tyr Gly Met Tyr Ser Arg Glu Glu Glu Leu Leu Arg Glu Arg Lys Arg130 135 140Ile Gly Thr Val Gly Ile Ala Ser Tyr Asp Tyr His Gln Gly Ser Gly145 150 155 160Thr Phe Leu Phe Gln Ala Gly Ser Gly Ile Tyr His Val Lys Asp Gly165 170 175Gly Pro Gln Gly Phe Thr Gln Gln Pro Leu Arg Pro Asn Leu Val Glu180 185 190Thr Ser Cys Pro Asn Ile Arg Met Asp Pro Lys Leu Cys Pro Ala Asp195 200 205Pro Asp Trp Ile Ala Phe Ile His Ser Asn Asp Ile Trp Ile Ser Asn210 215 220Ile Val Thr Arg Glu Glu Arg Arg Leu Thr Tyr Val His Asn Glu Leu225 230 235 240Ala Asn Met Glu Glu Asp Ala Arg Ser Ala Gly Val Ala Thr Phe Val245 250 255Leu Gln Glu Glu Phe Asp Arg Tyr Ser Gly Tyr Trp Trp Cys Pro Lys260 265 270Ala Glu Thr Thr Pro Ser Gly Gly Lys Ile Leu Arg Ile Leu Tyr Glu275 280 285Glu Asn Asp Glu Ser Glu Val Glu Ile Ile His Val Thr Ser Pro Met290 295 300Leu Glu Thr Arg Arg Ala Asp Ser Phe Arg Tyr Pro Lys Thr Gly Thr305 310 315 320Ala Asn Pro Lys Val Thr Phe Lys Met Ser Glu Ile Met Ile Asp Ala325 330 335Glu Gly Arg Ile Ile Asp Val Ile Asp Lys Glu Leu Ile Gln Pro Phe340 345 350Glu Ile Leu Phe Glu Gly Val Glu Tyr Ile Ala Arg Ala Gly Trp Thr355 360 365Pro Glu Gly Lys Tyr Ala Trp Ser Ile Leu Leu Asp Arg Ser Gln Thr370 375 380Arg Leu Gln Ile Val Leu Ile Ser Pro Glu Leu Phe Ile Pro Val Glu385 390 395 400Asp Asp Val Mat Glu Arg Gln Arg Leu Ile Glu Ser Val Pro Asp Ser405 410 415Val Thr Pro Leu Ile Ile Tyr Glu Glu Thr Thr Asp Ile Trp Ile Asn420 425 430Ile His Asp Ile Phe His Val Phe Pro Gln Ser His Glu Glu Glu Ile435 440 445Glu Phe Ile Phe Ala Ser Glu Cys Lys Thr Gly Phe Arg His Leu Tyr450 455 460Lys Ile Thr Ser Ile Leu Lys Glu Ser Lys Tyr Lys Arg Ser Ser Gly465 470 475 480Gly Leu Pro Ala Pro Ser Asp Phe Lys Cys Pro Ile Lys Glu Glu Ile485 490 495Ala Ile Thr Ser Gly Glu Trp Glu Val Leu Gly Arg His Gly Ser Asn500 505 510Ile Gln Val Asp Glu Val Arg Arg Leu Val Tyr Phe Glu Gly Thr Lys515 520 525Asp Ser Pro Leu Glu His His Leu Tyr Val Val Ser Tyr Val Asn Pro
530 535 540Gly Glu Val Thr Arg Leu Thr Asp Arg Gly Tyr Ser His Ser Cys Cys545 550 555 560Ile Ser Gln His Cys Asp Phe Phe Ile Ser Lys Tyr Ser Asn Gln Lys565 570 575Asn Pro His Cys Val Ser Leu Tyr Lys Leu Ser Ser Pro Glu Asp Asp580 585 590Pro Thr Cys Lys Thr Lye Glu Phe Trp Ala Thr Ile Leu Asp Ser Ala595 600 605Gly Pro Leu Pro Asp Tyr Thr Pro Pro Glu Ile Phe Ser Phe Glu Ser610 615 620Thr Thr Gly Phe Thr Leu Tyr Gly Met Leu Tyr Lys Pro His Asp Leu625 630 635 640Gln Pro Gly Lys Lys Tyr Pro Thr Val Leu Phe Ile Tyr Gly Gly Arg645 650 655Val Lys<210>20<211>4676<212>DNA<213>智人(Homo sapiens)<400>20aagtgctaaa gcctccgagg ccaaggccgc tgctactgcc gccgctgctt cttagtgccg 60cgttcgccgc ctgggttgtc accggcgccg ccgccgagga agccactgca accaggaccg120gagtggaggc ggcgcagcat gaagcggcgc aggcccgctc catagcgcac gtcgggacgg180tccgggcggg gccgggggga aggaaaatgc aacatggcag cagcaatgga aacagaacag240ctgggtgttg agatatttga aactgcggac tgtgaggaga atattgaatc acaggatcgg300cctaaattgg agccttttta tgttgagcgg tattcctgga gtcagcttaa aaagctgctt360gccgatacca gaaaatatca tggctacatg atggctaagg caccacatga tttcatgttt420gtgaagagga atgatccaga tggacctcat tcagacagaa tctattacct tgccatgtct480ggtgagaaca gagaaaatac actgttttat tctgaaattc ccaaaactat caatagagca540gcagtcttaa tgctctcttg gaagcctctt ttggatcttt ttcaggcaac actggactat600ggaatgtatt ctcgagaaga agaactatta agagaaagaa aacgcattgg aacagtcgga660attgcttctt acgattatca ccaaggaagt ggaacatttc tgtttcaagc cggtagtgga720atttatcacg taaaagatgg agggccacaa ggatttacgc aacaaccttt aaggcccaat780ctagtggaaa ctagttgtcc caacatacgg atggatccaa aattatgccc tgctgatcca840gactggattg cttttataca tagcaacgat atttggatat ctaacatcgt aaccagagaa900gaaaggagac tcacttatgt gcacaatgag ctagccaaca tggaagaaga tgccagatca960gctggagtcg ctacctttgt tctccaagaa gaatttgata gatattctgg ctattggtgg 1020tgtccaaaag ctgaaacaac tcccagtggt ggtaaaattc ttagaattct atatgaagaa 1080aatgatgaat ctgaggtgga aattattcat gttacatccc ctatgttgga aacaaggagg 1140gcagattcat tccgttatcc taaaacaggt acagcaaatc ctaaagtcac ttttaagatg 1200tcagaaataa tgattgatgc tgaaggaagg atcatagatg tcatagataa ggaactaatt 1260caaccttttg agattctatt tgaaggagtt gaatatattg ccagagctgg atggactcct 1320gagggaaaat atgcttggtc catcctacta gatcgctccc agactcgcct acagatagtg 1380ttgatctcac ctgaattatt tatcccagta gaagatgatg ttatggaaag gcagagactc 1440attgagtcag tgcctgattc tgtgacgcca ctaattatct atgaagaaac aacagacatc 1500tggataaata tccatgacat ctttcatgtt tttccccaaa gtcacgaaga ggaaattgag 1560tttatttttg cctctgaatg caaaacaggt ttccgtcatt tatacaaaat tacatctatt 1620ttaaaggaaa gcaaatataa acgatccagt ggtgggctgc ctgctccaag tgatttcaag 1680tgtcctatca aagaggagat agcaattacc agtggtgaat gggaagttct tggccggcat 1740ggatctaata tccaagttga tgaagtcaga aggctggtat attttgaagg caccaaagac 1800tcccctttag agcatcacct gtacgtagtc agttacgtaa atcctggaga ggtgacaagg 1860ctgactgacc gtggctactc acattcttgc tgcatcagtc agcactgtga cttctttata 1920agtaagtata gtaaccagaa gaatccacac tgtgtgtccc tttacaagct atcaagtcct 1980gaagatgacc caacttgcaa aacaaaggaa ttttgggcca ccattttgga ttcagcaggt 2040cctcttcctg actatactcc tccagaaatt ttctcttttg aaagtactac tggatttaca 2100ttgtatggga tgctctacaa gcctcatgat ctacagcctg gaaagaaata tcctactgtg 2160ctgttcatat atggtggtcg ggtcaaatag aaattgacga tcaggtggaa ggactccaat 2220
atctagcttc tcgatatgat ttcattgact tagatcgtgt gggcatccac ggctggtcct 2280atggaggata cctctccctg atggcattaa tgcagaggtc agatatcttc agggttgcta 2340ttgctggggc cccagtcact ctgtggatct tctatgatac aggatacacg gaacgttata 2400tgggtcaccc tgaccagaat gaacagggct attacttagg atctgtggcc atgcaagcag 2460aaaagttccc ctctgaacca aatcgtttac tgctcttaca tggtttcctg gatgagaatg 2520tccattttgc acataccagt atattactga gttttttagt gagggctgga aagccatatg 2580atttacagat ctatcctcag gagagacaca gcataagagt tcctgaatcg ggagaacatt 2640atgaactgca tcttttgcac taccttcaag aaaaccttgg atcacgtatt gctgctctaa 2700aagtgatata attttgacct gtgtagaact ctctggtata cactggctat ttaaccaaat 2760gaggaggttt aatcaacaga aaacacagaa ttgatcatca cattttgata cctgccatgt 2820aacatctact cctgaaaata aatgtggtgc catgcagggg tctacggttt gtggtagtaa 2880tctaatacct taaccccaca tgctcaaaat caaatgatac atattcctga gagacccagc 2940aataccataa gaattactaa aaaaaaaaaa aaaaaaaaga cattagcacc atgtattcat 3000actaccctat tttcactttt aatagtatta taaacttcat gaacttaatt agtgtatttt 3060tacagtatac ttttgagttt gttaaaatat gatgatatta gtgattggtt tggttcagtt 3120ccagaatctt tgactagtta cagatttgat agcacttaaa tgtaattgaa tagcttatgc 3180ttcattgctt gggcatatcc agcatgttat gaactaataa ctattaaact tgacttaacc 3240agtcattcat taataatttt tcaaggataa cttagtggcc tcctaaagac acttgttttg 3300gcactgacca gtttttagcc aatttaatct gtatctagta taaataattc tcatttttct 3360ttgatgatat taacagagtg ggcttttcct tttgcataaa ggctagtaac tgtatatgta 3420gcatggattt aattagtcat gatattgata attacaggca gaaaattttt aatcaaatga 3480ttagagctta aatatttgca ggcaagtttt tttttttcct ttaagaaaag gaaaaagtac 3540acattcacta gaattcttca gaaaatttag tggtgccagt ttccatttgg tatttcctta 3600ttaaaatatt ctagaatttt aaggagattg aagggaatca cagtggggtg gggagacctg 3660ggtttgggga atgacagaga gaagaggtgg tgagggcctg attaaaaact aagcagaagt 3720agttttaaca aaaatactca tgaaaatgtt tggaaactga aatttaaaca actgtaatat 3780taaggaaacc agaatcaata aatcactgtc ttgccagcac agctacagag taacatgatt 3840caggggagga aaagttcctt agagttactt ttataattct tttttttttt cctcttaggt 3900ttagaaatct tacaaattta aactttatcc ttttaaaatt atttgaacat aatttagata 3960ttgtaagctt aaaatacaaa tgtttataga taacctcttt accataaact aatccctggc 4020aagccatggc tctctttttt tttttggtgt ttaaagcctg taaacagttt ttctgaatga 4080tcatgaactt ttcttggttt agcactagga tttagctatg aagagagctc ataggctttc 4140aggtgctaat tgagatctgc cctgttagag tcttggggtg ctagattggt cacattgaca 4200ccagtggcag ggaaggcatc tatgagtttg atgcttttta tcacacactt cagtgtttag 4260aaagttatta ccaatacttt taaacaacac tccaagaaaa tttgctatat ttctttctca 4320tcactacaga gagagtagat ttccccatag agagcacagc ctccattagt aaggttggtg 4380actattggta agaggtggac ttcattgaca ccaagtggga ggtagggaaa gcccagaaat 4440ggcaggatga tatggtggtt ctgtcgttgg gaaaggtatt gggttttgct gtttgtattt 4500atactgtata atagatacca cgctttttct tattatctgt atatgtattg cttttcatgt 4560ttgatatttt cccatgccaa gatttgttta tatatatttt caatgttaaa ttaaattgat 4620ttgggtaact ttcttcccca agaaagtatt ttccccctta agtataaatc tgactg 4676<210>21<211>613<212>PRT<213>智人(Homo sapiens)<400>21Met Ala Ala Ala Met Glu Thr Glu Gln Leu Gly Val Glu Ile Phe Glu1 5 10 15Thr Ala Asp Cys Glu Glu Asn Ile Glu Ser Gln Asp Arg Pro Lys Leu20 25 30Glu Pro Phe Tyr Val Glu Arg Tyr Ser Trp Ser Gln Leu Lys Lys Leu35 40 45Leu Ala Asp Thr Arg Lys Tyr His Gly Tyr Met Met Ala Lys Ala Pro50 55 60His Asp Phe Met Phe Val Lys Arg Asn Asp Pro Asp Gly Pro His Ser65 70 75 80Asp Arg Ile Tyr Tyr Leu Ala Met Ser Gly Glu Asn Arg Glu Asn Thr85 90 95
Leu Phe Tyr Ser Glu Ile Pro Lys Thr Ile Asn Arg Ala Ala Val Leu100 105 110Met Leu Ser Trp Lys Pro Leu Leu Asp Leu Phe Gln Ala Thr Leu Asp115 120 125Tyr Gly Met Tyr Ser Arg Glu Glu Glu Leu Leu Arg Glu Arg Lys Arg130 135 140Ile Gly Thr Val Gly Ile Ala Ser Tyr Asp Tyr His Gln Gly Ser Gly145 150 155 160Thr Phe Leu Phe Gln Ala Gly Ser Gly Ile Tyr His Val Lys Asp Gly165 170 175Gly Pro Gln Gly Phe Thr Gln Gln Pro Leu Arg Pro Asn Leu Val Glu180 185 190Thr Ser Cys Pro Asn Ile Arg Met Asp Pro Lys Leu Cys Pro Ala Asp195 200 205Pro Asp Trp Ile Ala Phe Ile His Ser Asn Asp Ile Trp Ile Ser Asn210 215 220Ile Val Thr Arg Glu Glu Arg Arg Leu Thr Tyr Val His Asn Glu Leu225 230 235 240Ala Asn Met Glu Glu Asp Ala Arg Ser Ala Gly Val Ala Thr Phe Val245 250 255Leu Gln Glu Glu Phe Asp Arg Tyr Ser Gly Tyr Trp Trp Cys Pro Lys260 265 270Ala Glu Thr Thr Pro Ser Gly Gly Lys Ile Leu Arg Ile Leu Tyr Glu275 280 285Glu Asn Asp Glu Ser Glu Val Glu Ile Ile His Val Thr Ser Pro Met290 295 300Leu Glu Thr Arg Arg Ala Asp Ser Phe Arg Tyr Pro Lys Thr Gly Thr305 310 315 320ala Asn Pro Lys Val Thr Phe Lys Met Ser Glu Ile Met Ile Asp Ala325 330 335Glu Gly Arg Ile Ile Asp Val Ile Asp Lys Glu Leu Ile Gln Pro Phe340 345 350Glu Ile Leu Phe Glu Gly Val Glu Tyr Ile Ala Arg Ala Gly Trp Thr355 360 365Pro Glu Gly Lys Tyr Ala Trp Ser Ile Leu Leu Asp Arg Ser Gln Thr370 375 380Arg Leu Gln Ile Val Leu Ile Ser Pro Glu Leu Phe Ile Pro Val Glu385 390 395 400Asp Asp Val Met Glu Arg Gln Arg Leu Ile Glu Ser Val Pro Asp Ser405 410 415Val Thr Pro Leu Ile Ile Tyr Glu Glu Thr Thr Asp Ile Trp Ile Asn420 425 430Ile His Asp Ile Phe His Val Phe Pro Gln Ser His Glu Glu Glu Ile435 440 445Glu Phe Ile Phe Ala Ser Glu Cys Lys Thr Gly Phe Arg His Leu Tyr450 455 460Lys Ile Thr Ser Ile Leu Lys Glu Ser Lys Tyr Lys Arg Ser Ser Gly465 470 475 480Gly Leu Pro Ala Pro Ser Asp Phe Lys Cys Pro Ile Lys Glu Glu Ile485 490 495Ala Ile Tyr Ser Gly Glu Trp Glu Val Leu Gly Arg His Gly Ser Asn500 505 510Ile Gln Val Asp Glu Val Arg Arg Leu Val Tyr Phe Glu Gly Thr Lys515 520 525Asp Ser Pro Leu Glu His His Leu Tyr Val Val Ser Tyr Val Asn Pro530 535 540Gly Glu Val Thr Arg Leu Thr Asp Arg Gly Tyr Ser His Ser Cys Cys545 550 555 560Ile Ser Gln His Cys Asp Phe Phe Ile Ser Lys Tyr Ser Asn Gln Lys565 570 575
Asn Pro His Cys Val Ser Leu Tyr Lys Leu Ser Ser Pro Glu Asp Asp580 585 590Pro Thr Cys Lys Thr Lys Glu Phe Trp Ala Thr Ile Leu Asp Ser Val595 600 605Leu Arg Cys Ser Trp610<210>22<211>4685<212>DNA<213>智人(Homo sapiens)<400>22aagtgctaaa gcctccgagg ccaaggccgc tgctactgcc gccgctgctt cttagtgccg 60cgttcgccgc ctgggttgtc accggcgccg ccgccgagga agccactgca accaggaccg120gagtggaggc ggcgcagcat gaagcggcgc aggcccgctc catagcgcac gtcgggacgg180tccgggcggg gccgggggga aggaaaatgc aacatggcag cagcaatgga aacagaacag240ctgggtgttg agatatttga aactgcggac tgtgaggaga atattgaatc acaggatcgg300cctaaattgg agccttttta tgttgagcgg tattcctgga gtcagcttaa aaagctgctt360gccgatacca gaaaatatca tggctacatg atggctaagg caccacatga tttcatgttt420gtgaagagga atgatccaga tggacctcat tcagacagaa tctattacct tgccatgtct480ggtgagaaca gagaaaatac actgttttat tctgaaattc ccaaaactat caatagagca540gcagtcttaa tgctctcttg gaagcctctt ttggatcttt ttcaggcaac actggactat600ggaatgtatt ctcgagaaga agaactatta agagaaagaa aacgcattgg aacagtcgga660attgcttctt acgattatca ccaaggaagt ggaacatttc tgtttcaagc cggtagtgga720atttatcacg taaaagatgg agggccacaa ggatttacgc aacaaccttt aaggcccaat780ctagtggaaa ctagttgtcc caacatacgg atggatccaa aattatgccc tgctgatcca840gactggattg cttttataca tagcaacgat atttggatat ctaacatcgt aaccagagaa900gaaaggagac tcacttatgt gcacaatgag ctagccaaca tggaagaaga tgccagatca960gctggagtcg ctacctttgt tctccaagaa gaatttgata gatattctgg ctattggtgg 1020tgtccaaaag ctgaaacaac tcccagtggt ggtaaaattc ttagaattct atatgaagaa 1080aatgatgaat ctgaggtgga aattattcat gttacatccc ctatgttgga aacaaggagg 1140gcagattcat tccgttatcc taaaacaggt acagcaaatc ctaaagtcac ttttaagatg 1200tcagaaataa tgattgatgc tgaaggaagg atcatagatg tcatagataa ggaactaatt 1260caaccttttg agattctatt tgaaggagtt gaatatattg ccagagctgg atggactcct 1320gagggaaaat atgcttggtc catcctacta gatcgctccc agactcgcct acagatagtg 1380ttgatctcac ctgaattatt tatcccagta gaagatgatg ttatggaaag gcagagactc 1440attgagtcag tgcctgattc tgtgacgcca ctaattatct atgaagaaac aacagacatc 1500tggataaata tccatgacat ctttcatgtt tttccccaaa gtcacgaaga ggaaattgag 1560tttatttttg cctctgaatg caaaacaggt ttccgtcatt tatacaaaat tacatctatt 1620ttaaaggaaa gcaaatataa acgatccagt ggtgggctgc ctgctccaag tgatttcaag 1680tgtcctatca aagaggagat agcaattacc agtggtgaat gggaagttct tggccggcat 1740ggatctaata tccaagttga tgaagtcaga aggctggtat attttgaagg caccaaagac 1800tcccctttag agcatcacct gtacgtagtc agttacgtaa atcctggaga ggtgacaagg 1860ctgactgacc gtggctactc acattcttgc tgcatcagtc agcactgtga cttctttata 1920agtaagtata gtaaccagaa gaatccacac tgtgtgtccc tttacaagct atcaagtcct 1980gaagatgacc caacttgcaa aacaaaggaa ttttgggcca ccattttgga ttcagtcctc 2040aggtgcagtt ggtgaataat cggtttaaag gagtcaagta tttccgcttg aataccctag 2100cctctctagg ttatgtggtt gtagtgatag acaacagggg atcctgtcac cgagggctta 2160aatttgaagg cgcctttaaa tataaaatgg gtcaaataga aattgacgat caggtggaag 2220gactccaata tctagcttct cgatatgatt tcattgactt agatcgtgtg ggcatccacg 2280gctggtccta tggaggatac ctctccctga tggcattaat gcagaggtca gatatcttca 2340gggttgctat tgctggggcc ccagtcactc tgtggatctt ctatgataca ggatacacgg 2400aacgttatat gggtcaccct gaccagaatg aacagggcta ttacttagga tctgtggcca 2460tgcaagcaga aaagttcccc tctgaaccaa atcgtttact gctcttacat ggtttcctgg 2520atgagaatgt ccattttgca cataccagta tattactgag ttttttagtg agggctggaa 2580agccatatga tttacagatc tatcctcagg agagacacag cataagagtt cctgaatcgg 2640gagaacatta tgaactgcat cttttgcact accttcaaga aaaccttgga tcacgtattg 2700ctgctctaaa agtgatataa ttttgacctg tgtagaactc tctggtatac actggctatt 2760taaccaaatg aggaggttta atcaacagaa aacacagaat tgatcatcac attttgatac 2820
ctgccatgta acatctactc ctgaaaataa atgtggtgcc atgcaggggt ctacggtttg 2880tggtagtaat ctaatacctt aaccccacat gctcaaaatc aaatgataca tattcctgag 2940agacccagca ataccataag aattactaaa aaaaaaaaaa aaaaaaagac attagcacca 3000tgtattcata ctaccctatt ttcactttta atagtattat aaacttcatg aacttaatta 3060gtgtattttt acagtatact tttgagtttg ttaaaatatg atgatattag tgattggttt 3120ggttcagttc cagaatcttt gactagttac agatttgata gcacttaaat gtaattgaat 3180agcttatgct tcattgcttg ggcatatcca gcatgttatg aactaataac tattaaactt 3240gacttaacca gtcattcatt aataattttt caaggataac ttagtggcct cctaaagaca 3300cttgttttgg cactgaccag tttttagcca atttaatctg tatctagtat aaataattct 3360catttttctt tgatgatatt aacagagtgg gcttttcctt ttgcataaag gctagtaact 3420gtatatgtag catggattta attagtcatg atattgataa ttacaggcag aaaattttta 3480atcaaatgat tagagcttaa atatttgcag gcaagttttt ttttttcctt taagaaaagg 3540aaaaagtaca cattcactag aattcttcag aaaatttagt ggtgccagtt tccatttggt 3600atttccttat taaaatattc tagaatttta aggagattga agggaatcac agtggggtgg 3660ggagacctgg gtttggggaa tgacagagag aagaggtggt gagggcctga ttaaaaacta 3720agcagaagta gttttaacaa aaatactcat gaaaatgttt ggaaactgaa atttaaacaa 3780ctgtaatatt aaggaaacca gaatcaataa atcactgtct tgccagcaca gctacagagt 3840aacatgattc aggggaggaa aagttcctta gagttacttt tataattctt tttttttttc 3900ctcttaggtt tagaaatctt acaaatttaa actttatcct tttaaaatta tttgaacata 3960atttagatat tgtaagctta aaatacaaat gtttatagat aacctcttta ccataaacta 4020atccctggca agccatggct ctcttttttt ttttggtgtt taaagcctgt aaacagtttt 4080tctgaatgat catgaacttt tcttggttta gcactaggat ttagctatga agagagctca 4140taggctttca ggtgctaatt gagatctgcc ctgttagagt cttggggtgc tagattggtc 4200acattgacac cagtggcagg gaaggcatct atgagtttga tgctttttat cacacacttc 4260agtgtttaga aagttattac caatactttt aaacaacact ccaagaaaat ttgctatatt 4320tctttctcat cactacagag agagtagatt tccccataga gagcacagcc tccattagta 4380aggttggtga ctattggtaa gaggtggact tcattgacac caagtgggag gtagggaaag 4440cccagaaatg gcaggatgat atggtggttc tgtcgttggg aaaggtattg ggttttgctg 4500tttgtattta tactgtataa tagataccac gctttttctt attatctgta tatgtattgc 4560ttttcatgtt tgatattttc ccatgccaag atttgtttat atatattttc aatgttaaat 4620taaattgatt tgggtaactt tcttccccaa gaaagtattt tcccccttaa gtataaatct 4680gactg 4685<210>23<211>892<212>PRT<213>智人(Homo sapiens)<400>23Met Arg Lys Val Lys Lys Leu Arg Leu Asp Lys Glu Asn Thr Gly Ser1 5 10 15Trp Arg Ser Phe Ser Leu Asn Ser Glu Gly Ala Glu Arg Met Ala Thr20 25 30Thr Gly Thr Pro Thr Ala Asp Arg Gly Asp Ala Ala Ala Thr Asp Asp35 40 45Pro Ala Ala Arg Phe Gln Val Gln Lys His Ser Trp Asp Gly Leu Arg50 55 60Ser Ile Ile His Gly Ser Arg Lys Tyr Ser Gly Leu Ile Val Asn Lys65 70 75 80Ala Pro His Asp Phe Gln Phe Val Gln Lys Thr Asp Glu Ser Gly Pro85 90 95His Ser His Arg Leu Tyr Tyr Leu Gly Met Pro Tyr Gly Ser Arg Glu100 105 110Asn Ser Leu Leu Tyr Ser Glu Ile Pro Lys Lys Val Arg Lys Glu Ala115 120 125Leu Leu Leu Leu Ser Trp Lys Gln Met Leu Asp His Phe Gln Ala Thr130 135 140Pro His His Gly Val Tyr Ser Arg Glu Glu Glu Leu Leu Arg Glu Arg145 150 155 160Lys Arg Leu Gly Val Phe Gly Ile Thr Ser Tyr Asp Phe His Ser Glu
165 170 175Ser Gly Leu Phe Leu Phe Gln Ala Ser Asn Ser Leu Phe His Cys Arg180 185 190Asp Gly Gly Lys Asn Gly Phe Met Val Ser Pro Met Lys Pro Leu Glu195 200 205Ile Lys Thr Gln Cys Ser Gly Pro Arg Met Asp Pro Lys Ile Cys Pro210 215 220Ala Asp Pro Ala Phe Phe Ser Phe Ile Asn Asn Ser Asp Leu Trp Val225 230 235 240Ala Asn Ile Glu Thr Gly Glu Glu Arg Arg Leu Thr Phe Cys His Gln245 250 255Gly Leu Ser Asn Val Leu Asp Asp Pro Lys Ser Ala Gly Val Ala Thr260 265 270Phe Val Ile Gln Glu Glu Phe Asp Arg Phe Thr Gly Tyr Trp Trp Cys275 280 285Pro Thr Ala Ser Trp Glu Gly Ser Glu Gly Leu Lys Thr Leu Arg Ile290 295 300Leu Tyr Glu Glu Val Asp Glu Ser Glu Val Glu Val Ile His Val Pro305 310 315 320Ser Pro Ala Leu Glu Glu Arg Lys Thr Asp Ser Tyr Arg Tyr Pro Arg325 330 335Thr Gly Ser Lys Asn Pro Lys Ile Ala Leu Lys Leu Ala Glu Phe Gln340 345 350Thr Asp Ser Gln Gly Lys Ile Val Ser Thr Gln Glu Lys Glu Leu Val355 360 365Gln Pro Phe Ser Ser Leu Phe Pro Lys Val Glu Tyr Ile Ala Arg Ala370 375 380Gly Trp Thr Arg Asp Gly Lys Tyr Ala Trp Ala Met Phe Leu Asp Arg385 390 395 400Pro Gln Gln Trp Leu Gln Leu Val Leu Leu Pro Pro Ala Leu Phe Ile405 410 415Pro Ser Thr Glu Asn Glu Glu Gln Arg Leu Ala Ser Ala Arg Ala Val420 425 430Pro Arg Asn Val Gln Pro Tyr Val Val Tyr Glu Glu Val Thr Asn Val435 440 445Trp Ile Asn Val His Asp Ile Phe Tyr Pro Phe Pro Gln Ser Glu Gly450 455 460Glu Asp Glu Leu Cys Phe Leu Arg Ala Asn Glu Cys Lys Thr Gly Phe465 470 475 480Cys His Leu Tyr Lys Val Thr Ala Val Leu Lys Ser Gln Gly Tyr Asp485 490 495Trp Ser Glu Pro Phe Ser Pro Gly Glu Asp Glu Phe Lys Cys Pro Ile500 505 510Lys Glu Glu Ile Ala Leu Thr Ser Gly Glu Trp Glu Val Leu Ala Arg515 520 525His Gly Ser Lys Ile Trp Val Asn Glu Glu Thr Lys Leu Val Tyr Phe530 535 540Gln Gly Thr Lys Asp Thr Pro Leu Glu His His Leu Tyr Val Val Ser545 550 555 560Tyr Glu Ala Ala Gly Glu Ile Val Arg Leu Thr Thr Pro Gly Phe Ser565 570 575His Ser Cys Ser Met Ser Gln Asn Phe Asp Met Phe Val Ser His Tyr580 585 590Ser Ser Val Ser Thr Pro Pro Cys Val His Val Tyr Lys Leu Ser Gly595 600 605Pro Asp Asp Asp Pro Leu His Lys Gln Pro Arg Phe Trp Ala Ser Met610 615 620Met Glu Ala Ala Ser Cys Pro Pro Asp Tyr Val Pro Pro Glu Ile Phe625 630 635 640His Phe His Thr Arg Ser Asp Val Arg Leu Tyr Gly Met Ile Tyr Lys
645 650 655Pro His Ala Leu Gln Pro Gly Lys Lys His Pro Thr Val Leu Phe Val660 665 670Tyr Gly Gly Pro Gln Val Gln Leu Val Asn Asn Ser Phe Lys Gly Ile675 680 685Lys Tyr Leu Arg Leu Asn Thr Leu Ala Ser Leu Gly Tyr Ala Val Val690 695 700Val Ile Asp Gly Arg Gly Ser Cys Gln Arg Gly Leu Arg Phe Glu Gly705 710 715 720Ala Leu Lys Asn Gln Met Gly Gln Val Glu Ile Glu Asp Gln Val Glu725 730 735Gly Leu Gln Phe Val Ala Glu Lys Tyr Gly Phe Ile Asp Leu Ser Arg740 745 750Val Ala Ile His Gly Trp Ser Tyr Gly Gly Phe Leu Ser Leu Met Gly755 760 765Leu Ile His Lys Pro Gln Val Phe Lys Val Ala Ile Ala Gly Ala Pro770 775 780Val Thr Val Trp Met Ala Tyr Asp Thr Gly Tyr Thr Glu Arg Tyr Met785 790 795 800Asp Val Pro Glu Asn Asn Gln His Gly Tyr Glu Ala Gly Ser Val Ala805 810 815Leu His Val Glu Lys Leu Pro Asn Glu Pro Asn Arg Leu Leu Ile Leu820 825 830His Gly Phe Leu Asp Glu Asn Val His Phe Phe His Thr Asn Phe Leu835 840 845Val Ser Gln Leu Ile Arg Ala Gly Lys Pro Tyr Gln Leu Gln Ile Tyr850 855 860Pro Asn Glu Arg His Ser Ile Arg Cys Pro Glu Ser Gly Glu His Tyr865 870 875 880Glu Val Thr Leu Leu His Phe Leu Gln Glu Tyr Leu885 890<210>24<211>4302<212>DNA<213>智人(Homo sapiens)<400>24caggccgccg cctgggtcgc tcaacttccg ggtcaaaggt gcctgagccg gcgggtcccc 60tgtgtccgcc gcggctgtcg tcccccgctc ccgccacttc cggggtcgca gtcccgggca120tggagccgcg accgtgaggc gccgctggac ccgggacgac ctgcccagtc cggccgccgc180cccacgtccc ggtctgtgtc ccacgcctgc agctggaatg gaggctctct ggacccttta240gaaggcaccc ctgccctcct gaggtcagct gagcggttaa tgcggaaggt taagaaactg300cgcctggaca aggagaacac cggaagttgg agaagcttct cgctgaattc cgagggggct360gagaggatgg ccaccaccgg gaccccaacg gccgaccgag gcgacgcagc cgccacagat420gacccggccg cccgcttcca ggtgcagaag cactcgtggg acgggctccg gagcatcatc480cacggcagcc gcaagtactc gggcctcatt gtcaacaagg cgccccacga cttccagttt540gtgcagaaga cggatgagtc tgggccccac tcccaccgcc tctactacct gggaatgcca600tatggcagcc gagagaactc cctcctctac tctgagattc ccaagaaggt ccggaaagag660gctctgctgc tcctgtcctg gaagcagatg ctggatcatt tccaggccac gccccaccat720ggggtctact ctcgggagga ggagctgctg agggagcgga aacgcctggg ggtcttcggc780atcacctcct acgacttcca cagcgagagt ggcctcttcc tcttccaggc cagcaacagc840ctcttccact gccgcgacgg cggcaagaac ggcttcatgg tgtcccctat gaaaccgctg900gaaatcaaga cccagtgctc agggccccgg atggacccca aaatctgccc tgccgaccct960gccttcttct ccttcatcaa taacagcgac ctgtgggtgg ccaacatcga gacaggcgag 1020gagcggcggc tgaccttctg ccaccaaggt ttatccaatg tcctggatga ccccaagtct 1080gcgggtgtgg ccaccttcgt catacaggaa gagttcgacc gcttcactgg gtactggtgg 1140tgccccacag cctcctggga aggttcagag ggcctcaaga cgctgcgaat cctgtatgag 1200gaagtcgatg agtccgaggt ggaggtcatt cacgtcccct ctcctgcgct agaagaaagg 1260aagacggact cgtatcggta ccccaggaca ggcagcaaga atcccaagat tgccttgaaa 1320
ctggctgagt tccagactga cagccagggc aagatcgtct cgacccagga gaaggagctg 1380gtgcagccct tcagctcgct gttcccgaag gtggagtaca tcgccagggc cgggtggacc 1440cgggatggca aatacgcctg ggccatgttc ctggaccggc cccagcagtg gctccagctc 1500gtcctcctcc ccccggccct gttcatcccg agcacagaga atgaggagca gcggctagcc 1560tctgccagag ctgtccccag gaatgtccag ccgtatgtgg tgtacgagga ggtcaccaac 1620gtctggatca atgttcatga catcttctat cccttccccc aatcagaggg agaggacgag 1680ctctgctttc tccgcgccaa tgaatgcaag accggcttct gccatttgta caaagtcacc 1740gccgttttaa aatcccaggg ctacgattgg agtgagccct tcagccccgg ggaagatgaa 1800tttaagtgcc ccattaagga agagattgct ctgaccagcg gtgaatggga ggttttggcg 1860aggcacggct ccaagatctg ggtcaatgag gagaccaagc tggtgtactt ccagggcacc 1920aaggacacgc cgctggagca ccacctctac gtggtcagct atgaggcggc cggcgagatc 1980gtacgcctca ccacgcccgg cttctcccat agctgctcca tgagccagaa cttcgacatg 2040ttcgtcagcc actacagcag cgtgagcacg ccgccctgcg tgcacgtcta caagctgagc 2100ggccccgacg acgaccccct gcacaagcag ccccgcttct gggctagcat gatggaggca 2160gccagctgcc ccccggatta tgttcctcca gagatcttcc atttccacac gcgctcggat 2220gtgcggctct acggcatgat ctacaagccc cacgccttgc agccagggaa gaagcacccc 2280accgtcctct ttgtatatgg aggcccccag gtgcagctgg tgaataactc cttcaaaggc 2340atcaagtact tgcggctcaa cacactggcc tccctgggct acgccgtggt tgtgattgac 2400ggcaggggct cctgtcagcg agggcttcgg ttcgaagggg ccctgaaaaa ccaaatgggc 2460caggtggaga tcgaggacca ggtggagggc ctgcagttcg tggccgagaa gtatggcttc 2520atcgacctga gccgagttgc catccatggc tggtcctacg ggggcttcct ctcgctcatg 2580gggctaatcc acaagcccca ggtgttcaag gtggccatcg cgggtgcccc ggtcaccgtc 2640tggatggcct acgacacagg gtacactgag cgctacatgg acgtccctga gaacaaccag 2700cacggctatg aggcgggttc cgtggccctg cacgtggaga agctgcccaa tgagcccaac 2760cgcttgctta tcctccacgg cttcctggac gaaaacgtgc actttttcca cacaaacttc 2820ctcgtctccc aactgatccg agcagggaaa ccttaccagc tccagatcta ccccaacgag 2880agacacagta ttcgctgccc cgagtcgggc gagcactatg aagtcacgtt gctgcacttt 2940ctacaggaat acctctgagc ctgcccaccg ggagccgcca catcacagca caagtggctg 3000cagcctccgc ggggaaccag gcgggaggga ctgagtggcc cgcgggcccc agtgaggcac 3060tttgtcccgc ccagcgctgg ccagccccga ggagccgctg ccttcaccgc cccgacgcct 3120tttatccttt tttaaacgct cttgggtttt atgtccgctg cttcttggtt gccgagacag 3180agagatggtg gtctcgggcc agcccctcct ctccccgcct tctgggagga ggaggtcaca 3240cgctgatggg cactggagag gccagaagag actcagagga gcgggctgcc ttccgcctgg 3300ggctccctgt gacctctcag tcccctggcc cggccagcca ccgtccccag cacccaagca 3360tgcaattgcc tgtccccccc ggccagcctc cccaacttga tgtttgtgtt ttgtttgggg 3420ggatattttt cataattatt taaaagacag gccgggcgcg gtggctcacg tctgtaatcc 3480cagcactttg ggaggctgag gcgggcggat cacctgaggt tgggagttca agaccagcct 3540ggccaacatg gggaaacccc gtctctacta aaaatacaaa aaattagccg ggtgtggtgg 3600cgcgtgccta taatcccagc tactcgggag gctgaggcag gagaatcgct tgaacccggg 3660aggtggaggt tgcggtgagc caagatcgca ccattgcact ccagcctggg caacaagagc 3720gaaactctgt ctcaaaataa ataaaaaata aaagacagaa agcaaggggt gcctaaatct 3780agacttgggg tccacaccgg gcagcggggt tgcaacccag cacctggtag gctccatttc 3840ttcccaagcc cgagcagagg gtcatgcggg ccccacagga gaagcggcca gggcccgcgg 3900ggggcaccac ctgtggacag ccctcctgtc cccaagcttt caggcaggca ctgaaacgca 3960ccgaacttcc acgctctgct ggtcagtggc ggctgtcccc tccccagccc agccgcccag 4020ccacatgtgt ctgcctgacc cgtacacacc aggggttccg gggttgggag ctgaaccatc 4080cccacctcag ggttatattt ccctctcccc ttccctcccc gccaagagct ctgccagggg 4140cgggcaaaaa aaaaagtaaa aagaaaagaa aaaaaaaaaa aagaaacaaa ccacctctac 4200atattatgga aagaaaatat ttttgtcgat tcttattctt ttataattat gcgtggaaga 4260agtagacaca ttaaacgatt ccagttggaa acatgtcacc tg 4302<210>25<211>518<212>PRT<213>智人(Homo sapiens)<400>25Met Arg Lys Val Lys Lys Leu Arg Leu Asp Lys Glu Asn Thr Gly Ser1 5 10 15Trp Arg Ser Phe Ser Leu Asn Ser Glu Gly Ala Glu Arg Met Ala Thr
20 25 30Thr Gly Thr Pro Thr Ala Asp Arg Gly Asp Ala Ala Ala Thr Asp Asp35 40 45Pro Ala Ala Arg Phe Gln Val Gln Lys His Ser Trp Asp Gly Leu Arg50 55 60Ser Ile Ile His Gly Ser Arg Lys Tyr Ser Gly Leu Ile Val Asn Lys65 70 75 80Ala Pro His Asp Phe Gln Phe Val Gln Lys Thr Asp Glu Ser Gly Pro85 90 95His Ser His Arg Leu Tyr Tyr Leu Gly Met Pro Tyr Gly Ser Arg Glu100 105 110Asn Ser Leu Leu Tyr Ser Glu Ile Pro Lys Lys Val Arg Lys Glu Ala115 120 125Leu Leu Leu Leu Ser Trp Lys Gln Met Leu Asp His Phe Gln Ala Thr130 135 140Pro His His Gly Val Tyr Ser Arg Glu Glu Glu Leu Leu Arg Glu Arg145 150 155 160Lys Arg Leu Gly Val Phe Gly Ile Thr Ser Tyr Asp Phe His Ser Glu165 170 175Ser Gly Leu Phe Leu Phe Gln Ala Ser Asn Ser Leu Phe His Cys Arg180 185 190Asp Gly Gly Lys Asn Gly Phe Met Val Ser Pro Met Lys Pro Leu Glu195 200 205Ile Lys Thr Gln Cys Ser Gly Pro Arg Met Asp Pro Lys Ile Cys Pro210 215 220Ala Asp Pro Ala Phe Phe Ser Phe Ile Asn Asn Ser Asp Leu Trp Val225 230 235 240Ala Asn Ile Glu Thr Gly Glu Glu Arg Arg Leu Thr Phe Cys His Gln245 250 255Gly Leu Ser Asn Val Leu Asp Asp Pro Lys Ser Ala Gly Val Ala Thr260 265 270Phe Val Ile Gln Glu Glu Phe Asp Arg Phe Thr Gly Tyr Trp Trp Cys275 280 285Pro Thr Ala Ser Trp Glu Gly Ser Glu Gly Leu Lys Thr Leu Arg Ile290 295 300Leu Tyr Glu Glu Val Asp Glu Ser Glu Val Glu Val Ile His Val Pro305 310 315 320Ser Pro Ala Leu Glu Glu Arg Lys Thr Asp Ser Tyr Arg Tyr Pro Arg325 330 335Thr Gly Ser Lys Asn Pro Lys Ile Ala Leu Lys Leu Ala Glu Phe Gln340 345 350Thr Asp Ser Gln Gly Lys Ile Val Ser Thr Gln Glu Lys Glu Leu Val355 360 365Gln Pro Phe Ser Ser Leu Phe Pro Lys Val Glu Tyr Ile Ala Arg Ala370 375 380Gly Trp Thr Arg Asp Gly Lys Tyr Ala Trp Ala Met Phe Leu Asp Arg385 390 395 400Pro Gln Gln Trp Leu Gln Leu Val Leu Leu Pro Pro Ala Leu Phe Ile405 410 415Pro Ser Thr Glu Asn Glu Glu Gln Arg Leu Ala Ser Ala Arg Ala Val420 425 430Pro Arg Asn Val Gln Pro Tyr Val Val Tyr Glu Glu Val Thr Asn Val435 440 445Trp Ile Asn Val His Asp Ile Phe Tyr Pro Phe Pro Gln Ser Glu Gly450 455 460Glu Asp Glu Leu Cys Phe Leu Arg Ala Asn Glu Cys Lys Thr Gly Phe465 470 475 480Cys His Leu Tyr Lys Val Thr Ala Val Leu Lys Ser Gln Gly Tyr Asp485 490 495Trp Ser Glu Pro Phe Ser Pro Gly Glu Gly Glu Gln Ser Leu Thr Asn
500 505 510Ala Val Asp Ser Ser Arg515<210>26<21l>2411<212>DNA<213>智人(Homo sapiens)<400>26caggccgccg cctgggtcgc tcaacttccg ggtcaaaggt gcctgagccg gcgggtcccc 60tgtgtccgcc gcggctgtcg tcccccgctc ccgccacttc cggggtcgca gtcccgggca120tggagccgcg accgtgaggc gccgctggac ccgggacgac ctgcccagtc cggccgccgc180cccacgtccc ggtctgtgtc ccacgcctgc agctggaatg gaggctctct ggacccttta240gaaggcaccc ctgccctcct gaggtcagct gagcggttaa tgcggaaggt taagaaactg300cgcctggaca aggagaacac cggaagttgg agaagcttct cgctgaattc cgagggggct360gagaggatgg ccaccaccgg gaccccaacg gccgaccgag gcgacgcagc cgccacagat420gacccggccg cccgcttcca ggtgcagaag cactcgtggg acgggctccg gagcatcatc480cacggcagcc gcaagtactc gggcctcatt gtcaacaagg cgccccacga cttccagttt540gtgcagaaga cggatgagtc tgggccccac tcccaccgcc tctactacct gggaatgcca600tatggcagcc gagagaactc cctcctctac tctgagattc ccaagaaggt ccggaaagag660gctctgctgc tcctgtcctg gaagcagatg ctggatcatt tccaggccac gccccaccat720ggggtctact ctcgggagga ggagctgctg agggagcgga aacgcctggg ggtcttcggc780atcacctcct acgacttcca cagcgagagt ggcctcttcc tcttccaggc cagcaacagc840ctcttccact gccgcgacgg cggcaagaac ggcttcatgg tgtcccctat gaaaccgctg900gaaatcaaga cccagtgctc agggccccgg atggacccca aaatctgccc tgccgaccct960gccttcttct ccttcatcaa taacagcgac ctgtgggtgg ccaacatcga gacaggcgag 1020gagcggcggc tgaccttctg ccaccaaggt ttatccaatg tcctggatga ccccaagtct 1080gcgggtgtgg ccaccttcgt catacaggaa gagttcgacc gcttcactgg gtactggtgg 1140tgccccacag cctcctggga aggttcagag ggcctcaaga cgctgcgaat cctgtatgag 1200gaagtcgatg agtccgaggt ggaggtcatt cacgtcccct ctcctgcgct agaagaaagg 1260aagacggact cgtatcggta ccccaggaca ggcagcaaga atcccaagat tgccttgaaa 1320ctggctgagt tccagactga cagccagggc aagatcgtct cgacccagga gaaggagctg 1380gtgcagccct tcagctcgct gttcccgaag gtggagtaca tcgccagggc cgggtggacc 1440cgggatggca aatacgcctg ggccatgttc ctggaccggc cccagcagtg gctccagctc 1500gtcctcctcc ccccggccct gttcatcccg agcacagaga atgaggagca gcggctagcc 1560tctgccagag ctgtccccag gaatgtccag ccgtatgtgg tgtacgagga ggtcaccaac 1620gtctggatca atgttcatga catcttctat cccttccccc aatcagaggg agaggacgag 1680ctctgctttc tccgcgccaa tgaatgcaag accggcttct gccatttgta caaagtcacc 1740gccgttttaa aatcccaggg ctacgattgg agtgagccct tcagccccgg ggaaggtgag 1800cagagcctga cgaatgctgt cgactcatcg cgttagtcac gtgtggttca atatgctgtt 1860tgttcattgg tcggcccccc cactcagcca gcacaccctg cgggagaagg aacagggatc 1920ggcaggaagc cagccttccc cagtgactgc atgatctggc agggcttaga gcacccaact 1980gttggcttat tcaggcagca gatttactga gcacctcccc tgtgccaggc ccttagcaca 2040accaggggtt ggccacctac ggcccacagg tcaaatccgg cccaccacct gtgttcataa 2100ataaagtttt attggcactg agccacagcc acttgtttac agagactgtc tgtggtcgct 2160tttgtgctgc agcagcagaa ctgggtagtc ccagcagaaa ctgttgtgca aggccaagat 2220ttactgtcta gccctttgta gaaacatttg ccagctcctg ctgtaggtag ctgtgatgga 2280attgttcact gtaaataaag aaaaaggaaa atccctgctc ttgggacctt ctagtggagg 2340aggcagtatt ccagaaacag ttagaggtgc tgcctctggt gtgctgtggg tggcagatgc 2400agatcctagt c2411<210>27<211>892<212>PRT<213>智人(Homo sapiens)<400>27Met Arg Lys Val Lys Lys Leu Arg Leu Asp Lys Glu Asn Thr Gly Ser1 5 10 15
Trp Arg Ser Phe Ser Leu Asn Ser Glu Gly Ala Glu Arg Met Ala Thr20 25 30Thr Gly Thr Pro Thr Ala Asp Arg Gly Asp Ala Ala Ala Thr Asp Asp35 40 45Pro Ala Ala Arg Phe Gln Val Gln Lys His Ser Trp Asp Gly Leu Arg50 55 60Ser Ile Ile His Gly Ser Arg Lys Tyr Ser Gly Leu Ile Val Asn Lys65 70 75 80Ala Pro His Asp Phe Gln Phe Val Gln Lys Thr Asp Glu Ser Gly Pro85 90 95His Ser His Arg Leu Tyr Tyr Leu Gly Met Pro Tyr Gly Ser Arg Glu100 105 110Asn Ser Leu Leu Tyr Ser Glu Ile Pro Lys Lys Val Arg Lys Glu Ala115 120 125Leu Leu Leu Leu Ser Trp Lys Gln Met Leu Asp His Phe Gln Ala Thr130 135 140Pro His His Gly Val Tyr Ser Arg Glu Glu Glu Leu Leu Arg Glu Arg145 150 155 160Lys Arg Leu Gly Val Phe Gly Ile Thr Ser Tyr Asp Phe His Ser Glu165 170 175Ser Gly Leu Phe Leu Phe Gln Ala Ser Asn Ser Leu Phe His Cys Arg180 185 190Asp Gly Gly Lys Asn Gly Phe Met Val Ser Pro Met Lys Pro Leu Glu195 200 205Ile Lys Thr Gln Cys Ser Gly Pro Arg Met Asp Pro Lys Ile Cys Pro210 215 220Ala Asp Pro Ala Phe Phe Ser Phe Ile Asn Asn Ser Asp Leu Trp Val225 230 235 240Ala Asn Ile Glu Thr Gly Glu Glu Arg Arg Leu Thr Phe Cys His Gln245 250 255Gly Leu Ser Asn Val Leu Asp Asp Pro Lys Ser Ala Gly Val Ala Thr260 265 270Phe Val Ile Gln Glu Glu Phe Asp Arg Phe Thr Gly Tyr Trp Trp Cys275 280 285Pro Thr Ala Ser Trp Glu Gly Ser Glu Gly Leu Lys Thr Leu Arg Ile290 295 300Leu Tyr Glu Glu Val Asp Glu Ser Glu Val Glu Val Ile His Val Pro305 310 315 320Ser Pro Ala Leu Glu Glu Arg Lys Thr Asp Ser Tyr Arg Tyr Pro Arg325 330 335Thr Gly Ser Lys Asn Pro Lys Ile Ala Leu Lys Leu Ala Glu Phe Gln340 345 350Thr Asp Ser Gln Gly Lys Ile Val Ser Thr Gln Glu Lys Glu Leu Val355 360 365Gln Pro Phe Ser Ser Leu Phe Pro Lys Val Glu Tyr Ile Ala Arg Ala370 375 380Gly Trp Thr Arg Asp Gly Lys Tyr Ala Trp Ala Met Phe Leu Asp Arg385 390 395 400Pro Gln Gln Trp Leu Gln Leu Val Leu Leu Pro Pro Ala Leu Phe Ile405 410 415Pro Ser Thr Glu Asn Glu Glu Gln Arg Leu Ala Ser Ala Arg Ala Val420 425 430Pro Arg Asn Val Gln Pro Tyr Val Val Tyr Glu Glu Val Thr Asn Val435 440 445Trp Ile Asn Val His Asp Ile Phe Tyr Pro Phe Pro Gln Ser Glu Gly450 455 460Glu Asp Glu Leu Cys Phe Leu Arg Ala Asn Glu Cys Lys Thr Gly Phe465 470 475 480Cys His Leu Tyr Lys Val Thr Ala Val Leu Lys Ser Gln Gly Tyr Asp485 490 495
Trp Ser Glu Pro Phe Ser Pro Gly Glu Asp Glu Phe Lys Cys Pro Ile500 505 510Lys Glu Glu Ile Ala Leu Thr Ser Gly Glu Trp Glu Val Leu Ala Arg515 520 525His Gly Ser Lys Ile Trp Val Asn Glu Glu Thr Lys Leu Val Tyr Phe530 535 540Gln Gly Thr Lys Asp Thr Pro Leu Glu His His Leu Tyr Val Val Ser545 550 555 560Tyr Glu Ala Ala Gly Glu Ile Val Arg Leu Thr Thr Pro Gly Phe Ser565 570 575His Ser Cys Ser Met Ser Gln Asn Phe Asp Met Phe Val Ser His Tyr580 585 590Ser Ser Val Ser Thr Pro Pro Cys Val His Val Tyr Lys Leu Ser Gly595 600 605Pro Asp Asp Asp Pro Leu His Lys Gln Pro Arg Phe Trp Ala Ser Met610 615 620Met Glu Ala Ala Ser Cys Pro Pro Asp Tyr Val Pro Pro Glu Ile Phe625 630 635 640His Phe His Thr Arg Ser Asp Val Arg Leu Tyr Gly Met Ile Tyr Lys645 650 655Pro His Ala Leu Gln Pro Gly Lys Lys His Pro Thr Val Leu Phe Val660 665 670Tyr Gly Gly Pro Gln Val Gln Leu Val Asn Asn Ser Phe Lys Gly Ile675 680 685Lys Tyr Leu Arg Leu Asn Thr Leu Ala Ser Leu Gly Tyr Ala Val Val690 695 700Val Ile Asp Gly Arg Gly Ser Cys Gln Arg Gly Leu Arg Phe Glu Gly705 710 715 720Ala Leu Lys Asn Gln Met Gly Gln Val Glu Ile Glu Asp Gln Val Glu725 730 735Gly Leu Gln Phe Val Ala Glu Lys Tyr Gly Phe Ile Asp Leu Ser Arg740 745 750Val Ala Ile His Gly Trp Ser Tyr Gly Gly Phe Leu Ser Leu Met Gly755 760 765Leu Ile His Lys Pro Gln Val Phe Lys Val Ala Ile Ala Gly Ala Pro770 775 780Val Thr Val Trp Met Ala Tyr Asp Thr Gly Tyr Thr Glu Arg Tyr Met785 790 795 800Asp Val Pro Glu Asn Asn Gln His Gly Tyr Glu Ala Gly Ser Val Ala805 810 815Leu His Val Glu Lys Leu Pro Asn Glu Pro Asn Arg Leu Leu Ile Leu820 825 830His Gly Phe Leu Asp Glu Asn Val His Phe Phe His Thr Asn Phe Leu835 840 845Val Ser Gln Leu Ile Arg Ala Gly Lys Pro Tyr Gln Leu Gln Ile Tyr850 855 860
Pro Asn Glu Arg His Ser Ile Arg Cys Pro Glu Ser Gly Glu His Tyr865 870 875 880Glu Val Thr Leu Leu His Phe Leu Gln Glu Tyr Leu885 890<210>28<211>4219<212>DNA<213>智人(Homo sapiens)<400>28caggccgccg cctgggtcgc tcaacttccg ggtcaaaggt gcctgagccg gcgggtcccc 60tgtgtccgcc gcggctgtcg tcccccgctc ccgccacttc cggggtcgca gtcccgggca120tggagccgcg accgtgaggc gccgctggac ccgggacgac ctgcccagtc cggccgccgc180cccacgtccc ggtctgtgtc ccacgcctgc agctggaatg gaggctctct ggacccttta240gaaggcaccc ctgccctcct gaggtcagct gagcggttaa tgcggaaggt taagaaactg300cgcctggaca aggagaacac cggaagttgg agaagcttct cgctgaattc cgagggggct360gagaggatgg ccaccaccgg gaccccaacg gccgaccgag gcgacgcagc cgccacagat420gacccggccg cccgcttcca ggtgcagaag cactcgtggg acgggctccg gagcatcatc480cacggcagcc gcaagtactc gggcctcatt gtcaacaagg cgccccacga cttccagttt540gtgcagaaga cggatgagtc tgggccccac tcccaccgcc tctactacct gggaatgcca600tatggcagcc gagagaactc cctcctctac tctgagattc ccaagaaggt ccggaaagag660gctctgctgc tcctgtcctg gaagcagatg ctggatcatt tccaggccac gccccaccat720ggggtctact ctcgggagga ggagctgctg agggagcgga aacgcctggg ggtcttcggc780atcacctcct acgacttcca cagcgagagt ggcctcttcc tcttccaggc cagcaacagc840ctcttccact gccgcgacgg cggcaagaac ggcttcatgg tgtcccctat gaaaccgctg900gaaatcaaga cccagtgctc agggccccgg atggacccca aaatctgccc tgccgaccct960gccttcttct ccttcatcaa taacagcgac ctgtgggtgg ccaacatcga gacaggcgag 1020gagcggcggc tgaccttctg ccaccaaggt ttatccaatg tcctggatga ccccaagtct 1080gcgggtgtgg ccaccttcgt catacaggaa gagttcgacc gcttcactgg gtactggtgg 1140tgccccacag cctcctggga aggttcagag ggcctcaaga cgctgcgaat cctgtatgag 1200gaagtcgatg agtccgaggt ggaggtcatt cacgtcccct ctcctgcgct agaagaaagg 1260aagacggact cgtatcggta ccccaggaca ggcagcaaga atcccaagat tgccttgaaa 1320ctggctgagt tccagactga cagccagggc aagatcgtct cgacccagga gaaggagctg 1380gtgcagccct tcagctcgct gttcccgaag gtggagtaca tcgccagggc cgggtggacc 1440cgggatggca aatacgcctg ggccatgttc ctggaccggc cccagcagtg gctccagctc 1500gtcctcctcc ccccggccct gttcatcccg agcacagaga atgaggagca gcggctagcc 1560tctgccagag ctgtccccag gaatgtccag ccgtatgtgg tgtacgagga ggtcaccaac 1620gtctggatca atgttcatga catcttctat cccttccccc aatcagaggg agaggacgag 1680ctctgctttc tccgcgccaa tgaatgcaag accggcttct gccatttgta caaagtcacc 1740gccgttttaa aatcccaggg ctacgattgg agtgagccct tcagccccgg ggaagatgaa 1800tttaagtgcc ccattaagga agagattgct ctgaccagcg gtgaatggga ggttttggcg 1860aggcacggct ccaagatctg ggtcaatgag gagaccaagc tggtgtactt ccagggcacc 1920aaggacacgc cgctggagca ccacctctac gtggtcagct atgaggcggc cggcgagatc 1980gtacgcctca ccacgcccgg cttctcccat agctgctcca tgagccagaa cttcgacatg 2040ttcgtcagcc actacagcag cgtgagcacg ccgccctgcg tgcacgtcta caagctgagc 2100ggccccgacg acgaccccct gcacaagcag ccccgcttct gggctagcat gatggaggca 2160gccagctgcc ccccggatta tgttcctcca gagatcttcc atttccacac gcgctcggat 2220gtgcggctct acggcatgat ctacaagccc cacgccttgc agccagggaa gaagcacccc 2280accgtcctct ttgtatatgg aggcccccag gtgcagctgg tgaataactc cttcaaaggc 2340atcaagtact tgcggctcaa cacactggcc tccctgggct acgccgtggt tgtgattgac 2400ggcaggggct cctgtcagcg agggcttcgg ttcgaagggg ccctgaaaaa ccaaatgggc 2460caggtggaga tcgaggacca ggtggagggc ctgcagttcg tggccgagaa gtatggcttc 2520atcgacctga gccgagttgc catccatggc tggtcctacg ggggcttcct ctcgctcatg 2580gggctaatcc acaagcccca ggtgttcaag gtggccatcg cgggtgcccc ggtcaccgtc 2640tggatggcct acgacacagg gtacactgag cgctacatgg acgtccctga gaacaaccag 2700cacggctatg aggcgggttc cgtggccctg cacgtggaga agctgcccaa tgagcccaac 2760cgcttgctta tcctccacgg cttcctggac gaaaacgtgc actttttcca cacaaacttc 2820ctcgtctccc aactgatccg agcagggaaa ccttaccagc tccagatcta ccccaacgag 2880agacacagta ttcgctgccc cgagtcgggc gagcactatg aagtcacgtt gctgcacttt 2940
ctacaggaat acctctgagc ctgcccaccg ggagccgcca catcacagca caagtggctg 3000cagcctccgc ggggaaccag gcgggaggga ctgagtggcc cgcgggcccc agtgaggcac 3060tttgtcccgc ccagcgctgg ccagccccga ggagccgctg ccttcaccgc cccgacgcct 3120tttatccttt tttaaacgct cttgggtttt atgtccgctg cttcttggtt gccgagacag 3180agagatggtg gtctcgggcc agcccctcct ctccccgcct tctgggagga ggaggtcaca 3240cgctgatggg cactggagag gccagaagag actcagagga gcgggctgcc ttccgcctgg 3300ggctccctgt gacctctcag tcccctggcc cggccagcca ccgtccccag cacccaagca 3360tgcaattgcc tgtccccccc ggccagcctc cccaacttga tgtttgtgtt ttgtttgggg 3420ggatattttt cataattatt taaaagacag gccgggcgcg gtggctcacg tctgtaatcc 3480cagcactttg ggaggctgag gcgggcggat cacctgaggt tgggagttca agaccagcct 3540ggccaacatg gggaaacccc gtctctacta aaaatacaaa aaattagccg ggtgtggtgg 3600cgcgtgccta taatcccagc tactcgggag gctgaggcag gagaatcgct tgaacccggg 3660aggtggaggt tgcggtgagc caagatcgca ccattgcact ccagcctggg caacaagagc 3720gaaactctgt ctcaaaataa ataaaaaata aaagacagaa agcaaggggt gcctaaatct 3780agacttgggg tccacaccgg gcagcggggt tgcaacccag cacctggtag gctccatttc 3840ttcccaagcc cgactttcag gcaggcactg aaacgcaccg aacttccacg ctctgctggt 3900cagtggcggc tgtcccctcc ccagcccagc cgcccagcca catgtgtctg cctgacccgt 3960acacaccagg ggttccgggg ttgggagctg aaccatcccc acctcagggt tatatttccc 4020tctccccttc cctccccgcc aagagctctg ccaggggcgg gcaaaaaaaa aagtaaaaag 4080aaaagaaaaa aaaaaaaaag saacaaacca cctctacata ttatggaaag aaaatatttt 4140tgtcgattct tattctttta taattatgcg tggaagaagt agacacatta aacgattcca 4200gttggaaaca tgtcacctg4219<210>29<211>832<212>PRT<213>智人(Homo sapiens)<400>29Met Arg Lys Val Lys Lys Leu Arg Leu Asp Lys Glu Asn Thr Gly Ser1 5 10 15Trp Arg Ser Phe Ser Leu Asn Ser Glu Gly Ala Glu Arg Met Ala Thr20 25 30Thr Gly Thr Pro Thr Ala Asp Arg Gly Asp Ala Ala Ala Thr Asp Asp35 40 45Pro Ala Ala Arg Phe Gln Val Gln Lys His Ser Trp Asp Gly Leu Arg50 55 60Ser Ile Ile His Gly Ser Arg Lys Tyr Ser Gly Leu Ile Val Asn Lys65 70 75 80Ala Pro His Asp Phe Gln Phe Val Gln Lys Thr Asp Glu Ser Gly Pro85 90 95His Ser His Arg Leu Tyr Tyr Leu Gly Met Pro Tyr Gly Ser Arg Glu100 105 110Asn Ser Leu Leu Tyr Ser Glu Ile Pro Lys Lys Val Arg Lys Glu Ala115 120 125Leu Leu Leu Leu Ser Trp Lys Gln Met Leu Asp His Phe Gln Ala Thr130 135 140Pro His His Gly Val Tyr Ser Arg Glu Glu Glu Leu Leu Arg Glu Arg145 150 155 160Lys Arg Leu Gly Val Phe Gly Ile Thr Ser Tyr Asp Phe His Ser Glu165 170 175Ser Gly Leu Phe Leu Phe Gln Ala Ser Asn Ser Leu Phe His Cys Arg180 185 190Asp Gly Gly Lys Asn Gly Phe Met Val Ser Pro Met Lys Pro Leu Glu195 200 205Ile Lys Thr Gln Cys Ser Gly Pro Arg Met Asp Pro Lys Ile Cys Pro210 215 220Ala Asp Pro Ala Phe Phe Ser Phe Ile Asn Asn Ser Asp Leu Trp Val225 230 235 240Ala Asn Ile Glu Thr Gly Glu Glu Arg Arg Leu Thr Phe Cys His Gln
245 250 255Gly Leu Ser Asn Val Leu Asp Asp Pro Lys Ser Ala Gly Val Ala Thr260 265 270Phe Val Ile Gln Glu Glu Phe Asp Arg Phe Thr Gly Tyr Trp Trp Cys275 280 285Pro Thr Ala Ser Trp Glu Gly Ser Glu Gly Leu Lys Thr Leu Arg Ile290 295 300Leu Tyr Glu Glu Val Asp Glu Ser Glu Val Glu Val Ile His Val Pro305 310 315 320Ser Pro Ala Leu Glu Glu Arg Lys Thr Asp Ser Tyr Arg Tyr Pro Arg325 330 335Thr Gly Ser Lys Asn Pro Lys Ile Ala Leu Lys Leu Ala Glu Phe Gln340 345 350Thr Asp Ser Gln Gly Lys Ile Val Ser Thr Gln Glu Lys Glu Leu Val355 360 365Gln Pro Phe Ser Ser Leu Phe Pro Lys Val Glu Tyr Ile Ala Arg Ala370 375 380Gly Trp Thr Arg Asp Gly Lys Tyr Ala Trp Ala Met Phe Leu Asp Arg385 390 395 400Pro Gln Gln Trp Leu Gln Leu Val Leu Leu Pro Pro Ala Leu Phe Ile405 410 415Pro Ser Thr Glu Asn Glu Glu Gln Arg Leu Ala Ser Ala Arg Ala Val420 425 430Pro Arg Asn Val Gln Pro Tyr Val Val Tyr Glu Glu Val Thr Asn Val435 440 445Trp Ile Asn Val His Asp Ile Phe Tyr Pro Phe Pro Gln Ser Glu Gly450 455 460Glu Asp Glu Leu Cys Phe Leu Arg Ala Asn Glu Cys Lys Thr Gly Phe465 470 475 480Cys His Leu Tyr Lys Val Thr Ala Val Leu Lys Ser Gln Gly Tyr Asp485 490 495Trp Ser Glu Pro Phe Ser Pro Gly Glu Asp Glu Phe Lys Cys Pro Ile500 505 510Lys Glu Glu Ile Ala Leu Thr Ser Gly Glu Trp Glu Val Leu Ala Arg515 520 525His Gly Ser Lys Ile Trp Val Asn Glu Glu Thr Lys Leu Val Tyr Phe530 535 540Gln Gly Thr Lys Asp Thr Pro Leu Glu His His Leu Tyr Val Val Ser545 550 555 560Tyr Glu Ala Ala Gly Glu Ile Val Arg Leu Thr Thr Pro Gly Phe Ser565 570 575His Ser Cys Ser Met Ser Gln Asn Phe Asp Met Phe Val Ser His Tyr580 585 590Ser Ser Val Ser Thr Pro Pro Cys Val His Val Tyr Lys Leu Ser Gly595 600 605Pro Asp Asp Asp Pro Leu His Lys Gln Pro Arg Phe Trp Ala Ser Met610 615 620Met Glu Ala Ala Ser Cys Pro Pro Asp Tyr Val Pro Pro Glu Ile Phe625 630 635 640His Phe His Thr Arg Ser Asp Val Arg Leu Tyr Gly Met Ile Tyr Lys645 650 655Pro His Ala Leu Gln Pro Gly Lys Lys His Pro Thr Val Leu Phe Val660 665 670Tyr Gly Gly Pro Gln Val Gln Leu Val Asn Asn Ser Phe Lys Gly Ile675 680 685Lys Tyr Leu Arg Leu Asn Thr Leu Ala Ser Leu Gly Tyr Ala Val Val690 695 700Val Ile Asp Gly Arg Gly Ser Cys Gln Arg Gly Leu Arg Phe Glu Gly705 710 715 720Ala Leu Lys Asn Gln Met Gly Gln Val Glu Ile Glu Asp Gln Val Glu
725 730 735Gly Leu Gln Phe Val Ala Glu Lys Tyr Gly Phe Ile Asp Leu Ser Arg740 745 750Val Ala Ile His Gly Trp Ser Tyr Gly Gly Phe Leu Ser Leu Met Gly755 760 765Leu Ile His Lys Pro Gln Val Phe Lys Ala Gln Pro Leu Ala Tyr Pro770 775 780Pro Arg Leu Pro Gly Arg Lys Arg Ala Leu Phe Pro His Lys Leu Pro785 790 795 800Arg Leu Pro Thr Asp Pro Ser Arg Glu Thr Leu Pro Ala Pro Asp Leu805 810 815Pro Gln Arg Glu Thr Gln Tyr Ser Leu Pro Arg Val Gly Arg Ala Leu820 825 830<210>30<211>4159<212>DNA<213>智人(Homo sapiens)<400>30caggccgccg cctgggtcgc tcaacttccg ggtcaaaggt gcctgagccg gcgggtcccc 60tgtgtccgcc gcggctgtcg tcccccgctc ccgccacttc cggggtcgca gtcccgggca120tggagccgcg accgtgaggc gccgctggac ccgggacgac ctgcccagtc cggccgccgc180cccacgtccc ggtctgtgtc ccacgcctgc agctggaatg gaggctctct ggacccttta240gaaggcaccc ctgccctcct gaggtcagct gagcggttaa tgcggaaggt taagaaactg300cgcctggaca aggagaacac cggaagttgg agaagcttct cgctgaattc cgagggggct360gagaggatgg ccaccaccgg gaccccaacg gccgaccgag gcgacgcagc cgccacagat420gacccggccg cccgcttcca ggtgcagaag cactcgtggg acgggctccg gagcatcatc480cacggcagcc gcaagtactc gggcctcatt gtcaacaagg cgccccacga cttccagttt540gtgcagaaga cggatgagtc tgggccccac tcccaccgcc tctactacct gggaatgcca600tatggcagcc gagagaactc cctcctctac tctgagattc ccaagaaggt ccggaaagag660gctctgctgc tcctgtcctg gaagcagatg ctggatcatt tccaggccac gccccaccat720ggggtctact ctcgggagga ggagctgctg agggagcgga aacgcctggg ggtcttcggc780atcacctcct acgacttcca cagcgagagt ggcctcttcc tcttccaggc cagcaacagc840ctcttccact gccgcgacgg cggcaagaac ggcttcatgg tgtcccctat gaaaccgctg900gaaatcaaga cccagtgctc agggccccgg atggacccca aaatctgccc tgccgaccct960gccttcttct ccttcatcaa taacagcgac ctgtgggtgg ccaacatcga gacaggcgag 1020gagcggcggc tgaccttctg ccaccaaggt ttatccaatg tcctggatga ccccaagtct 1080gcgggtgtgg ccaccttcgt catacaggaa gagttcgacc gcttcactgg gtactggtgg 1140tgccccacag cctcctggga aggttcagag ggcctcaaga cgctgcgaat cctgtatgag 1200gaagtcgatg agtccgaggt ggaggtcatt cacgtcccct ctcctgcgct agaagaaagg 1260aagacggact cgtatcggta ccccaggaca ggcagcaaga atcccaagat tgccttgaaa 1320ctggctgagt tccagactga cagccagggc aagatcgtct cgacccagga gaaggagctg 1380gtgcagccct tcagctcgct gttcccgaag gtggagtaca tcgccagggc cgggtggacc 1440cgggatggca aatacgcctg ggccatgttc ctggaccggc cccagcagtg gctccagctc 1500gtcctcctcc ccccggccct gttcatcccg agcacagaga atgaggagca gcggctagcc 1560tctgccagag ctgtccccag gaatgtccag ccgtatgtgg tgtacgagga ggtcaccaac 1620gtctggatca atgttcatga catcttctat cccttccccc aatcagaggg agaggacgag 1680ctctgctttc tccgcgccaa tgaatgcaag accggcttct gccatttgta caaagtcacc 1740gccgttttaa aatcccaggg ctacgattgg agtgagccct tcagccccgg ggaagatgaa 1800tttaagtgcc ccattaagga agagattgct ctgaccagcg gtgaatggga ggttttggcg 1860aggcacggct ccaagatctg ggtcaatgag gagaccaagc tggtgtactt ccagggcacc 1920aaggacacgc cgctggagca ccacctctac gtggtcagct atgaggcggc cggcgagatc 1980gtacgcctca ccacgcccgg cttctcccat agctgctcca tgagccagaa cttcgacatg 2040ttcgtcagcc actacagcag cgtgagcacg ccgccctgcg tgcacgtcta caagctgagc 2100ggccccgacg acgaccccct gcacaagcag ccccgcttct gggctagcat gatggaggca 2160gccagctgcc ccccggatta tgttcctcca gagatcttcc atttccacac gcgctcggat 2220gtgcggctct acggcatgat ctacaagccc cacgccttgc agccagggaa gaagcacccc 2280accgtcctct ttgtatatgg aggcccccag gtgcagctgg tgaataactc cttcaaaggc 2340atcaagtact tgcggctcaa cacactggcc tccctgggct acgccgtggt tgtgattgac 2400
ggcaggggct cctgtcagcg agggcttcgg ttcgaagggg ccctgaaaaa ccaaatgggc 2460caggtggaga tcgaggacca ggtggagggc ctgcagttcg tggccgagaa gtatggcttc 2520atcgacctga gccgagttgc catccatggc tggtcctacg ggggcttcct ctcgctcatg 2580gggctaatcc acaagcccca ggtgttcaag gcccaaccgc ttgcttatcc tccacggctt 2640cctggacgaa aacgtgcact ttttccacac aaacttcctc gtctcccaac tgatccgagc 2700agggaaacct taccagctcc agatctaccc caacgagaga cacagtattc gctgccccga 2760gtcgggcgag cactatgaag tcacgttgct gcactttcta caggaatacc tctgagcctg 2820cccaccggga gccgccacat cacagcacaa gtggctgcag cctccgcggg gaaccaggcg 2880ggagggactg agtggcccgc gggccccagt gaggcacttt gtcccgccca gcgctggcca 2940gccccgagga gccgctgcct tcaccgcccc gacgcctttt atcctttttt aaacgctctt 3000gggttttatg tccgctgctt cttggttgcc gagacagaga gatggtggtc tcgggccagc 3060ccctcctctc cccgccttct gggaggagga ggtcacacgc tgatgggcac tggagaggcc 3120agaagagact cagaggagcg ggctgccttc cgcctggggc tccctgtgac ctctcagtcc 3180cctggcccgg ccagccaccg tccccagcac ccaagcatgc aattgcctgt cccccccggc 3240cagcctcccc aacttgatgt ttgtgttttg tttgggggga tatttttcat aattatttaa 3300aagacaggcc gggcgcggtg gctcacgtct gtaatcccag cactttggga ggctgaggcg 3360ggcggatcac ctgaggttgg gagttcaaga ccagcctggc caacatgggg aaaccccgtc 3420tctactaaaa atacaaaaaa ttagccgggt gtggtggcgc gtgcctataa tcccagctac 3480tcgggaggct gaggcaggag aatcgcttga acccgggagg tggaggttgc ggtgagccaa 3540gatcgcacca ttgcactcca gcctgggcaa caagagcgaa actctgtctc aaaataaata 3600aaaaataaaa gacagaaagc aaggggtgcc taaatctaga cttggggtcc acaccgggca 3660gcggggttgc aacccagcac ctggtaggct ccatttcttc ccaagcccga gcagagggtc 3720atgcgggccc cacaggagaa gcggccaggg cccgcggggg gcaccacctg tggacagccc 3780tcctgtcccc aagctttcag gcaggcactg aaacgcaccg aacttccacg ctctgctggt 3840cagtggcggc tgtcccctcc ccagcccagc cgcccagcca catgtgtctg cctgacccgt 3900acacaccagg ggttccgggg ttgggagctg aaccatcccc acctcagggt tatatttccc 3960tctccccttc cctccccgcc aagagctctg ccaggggcgg gcaaaaaaaa aagtaaaaag 4020aaaagaaaaa aaaaaaaaag aaacaaacca cctctacata ttatggaaag aaaatatttt 4080tgtcgattct tattctttta taattatgcg tggaagaagt agacacatta aacgattcca 4140gttggaaaca tgtcacctg4159<210>31<211>832<212>PRT<213>智人(Homo sapiens)<400>31Met Arg Lys Val Lys Lys Leu Arg Leu Asp Lys Glu Asn Thr Gly Ser1 5 10 15Trp Arg Ser Phe Ser Leu Asn Ser Glu Gly Ala Glu Arg Met Ala Thr20 25 30Thr Gly Thr Pro Thr Ala Asp Arg Gly Asp Ala Ala Ala Thr Asp Asp35 40 45Pro Ala Ala Arg Phe Gln Val Gln Lys His Ser Trp Asp Gly Leu Arg50 55 60Ser Ile Ile His Gly Ser Arg Lys Tyr Ser Gly Leu Ile Val Asn Lys65 70 75 80Ala Pro His Asp Phe Gln Phe Val Gln Lys Thr Asp Glu Ser Gly Pro85 90 95His Ser His Arg Leu Tyr Tyr Leu Gly Met Pro Tyr Gly Ser Arg Glu100 105 110Asn Ser Leu Leu Tyr Ser Glu Ile Pro Lys Lys Val Arg Lys Glu Ala115 120 125Leu Leu Leu Leu Ser Trp Lys Gln Met Leu Asp His Phe Gln Ala Thr130 135 140Pro His His Gly Val Tyr Ser Arg Glu Glu Glu Leu Leu Arg Glu Arg145 150 155 160Lys Arg Leu Gly Val Phe Gly Ile Thr Ser Tyr Asp Phe His Ser Glu165 170 175Ser Gly Leu Phe Leu Phe Gln Ala Ser Asn Ser Leu Phe His Cys Arg
180 185 190Asp Gly Gly Lys Asn Gly Phe Met Val Ser Pro Met Lys Pro Leu Glu195 200 205Ile Lys Thr Gln Cys Ser Gly Pro Arg Met Asp Pro Lys Ile Cys Pro210 215 220Ala Asp Pro Ala Phe Phe Ser Phe Ile Asn Asn Ser Asp Leu Trp Val225 230 235 240Ala Asn Ile Glu Thr Gly Glu Glu Arg Arg Leu Thr Phe Cys His Gln245 250 255Gly Leu Ser Asn Val Leu Asp Asp Pro Lys Ser Ala Gly Val Ala Thr260 265 270Phe Val Ile Gln Glu Glu Phe Asp Arg Phe Thr Gly Tyr Trp Trp Cys275 280 285Pro Thr Ala Ser Trp Glu Gly Ser Glu Gly Leu Lys Thr Leu Arg Ile290 295 300Leu Tyr Glu Glu Val Asp Glu Ser Glu Val Glu Val Ile His Val Pro305 310 315 320Ser Pro Ala Leu Glu Glu Arg Lys Thr Asp Ser Tyr Arg Tyr Pro Arg325 330 335Thr Gly Ser Lys Asn Pro Lys Ile Ala Leu Lys Leu Ala Glu Phe Gln340 345 350Thr Asp Ser Gln Gly Lys Ile Val Ser Thr Gln Glu Lys Glu Leu Val355 360 365Gln Pro Phe Ser Ser Leu Phe Pro Lys Val Glu Tyr Ile Ala Arg Ala370 375 380Gly Trp Thr Arg Asp Gly Lys Tyr Ala Trp Ala Met Phe Leu Asp Arg385 390 395 400Pro Gln Gln Trp Leu Gln Leu Val Leu Leu Pro Pro Ala Leu Phe Ile405 410 415Pro Ser Thr Glu Asn Glu Glu Gln Arg Leu Ala Ser Ala Arg Ala Val420 425 430Pro Arg Asn Val Gln Pro Tyr Val Val Tyr Glu Glu Val Thr Asn Val435 440 445Trp Ile Asn Val His Asp Ile Phe Tyr Pro Phe Pro Gln Ser Glu Gly450 455 460Glu Asp Glu Leu Cys Phe Leu Arg Ala Asn Glu Cys Lys Thr Gly Phe465 470 475 480Cys His Leu Tyr Lys Val Thr Ala Val Leu Lys Ser Gln Gly Tyr Asp485 490 495Trp Ser Glu Pro Phe Ser Pro Gly Glu Asp Glu Phe Lys Cys Pro Ile500 505 510Lys Glu Glu Ile Ala Leu Thr Ser Gly Glu Trp Glu Val Leu Ala Arg515 520 525His Gly Ser Lys Ile Trp Val Asn Glu Glu Thr Lys Leu Val Tyr Phe530 535 540Gln Gly Thr Lys Asp Thr Pro Leu Glu His His Leu Tyr Val Val Ser545 550 555 560Tyr Glu Ala Ala Gly Glu Ile Val Arg Leu Thr Thr Pro Gly Phe Ser565 570 575His Ser Cys Ser Met Ser Gln Asn Phe Asp Met Phe Val Ser His Tyr580 585 590Ser Ser Val Ser Thr Pro Pro Cys Val His Val Tyr Lys Leu Ser Gly595 600 605Pro Asp Asp Asp Pro Leu His Lys Gln Pro Arg Phe Trp Ala Ser Met610 615 620Met Glu Ala Ala Ser Cys Pro Pro Asp Tyr Val Pro Pro Glu Ile Phe625 630 635 640His Phe His Thr Arg Ser Asp Val Arg Leu Tyr Gly Met Ile Tyr Lys645 650 655Pro His Ala Leu Gln Pro Gly Lys Lys His Pro Thr Val Leu Phe Val
660 665 670Tyr Gly Gly Pro Gln Val Gln Leu Val Asn Asn Ser Phe Lys Gly Ile675 680 685Lys Tyr Leu Arg Leu Asn Thr Leu Ala Ser Leu Gly Tyr Ala Val Val690 695 700Val Ile Asp Gly Arg Gly Ser Cys Gln Arg Gly Leu Arg Phe Glu Gly705 710 715 720Ala Leu Lys Asn Gln Met Gly Gln Val Glu Ile Glu Asp Gln Val Glu725 730 735Gly Leu Gln Phe Val Ala Glu Lys Tyr Gly Phe Ile Asp Leu Ser Arg740 745 750Val Ala Ile His Gly Trp Ser Tyr Gly Gly Phe Leu Ser Leu Met Gly755 760 765Leu Ile His Lys Pro Gln Val Phe Lys Ala Gln Pro Leu Ala Tyr Pro770 775 780Pro Arg Leu Pro Gly Arg Lys Arg Ala Leu Phe Pro His Lys Leu Pro785 790 795 800Arg Leu Pro Thr Asp Pro Ser Arg Glu Thr Leu Pro Ala Pro Asp Leu805 810 815Pro Gln Arg Glu Thr Gln Tyr Ser Leu Pro Arg Val Gly Arg Ala Leu820 825 830<210>32<211>4076<212>DNA<213>智人(Homo sapiens)<400>32caggccgccg cctgggtcgc tcaacttccg ggtcaaaggt gcctgagccg gcgggtcccc 60tgtgtccgcc gcggctgtcg tcccccgctc ccgccacttc cggggtcgca gtcccgggca120tggagccgcg accgtgaggc gccgctggac ccgggacgac ctgcccagtc cggccgccgc180cccacgtccc ggtctgtgtc ccacgcctgc agctggaatg gaggctctct ggacccttta240gaaggcaccc ctgccctcct gaggtcagct gagcggttaa tgcggaaggt taagaaactg300cgcctggaca aggagaacac cggaagttgg agaagcttct cgctgaattc cgagggggct360gagaggatgg ccaccaccgg gaccccaacg gccgaccgag gcgacgcagc cgccacagat420gacccggccg cccgcttcca ggtgcagaag cactcgtggg acgggctccg gagcatcatc480cacggcagcc gcaagtactc gggcctcatt gtcaacaagg cgccccacga cttccagttt540gtgcagaaga cggatgagtc tgggccccac tcccaccgcc tctactacct gggaatgcca600tatggcagcc gagagaactc cctcctctac tctgagattc ccaagaaggt ccggaaagag660gctctgctgc tcctgtcctg gaagcagatg ctggatcatt tccaggccac gccccaccat720ggggtctact ctcgggagga ggagctgctg agggagcgga aacgcctggg ggtcttcggc780atcacctcct acgacttcca cagcgagagt ggcctcttcc tcttccaggc cagcaacagc840ctcttccact gccgcgacgg cggcaagaac ggcttcatgg tgtcccctat gaaaccgctg900gaaatcaaga cccagtgctc agggccccgg atggacccca aaatctgccc tgccgaccct960gccttcttct ccttcatcaa taacagcgac ctgtgggtgg ccaacatcga gacaggcgag 1020gagcggcggc tgaccttctg ccaccaaggt ttatccaatg tcctggatga ccccaagtct 1080gcgggtgtgg ccaccttcgt catacaggaa gagttcgacc gcttcactgg gtactggtgg 1140tgccccacag cctcctggga aggttcagag ggcctcaaga cgctgcgaat cctgtatgag 1200gaagtcgatg agtccgaggt ggaggtcatt cacgtcccct ctcctgcgct agaagaaagg 1260aagacggact cgtatcggta ccccaggaca ggcagcaaga atcccaagat tgccttgaaa 1320ctggctgagt tccagactga cagccagggc aagatcgtct cgacccagga gaaggagctg 1380gtgcagccct tcagctcgct gttcccgaag gtggagtaca tcgccagggc cgggtggacc 1440cgggatggca aatacgcctg ggccatgttc ctggaccggc cccagcagtg gctccagctc 1500gtcctcctcc ccccggccct gttcatcccg agcacagaga atgaggagca gcggctagcc 1560tctgccagag ctgtccccag gaatgtccag ccgtatgtgg tgtacgagga ggtcaccaac 1620gtctggatca atgttcatga catcttctat cccttccccc aatcagaggg agaggacgag 1680ctctgctttc tccgcgccaa tgaatgcaag accggcttct gccatttgta caaagtcacc 1740gccgttttaa aatcccaggg ctacgattgg agtgagccct tcagccccgg ggaagatgaa 1800tttaagtgcc ccattaagga agagattgct ctgaccagcg gtgaatggga ggttttggcg 1860aggcacggct ccaagatctg ggtcaatgag gagaccaagc tggtgtactt ccagggcacc 1920
aaggacacgc cgctggagca ccacctctac gtggtcagct atgaggcggc cggcgagatc 1980gtacgcctca ccacgcccgg cttctcccat agctgctcca tgagccagaa cttcgacatg 2040ttcgtcagcc actacagcag cgtgagcacg ccgccctgcg tgcacgtcta caagctgagc 2100ggccccgacg acgaccccct gcacaagcag ccccgcttct gggctagcat gatggaggca 2160gccagctgcc ccccggatta tgttcctcca gagatcttcc atttccacac gcgctcggat 2220gtgcggctct acggcatgat ctacaagccc cacgccttgc agccagggaa gaagcacccc 2280accgtcctct ttgtatatgg aggcccccag gtgcagctgg tgaataactc cttcaaaggc 2340atcaagtact tgcggctcaa cacactggcc tccctgggct acgccgtggt tgtgattgac 2400ggcaggggct cctgtcagcg agggcttcgg ttcgaagggg ccctgaaaaa ccaaatgggc 2460caggtggaga tcgaggacca ggtggagggc ctgcagttcg tggccgagaa gtatggcttc 2520atcgacctga gccgagttgc catccatggc tggtcctacg ggggcttcct ctcgctcatg 2580gggctaatcc acaagcccca ggtgttcaag gcccaaccgc ttgcttatcc tccacggctt 2640cctggacgaa aacgtgcact ttttccacac aaacttcctc gtctcccaac tgatccgagc 2700agggaaacct taccagctcc agatctaccc caacgagaga cacagtattc gctgccccga 2760gtcgggcgag cactatgaag tcacgttgct gcactttcta caggaatacc tctgagcctg 2820cccaccggga gccgccacat cacagcacaa gtggctgcag cctccgcggg gaaccaggcg 2880ggagggactg agtggcccgc gggccccagt gaggcacttt gtcccgccca gcgctggcca 2940gccccgagga gccgctgcct tcaccgcccc gacgcctttt atcctttttt aaacgctctt 3000gggttttatg tccgctgctt cttggttgcc gagacagaga gatggtggtc tcgggccagc 3060ccctcctctc cccgccttct gggaggagga ggtcacacgc tgatgggcac tggagaggcc 3120agaagagact cagaggagcg ggctgccttc cgcctggggc tccctgtgac ctctcagtcc 3180cctggcccgg ccagccaccg tccccagcac ccaagcatgc aattgcctgt cccccccggc 3240cagcctcccc aacttgatgt ttgtgttttg tttgggggga tatttttcat aattatttaa 3300aagacaggcc gggcgcggtg gctcacgtct gtaatcccag cactttggga ggctgaggcg 3360ggcggatcac ctgaggttgg gagttcaaga ccagcctggc caacatgggg aaaccccgtc 3420tctactaaaa atacaaaaaa ttagccgggt gtggtggcgc gtgcctataa tcccagctac 3480tcgggaggct gaggcaggag aatcgcttga acccgggagg tggaggttgc ggtgagccaa 3540gatcgcacca ttgcactcca gcctgggcaa caagagcgaa actctgtctc aaaataaata 3600aaaaataaaa gacagaaagc aaggggtgcc taaatctaga cttggggtcc acaccgggca 3660gcggggttgc aacccagcac ctggtaggct ccatttcttc ccaagcccga ctttcaggca 3720ggcactgaaa cgcaccgaac ttccacgctc tgctggtcag tggcggctgt cccctcccca 3780gcccagccgc ccagccacat gtgtctgcct gacccgtaca caccaggggt tccggggttg 3840ggagctgaac catccccacc tcagggttat atttccctct ccccttccct ccccgccaag 3900agctctgcca ggggcgggca aaaaaaaaag taaaaagaaa agaaaaaaaa aaaaaagaaa 3960caaaccacct ctacatatta tggaaagaaa atatttttgt cgattcttat tcttttataa 4020ttatgcgtgg aagaagtaga cacattaaac gattccagtt ggaaacatgt cacctg 4076<210>33<211>879<212>PRT<213>智人(Homo sapiens)<400>33Met Arg Lys Val Lys Lys Leu Arg Leu Asp Lys Glu Asn Thr Gly Ser1 5 10 15Trp Arg Ser Phe Ser Leu Asn Ser Glu Gly Ala Glu Arg Met Ala Thr20 25 30Thr Gly Thr Pro Thr Ala Asp Arg Gly Asp Ala Ala Ala Thr Asp Asp35 40 45Pro Ala Ala Arg Phe Gln Val Gln Lys His Ser Trp Asp Gly Leu Arg50 55 60Ser Ile Ile His Gly Ser Arg Lys Tyr Ser Gly Leu Ile Val Asn Lys65 70 75 80Ala Pro His Asp Phe Gln Phe Val Gln Lys Thr Asp Glu Ser Gly Pro85 90 95His Ser His Arg Leu Tyr Tyr Leu Gly Met Pro Tyr Gly Ser Arg Glu100 105 110Asn Ser Leu Leu Tyr Ser Glu Ile Pro Lys Lys Val Arg Lys Glu Ala115 120 125Leu Leu Leu Leu Ser Trp Lys Gln Met Leu Asp His Phe Gln Ala Thr
130 135 140Pro His His Gly Val Tyr Ser Arg Glu Glu Glu Leu Leu Arg Glu Arg145 150 155 160Lys Arg Leu Gly Val Phe Gly Ile Thr Ser Tyr Asp Phe His Ser Glu165 170 175Ser Gly Leu Phe Leu Phe Gln Ala Ser Asn Ser Leu Phe His Cys Arg180 185 190Asp Gly Gly Lys Asn Gly Phe Met Val Ser Pro Met Lys Pro Leu Glu195 200 205Ile Lys Thr Gln Cys Ser Gly Pro Arg Met Asp Pro Lys Ile Cys Pro210 215 220Ala Asp Pro Ala Phe Phe Ser Phe Ile Asn Asn Ser Asp Leu Trp Val225 230 235 240Ala Asn Ile Glu Thr Gly Glu Glu Arg Arg Leu Thr Phe Cys His Gln245 250 255Gly Leu Ser Asn Val Leu Asp Asp Pro Lys Ser Ala Gly Val Ala Thr260 265 270Phe Val Ile Gln Glu Glu Phe Asp Arg Phe Thr Gly Tyr Trp Trp Cys275 280 285Pro Thr Ala Ser Trp Glu Gly Ser Glu Gly Leu Lys Thr Leu Arg Ile290 295 300Leu Tyr Glu Glu Val Asp Glu Ser Glu Val Glu Val Ile His Val Pro305 310 315 320Ser Pro Ala Leu Glu Glu Arg Lys Thr Asp Ser Tyr Arg Tyr Pro Arg325 330 335Thr Gly Ser Lys Asn Pro Lys Ile Ala Leu Lys Leu Ala Glu Phe Gln340 345 350Thr Asp Ser Gln Gly Lys Ile Val Ser Thr Gln Glu Lys Glu Leu Val355 360 365Gln Pro Phe Ser Ser Leu Phe Pro Lys Val Glu Tyr Ile Ala Arg Ala370 375 380Gly Trp Thr Arg Asp Gly Lys Tyr Ala Trp Ala Met Phe Leu Asp Arg385 390 395 400Pro Gln Gln Trp Leu Gln Leu Val Leu Leu Pro Pro Ala Leu Phe Ile405 410 415Pro Ser Thr Glu Asn Glu Glu Gln Arg Leu Ala Ser Ala Arg Ala Val420 425 430Pro Arg Asn Val Gln Pro Tyr Val Val Tyr Glu Glu Val Thr Asn Val435 440 445Trp Ile Asn Val His Asp Ile Phe Tyr Pro Phe Pro Gln Ser Glu Gly450 455 460Glu Asp Glu Leu Cys Phe Leu Arg Ala Asn Glu Cys Lys Thr Gly Phe465 470 475 480Cys His Leu Tyr Lys Val Thr Ala Val Leu Lys Ser Gln Gly Tyr Asp485 490 495Trp Ser Glu Pro Phe Ser Pro Gly Glu Asp Glu Phe Lys Cys Pro Ile500 505 510Lys Glu Glu Ile Ala Leu Thr Ser Gly Glu Trp Glu Val Leu Ala Arg515 520 525His Gly Ser Lys Gly Thr Lys Asp Thr Pro Leu Glu His His Leu Tyr530 535 540Val Val Ser Tyr Glu Ala Ala Gly Glu Ile Val Arg Leu Thr Thr Pro545 550 555 560
Gly Phe Ser His Ser Cys Ser Met Ser Gln Asn Phe Asp Met Phe Val565 570 575Ser His Tyr Ser Ser Val Ser Thr Pro Pro Cys Val His Val Tyr Lys580 585 590Leu Ser Gly Pro Asp Asp Asp Pro Leu His Lys Gln Pro Arg Phe Trp595 600 605Ala Ser Met Met Glu Ala Ala Ser Cys Pro Pro Asp Tyr Val Pro Pro610 615 620Glu Ile Phe His Phe His Thr Arg Ser Asp Val Arg Leu Tyr Gly Met625 630 635 640Ile Tyr Lys Pro His Ala Leu Gln Pro Gly Lys Lys His Pro Thr Val645 650 655Leu Phe Val Tyr Gly Gly Pro Gln Val Gln Leu Val Asn Asn Ser Phe660 665 670Lys Gly Ile Lys Tyr Leu Arg Leu Asn Thr Leu Ala Ser Leu Gly Tyr675 680 685Ala Val Val Val Ile Asp Gly Arg Gly Ser Cys Gln Arg Gly Leu Arg690 695 700Phe Glu Gly Ala Leu Lys Asn Gln Met Gly Gln Val Glu Ile Glu Asp705 710 715 720Gln Val Glu Gly Leu Gln Phe Val Ala Glu Lys Tyr Gly Phe Ile Asp725 730 735Leu Ser Arg Val Ala Ile His Gly Trp Ser Tyr Gly Gly Phe Leu Ser740 745 750Leu Met Gly Leu Ile His Lys Pro Gln Val Phe Lys Val Ala Ile Ala755 760 765Gly Ala Pro Val Thr Val Trp Met Ala Tyr Asp Thr Gly Tyr Thr Glu770 775 780Arg Tyr Met Asp Val Pro Glu Asn Asn Gln His Gly Tyr Glu Ala Gly785 790 795 800Ser Val Ala Leu His Val Glu Lys Leu Pro Asn Glu Pro Asn Arg Leu805 810 815Leu Ile Leu His Gly Phe Leu Asp Glu Asn Val His Phe Phe His Thr820 825 830Asn Phe Leu Val Ser Gln Leu Ile Arg Ala Gly Lys Pro Tyr Gln Leu835 840 845Gln Ile Tyr Pro Asn Glu Arg His Ser Ile Arg Cys Pro Glu Ser Gly850 855 860Glu His Tyr Glu Val Thr Leu Leu His Phe Leu Gln Glu Tyr Leu865 870 875<210>34<211>4263<212>DNA<213>智人(Homo sapiens)<400>34caggccgccg cctgggtcgc tcaacttccg ggtcaaaggt gcctgagccg gcgggtcccc 60tgtgtccgcc gcggctgtcg tcccccgctc ccgccacttc cggggtcgca gtcccgggca120tggagccgcg accgtgaggc gccgctggac ccgggacgac ctgcccagtc cggccgccgc180cccacgtccc ggtctgtgtc ccacgcctgc agctggaatg gaggctctct ggacccttta240gaaggcaccc ctgccctcct gaggtcagct gagcggttaa tgcggaaggt taagaaactg300cgcctggaca aggagaacac cggaagttgg agaagcttct cgctgaattc cgagggggct360gagaggatgg ccaccaccgg gaccccaacg gccgaccgag gcgacgcagc cgccacagat420gacccggccg cccgcttcca ggtgcagaag cactcgtggg acgggctccg gagcatcatc480cacggcagcc gcaagtactc gggcctcatt gtcaacaagg cgccccacga cttccagttt540gtgcagaaga cggatgagtc tgggccccac tcccaccgcc tctactacct gggaatgcca600tatggcagcc gagagaactc cctcctctac tctgagattc ccaagaaggt ccggaaagag660gctctgctgc tcctgtcctg gaagcagatg ctggatcatt tccaggccac gccccaccat720ggggtctact ctcgggagga ggagctgctg agggagcgga aacgcctggg ggtcttcggc780
atcacctcct acgacttcca cagcgagagt ggcctcttcc tcttccaggc cagcaacagc840ctcttccact gccgcgacgg cggcaagaac ggcttcatgg tgtcccctat gaaaccgctg900gaaatcaaga cccagtgctc agggccccgg atggacccca aaatctgccc tgccgaccct960gccttcttct ccttcatcaa taacagcgac ctgtgggtgg ccaacatcga gacaggcgag 1020gagcggcggc tgaccttctg ccaccaaggt ttatccaatg tcctggatga ccccaagtct 1080gcgggtgtgg ccaccttcgt catacaggaa gagttcgacc gcttcactgg gtactggtgg 1140tgccccacag cctcctggga aggttcagag ggcctcaaga cgctgcgaat cctgtatgag 1200gaagtcgatg agtccgaggt ggaggtcatt cacgtcccct ctcctgcgct agaagaaagg 1260aagacggact cgtatcggta ccccaggaca ggcagcaaga atcccaagat tgccttgaaa 1320ctggctgagt tccagactga cagccagggc aagatcgtct cgacccagga gaaggagctg 1380gtgcagccct tcagctcgct gttcccgaag gtggagtaca tcgccagggc cgggtggacc 1440cgggatggca aatacgcctg ggccatgttc ctggaccggc cccagcagtg gctccagctc 1500gtcctcctcc ccccggccct gttcatcccg agcacagaga atgaggagca gcggctagcc 1560tctgccagag ctgtccccag gaatgtccag ccgtatgtgg tgtacgagga ggtcaccaac 1620gtctggatca atgttcatga catcttctat cccttccccc aatcagaggg agaggacgag 1680ctctgctttc tccgcgccaa tgaatgcaag accggcttct gccatttgta caaagtcacc 1740gccgttttaa aatcccaggg ctacgattgg agtgagccct tcagccccgg ggaagatgaa 1800tttaagtgcc ccattaagga agagattgct ctgaccagcg gtgaatggga ggttttggcg 1860aggcacggct ccaagggcac caaggacacg ccgctggagc accacctcta cgtggtcagc 1920tatgaggcgg ccggcgagat cgtacgcctc accacgcccg gcttctccca tagctgctcc 1980atgagccaga acttcgacat gttcgtcagc cactacagca gcgtgagcac gccgccctgc 2040gtgcacgtct acaagctgag cggccccgac gacgaccccc tgcacaagca gccccgcttc 2100tgggctagca tgatggaggc agccagctgc cccccggatt atgttcctcc agagatcttc 2160catttccaca cgcgctcgga tgtgcggctc tacggcatga tctacaagcc ccacgccttg 2220cagccaggga agaagcaccc caccgtcctc tttgtatatg gaggccccca ggtgcagctg 2280gtgaataact ccttcaaagg catcaagtac ttgcggctca acacactggc ctccctgggc 2340tacgccgtgg ttgtgattga cggcaggggc tcctgtcagc gagggcttcg gttcgaaggg 2400gccctgaaaa accaaatggg ccaggtggag atcgaggacc aggtggaggg cctgcagttc 2460gtggccgaga agtatggctt catcgacctg agccgagttg ccatccatgg ctggtcctac 2520gggggcttcc tctcgctcat ggggctaatc cacaagcccc aggtgttcaa ggtggccatc 2580gcgggtgccc cggtcaccgt ctggatggcc tacgacacag ggtacactga gcgctacatg 2640gacgtccctg agaacaacca gcacggctat gaggcgggtt ccgtggccct gcacgtggag 2700aagctgccca atgagcccaa ccgcttgctt atcctccacg gcttcctgga cgaaaacgtg 2760cactttttcc acacaaactt cctcgtctcc caactgatcc gagcagggaa accttaccag 2820ctccagatct accccaacga gagacacagt attcgctgcc ccgagtcggg cgagcactat 2880gaagtcacgt tgctgcactt tctacaggaa tacctctgag cctgcccacc gggagccgcc 2940acatcacagc acaagtggct gcagcctccg cggggaacca ggcgggaggg actgagtggc 3000ccgcgggccc cagtgaggca ctttgtcccg cccagcgctg gccagccccg aggagccgct 3060gccttcaccg ccccgacgcc ttttatcctt ttttaaacgc tcttgggttt tatgtccgct 3120gcttcttggt tgccgagaca gagagatggt ggtctcgggc cagcccctcc tctccccgcc 3180ttctgggagg aggaggtcac acgctgatgg gcactggaga ggccagaaga gactcagagg 3240agcgggctgc cttccgcctg gggctccctg tgacctctca gtcccctggc ccggccagcc 3300accgtcccca gcacccaagc atgcaattgc ctgtcccccc cggccagcct ccccaacttg 3360atgtttgtgt tttgtttggg gggatatttt tcataattat ttaaaagaca ggccgggcgc 3420ggtggctcac gtctgtaatc ccagcacttt gggaggctga ggcgggcgga tcacctgagg 3480ttgggagttc aagaccagcc tggccaacat ggggaaaccc cgtctctact aaaaatacaa 3540aaaattagcc gggtgtggtg gcgcgtgcct ataatcccag ctactcggga ggctgaggca 3600ggagaatcgc ttgaacccgg gaggtggagg ttgcggtgag ccaagatcgc accattgcac 3660tccagcctgg gcaacaagag cgaaactctg tctcaaaata aataaaaaat aaaagacaga 3720aagcaagggg tgcctaaatc tagacttggg gtccacaccg ggcagcgggg ttgcaaccca 3780gcacctggta ggctccattt cttcccaagc ccgagcagag ggtcatgcgg gccccacagg 3840agaagcggcc agggcccgcg gggggcacca cctgtggaca gccctcctgt ccccaagctt 3900tcaggcaggc actgaaacgc accgaacttc cacgctctgc tggtcagtgg cggctgtccc 3960ctccccagcc cagccgccca gccacatgtg tctgcctgac ccgtacacac caggggttcc 4020ggggttggga gctgaaccat ccccacctca gggttatatt tccctctccc cttccctccc 4080cgccaagagc tctgccaggg gcgggcaaaa aaaaaagtaa aaagaaaaga aaaaaaaaaa 4140aaagaaacaa accacctcta catattatgg aaagaaaata tttttgtcga ttcttattct 4200tttataatta tgcgtggaag aagtagacac attaaacgat tccagttgga aacatgtcac 4260ctg 4263
<210>35<211>879<212>PRT<213>智人(Homo sapiens)<400>35Met Arg Lys Val Lys Lys Leu Arg Leu Asp Lys Glu Asn Thr Gly Ser1 5 10 15Trp Arg Ser Phe Ser Leu Asn Ser Glu Gly Ala Glu Arg Met Ala Thr20 25 30Thr Gly Thr Pro Thr Ala Asp Arg Gly Asp Ala Ala Ala Thr Asp Asp35 40 45Pro Ala Ala Arg Phe Gln Val Gln Lys His Ser Trp Asp Gly Leu Arg50 55 60Ser Ile Ile His Gly Ser Arg Lys Tyr Ser Gly Leu Ile Val Asn Lys65 70 75 80Ala Pro His Asp Phe Gln Phe Val Gln Lys Thr Asp Glu Ser Gly Pro85 90 95His Ser His Arg Leu Tyr Tyr Leu Gly Met Pro Tyr Gly Ser Arg Glu100 105 110Asn Ser Leu Leu Tyr Ser Glu Ile Pro Lys Lys Val Arg Lys Glu Ala115 120 125Leu Leu Leu Leu Ser Trp Lys Gln Met Leu Asp His Phe Gln Ala Thr130 135 140Pro His His Gly Val Tyr Ser Arg Glu Glu Glu Leu Leu Arg Glu Arg145 150 155 160Lys Arg Leu Gly Val Phe Gly Ile Thr Ser Tyr Asp Phe His Ser Glu165 170 175Ser Gly Leu Phe Leu Phe Gln Ala Ser Asn Ser Leu Phe His Cys Arg180 185 190Asp Gly Gly Lys Asn Gly Phe Met Val Ser Pro Met Lys Pro Leu Glu195 200 205Ile Lys Thr Gln Cys Ser Gly Pro Arg Met Asp Pro Lys Ile Cys Pro210 215 220Ala Asp Pro Ala Phe Phe Ser Phe Ile Asn Asn Ser Asp Leu Trp Val225 230 235 240Ala Asn Ile Glu Thr Gly Glu Glu Arg Arg Leu Thr Phe Cys His Gln245 250 255Gly Leu Ser Asn Val Leu Asp Asp Pro Lys Ser Ala Gly Val Ala Thr260 265 270Phe Val Ile Gln Glu Glu Phe Asp Arg Phe Thr Gly Tyr Trp Trp Cys275 280 285Pro Thr Ala Ser Trp Glu Gly Ser Glu Gly Leu Lys Thr Leu Arg Ile290 295 300Leu Tyr Glu Glu Val Asp Glu Ser Glu Val Glu Val Ile His Val Pro305 310 315 320Ser Pro Ala Leu Glu Glu Arg Lys Thr Asp Ser Tyr Arg Tyr Pro Arg325 330 335Thr Gly Ser Lys Asn Pro Lys Ile Ala Leu Lys Leu Ala Glu Phe Gln340 345 350Thr Asp Ser Gln Gly Lys Ile Val Ser Thr Gln Glu Lys Glu Leu Val355 360 365Gln Pro Phe Ser Ser Leu Phe Pro Lys Val Glu Tyr Ile Ala Arg Ala370 375 380Gly Trp Thr Arg Asp Gly Lys Tyr Ala Trp Ala Met Phe Leu Asp Arg385 390 395 400Pro Gln Gln Trp Leu Gln Leu Val Leu Leu Pro Pro Ala Leu Phe Ile405 410 415
Pro Ser Thr Glu Asn Glu Glu Gln Arg Leu Ala Ser Ala Arg Ala Val420 425 430Pro Arg Asn Val Gln Pro Tyr Val Val Tyr Glu Glu Val Thr Asn Val435 440 445Trp Ile Asn Val His Asp Ile Phe Tyr Pro Phe Pro Gln Ser Glu Gly450 455 460Glu Asp Glu Leu Cys Phe Leu Arg Ala Asn Glu Cys Lys Thr Gly Phe465 470 475 480Cys His Leu Tyr Lys Val Thr Ala Val Leu Lys Ser Gln Gly Tyr Asp485 490 495Trp Ser Glu Pro Phe Ser Pro Gly Glu Asp Glu Phe Lys Cys Pro Ile500 505 510Lys Glu Glu Ile Ala Leu Thr Ser Gly Glu Trp Glu Val Leu Ala Arg515 520 525His Gly Ser Lys Gly Thr Lys Asp Thr Pro Leu Glu His His Leu Tyr530 535 540Val Val Ser Tyr Glu Ala Ala Gly Glu Ile Val Arg Leu Thr Thr Pro545 550 555 560Gly Phe Ser His Ser Cys Ser Met Ser Gln Asn Phe Asp Met Phe Val565 570 575Ser His Tyr Ser Ser Val Ser Thr Pro Pro Cys Val His Val Tyr Lys580 585 590Leu Ser Gly Pro Asp Asp Asp Pro Leu His Lys Gln Pro Arg Phe Trp595 600 605Ala Ser Met Met Glu Ala Ala Ser Cys Pro Pro Asp Tyr Val Pro Pro610 615 620Glu Ile Phe His Phe His Thr Arg Ser Asp Val Arg Leu Tyr Gly Met625 630 635 640Ile Tyr Lys Pro His Ala Leu Gln Pro Gly Lys Lys His Pro Thr Val645 650 655Leu Phe Val Tyr Gly Gly Pro Gln Val Gln Leu Val Asn Asn Ser Phe660 665 670Lys Gly Ile Lys Tyr Leu Arg Leu Asn Thr Leu Ala Ser Leu Gly Tyr675 680 685Ala Val Val Val Ile Asp Gly Arg Gly Ser Cys Gln Arg Gly Leu Arg690 695 700Phe Glu Gly Ala Leu Lys Asn Gln Met Gly Gln Val Glu Ile Glu Asp705 710 715 720Gln Val Glu Gly Leu Gln Phe Val Ala Glu Lys Tyr Gly Phe Ile Asp725 730 735Leu Ser Arg Val Ala Ile His Gly Trp Ser Tyr Gly Gly Phe Leu Ser740 745 750Leu Met Gly Leu Ile His Lys Pro Gln Val Phe Lys Val Ala Ile Ala755 760 765Gly Ala Pro Val Thr Val Trp Met Ala Tyr Asp Thr Gly Tyr Thr Glu770 775 780Arg Tyr Met Asp Val Pro Glu Asn Asn Gln His Gly Tyr Glu Ala Gly785 790 795 800Ser Val Ala Leu His Val Glu Lys Leu Pro Asn Glu Pro Asn Arg Leu805 810 815Leu Ile Leu His Gly Phe Leu Asp Glu Asn Val His Phe Phe His Thr820 825 830Asn Phe Leu Val Ser Gln Leu Ile Arg Ala Gly Lys Pro Tyr Gln Leu835 840 845Gln Ile Tyr Pro Asn Glu Arg His Ser Ile Arg Cys Pro Glu Ser Gly850 855 860Glu His Tyr Glu Val Thr Leu Leu His Phe Leu Gln Glu Tyr Leu865 870 875
<210>36<211>4180<212>DNA<213>智人(Homo sapiens)<400>36caggccgccg cctgggtcgc tcaacttccg ggtcaaaggt gcctgagccg gcgggtcccc 60tgtgtccgcc gcggctgtcg tcccccgctc ccgccacttc cggggtcgca gtcccgggca120tggagccgcg accgtgaggc gccgctggac ccgggacgac ccgcccagtc cggccgccgc180cccacgtccc ggtctgtgtc ccacgcctgc agctggaatg gaggctctct ggacccttta240gaaggcaccc ctgccctcct gaggtcagct gagcggttaa tgcggaaggt taagaaactg300cgcctggaca aggagaacac cggaagttgg agaagcttct cgctgaattc cgagggggct360gagaggatgg ccaccaccgg gaccccaacg gccgaccgag gcgacgcagc cgccacagat420gacccggccg cccgcttcca ggtgcagaag cactcgtggg acgggctccg gagcatcatc480cacggcagcc gcaagtactc gggcctcatt gtcaacaagg cgccccacga cttccagttt540gtgcagaaga cggatgagtc tgggccccac tcccaccgcc tctactacct gggaatgcca600tatggcagcc gagagaactc cctcctctac tctgagattc ccaagaaggt ccggaaagag660gctctgctgc tcctgtcctg gaagcagatg ctggatcatt tccaggccac gccccaccat720ggggtctact ctcgggagga ggagctgctg agggagcgga aacgcctggg ggtcttcggc780atcacctcct acgacttcca cagcgagagt ggcctcttcc tcttccaggc cagcaacagc840ctcttccact gccgcgacgg cggcaagaac ggcttcatgg tgtcccctat gaaaccgctg900gaaatcaaga cccagtgctc agggccccgg atggacccca aaatctgccc tgccgaccct960gccttcttct ccttcatcaa taacagcgac ctgtgggtgg ccaacatcga gacaggcgag 1020gagcggcggc tgaccttctg ccaccaaggt ttatccaatg tcctggatga ccccaagtct 1080gcgggtgtgg ccaccttcgt catacaggaa gagttcgacc gcttcactgg gtactggtgg 1140tgccccacag cctcctggga aggttcagag ggcctcaaga cgctgcgaat cctgtatgag 1200gaagtcgatg agtccgaggt ggaggtcatt cacgtcccct ctcctgcgct agaagaaagg 1260aagacggact cgtatcggta ccccaggaca ggcagcaaga atcccaagat tgccttgaaa 1320ctggctgagt tccagactga cagccagggc aagatcgtct cgacccagga gaaggagctg 1380gtgcagccct tcagctcgct gttcccgaag gtggagtaca tcgccagggc cgggtggacc 1440cgggatggca aatacgcctg ggccatgttc ctggaccggc cccagcagtg gctccagctc 1500gtcctcctcc ccccggccct gttcatcccg agcacagaga atgaggagca gcggctagcc 1560tctgccagag ctgtccccag gaatgtccag ccgtatgtgg tgtacgagga ggtcaccaac 1620gtctggatca atgttcatga catcttctat cccttccccc aatcagaggg agaggacgag 1680ctctgctttc tccgcgccaa tgaatgcaag accggcttct gccatttgta caaagtcacc 1740gccgttttaa aatcccaggg ctacgattgg agtgagccct tcagccccgg ggaagatgaa 1800tttaagtgcc ccattaagga agagattgct ctgaccagcg gtgaatggga ggttttggcg 1860aggcacggct ccaagggcac caaggacacg ccgctggagc accacctcta cgtggtcagc 1920tatgaggcgg ccggcgagat cgtacgcctc accacgcccg gcttctccca tagctgctcc 1980atgagccaga acttcgacat gttcgtcagc cactacagca gcgtgagcac gccgccctgc 2040gtgcacgtct acaagctgag cggccccgac gacgaccccc tgcacaagca gccccgcttc 2100tgggctagca tgatggaggc agccagctgc cccccggatt atgttcctcc agagatcttc 2160catttccaca cgcgctcgga tgtgcggctc tacggcatga tctacaagcc ccacgccttg 2220cagccaggga agaagcaccc caccgtcctc tttgtatatg gaggccccca ggtgcagctg 2280gtgaataact ccttcaaagg catcaagtac ttgcggctca acacactggc ctccctgggc 2340tacgccgtgg ttgtgattga cggcaggggc tcctgtcagc gagggcttcg gttcgaaggg 2400gccctgaaaa accaaatggg ccaggtggag atcgaggacc aggtggaggg cctgcagttc 2460gtggccgaga agtatggctt catcgacctg agccgagttg ccatccatgg ctggtcctac 2520gggggcttcc tctcgctcat ggggctaatc cacaagcccc aggtgttcaa ggtggccatc 2580gcgggtgccc cggtcaccgt ctggatggcc tacgacacag ggtacactga gcgctacatg 2640gacgtccctg agaacaacca gcacggctat gaggcgggtt ccgtggccct gcacgtggag 2700aagctgccca atgagcccaa ccgcttgctt atcctccacg gcttcctgga cgaaaacgtg 2760cactttttcc acacaaactt cctcgtctcc caactgatcc gagcagggaa accttaccag 2820ctccagatct accccaacga gagacacagt attcgctgcc ccgagtcggg cgagcactat 2880gaagtcacgt tgctgcactt tctacaggaa tacctctgag cctgcccacc gggagccgcc 2940acatcacagc acaagtggct gcagcctccg cggggaacca ggcgggaggg actgagtggc 3000ccgcgggccc cagtgaggca ctttgtcccg cccagcgctg gccagccccg aggagccgct 3060gccttcaccg ccccgacgcc ttttatcctt ttttaaacgc tcttgggttt tatgtccgct 3120gcttcttggt tgccgagaca gagagatggt ggtctcgggc cagcccctcc tctccccgcc 3180
ttctgggagg aggaggtcac acgctgatgg gcactggaga ggccagaaga gactcagagg 3240agcgggctgc cttccgcctg gggctccctg tgacctctca gtcccctggc ccggccagcc 3300accgtcccca gcacccaagc atgcaattgc ctgtcccccc cggccagcct ccccaacttg 3360atgtttgtgt tttgtttggg gggatatttt tcataattat ttaaaagaca ggccgggcgc 3420ggtggctcac gtctgtaatc ccagcacttt gggaggctga ggcgggcgga tcacctgagg 3480ttgggagttc aagaccagcc tggccaacat ggggaaaccc cgtctctact aaaaatacaa 3540aaaattagcc gggtgtggtg gcgcgtgcct ataatcccag ctactcggga ggctgaggca 3600ggagaatcgc ttgaacccgg gaggtggagg ttgcggtgag ccaagatcgc accattgcac 3660tccagcctgg gcaacaagag cgaaactctg tctcaaaata aataaaaaat aaaagacaga 3720aagcaagggg tgcctaaatc tagacttggg gtccacaccg ggcagcgggg ttgcaaccca 3780gcacctggta ggctccattt cttcccaagc ccgactttca ggcaggcact gaaacgcacc 3840gaacttccac gctctgctgg tcagtggcgg ctgtcccctc cccagcccag ccgcccagcc 3900acatgtgtct gcctgacccg tacacaccag gggttccggg gttgggagct gaaccatccc 3960cacctcaggg ttatatttcc ctctcccctt ccctccccgc caagagctct gccaggggcg 4020ggcaaaaaaa aaagtaaaaa gaaaagaaaa aaaaaaaaaa gaaacaaacc acctctacat 4080attatggaaa gaaaatattt ttgtcgattc ttattctttt ataattatgc gtggaagaag 4140tagacacatt aaacgattcc agttggaaac atgtcacctg 4180<210>37<211>819<212>PRT<213>智人(Homo sapiens)<400>37Met Arg Lys Val Lys Lys Leu Arg Leu Asp Lys Glu Asn Thr Gly Ser1 5 10 15Trp Arg Ser Phe Ser Leu Asn Ser Glu Gly Ala Glu Arg Met Ala Thr20 25 30Thr Gly Thr Pro Thr Ala Asp Arg Gly Asp Ala Ala Ala Thr Asp Asp35 40 45Pro Ala Ala Arg Phe Gln Val Gln Lys His Ser Trp Asp Gly Leu Arg50 55 60Ser Ile Ile His Gly Ser Arg Lys Tyr Ser Gly Leu Ile Val Asn Lys65 70 75 80Ala Pro His Asp Phe Gln Phe Val Gln Lys Thr Asp Glu Ser Gly Pro85 90 95His Ser His Arg Leu Tyr Tyr Leu Gly Met Pro Tyr Gly Ser Arg Glu100 105 110Asn Ser Leu Leu Tyr Ser Glu Ile Pro Lys Lys Val Arg Lys Glu Ala115 120 125Leu Leu Leu Leu Ser Trp Lys Gln Met Leu Asp His Phe Gln Ala Thr130 135 140Pro His His Gly Val Tyr Ser Arg Glu Glu Glu Leu Leu Arg Glu Arg145 150 155 160Lys Arg Leu Gly Val Phe Gly Ile Thr Ser Tyr Asp Phe His Ser Glu165 170 175Ser Gly Leu Phe Leu Phe Gln Ala Ser Asn Ser Leu Phe His Cys Arg180 185 190Asp Gly Gly Lys Asn Gly Phe Met Val Ser Pro Met Lys Pro Leu Glu195 200 205Ile Lys Thr Gln Cys Ser Gly Pro Arg Met Asp Pro Lys Ile Cys Pro210 215 220Ala Asp Pro Ala Phe Phe Ser Phe Ile Asn Asn Ser Asp Leu Trp Val225 230 235 240Ala Asn Ile Glu Thr Gly Glu Glu Arg Arg Leu Thr Phe Cys His Gln245 250 255Gly Leu Ser Asn Val Leu Asp Asp Pro Lys Ser Ala Gly Val Ala Thr260 265 270
Phe Val Ile Gln Glu Glu Phe Asp Arg Phe Thr Gly Tyr Trp Trp Cys275 280 285Pro Thr Ala Ser Trp Glu Gly Ser Glu Gly Leu Lys Thr Leu Arg Ile290 295 300Leu Tyr Glu Glu Val Asp Glu Ser Glu Val Glu Val Ile His Val Pro305 310 315 320Ser Pro Ala Leu Glu Glu Arg Lys Thr Asp Ser Tyr Arg Tyr Pro Arg325 330 335Thr Gly Ser Lys Asn Pro Lys Ile Ala Leu Lys Leu Ala Glu Phe Gln340 345 350Thr Asp Ser Gln Gly Lys Ile Val Ser Thr Gln Glu Lys Glu Leu Val355 360 365Gln Pro Phe Ser Ser Leu Phe Pro Lys Val Glu Tyr Ile Ala Arg Ala370 375 380Gly Trp Thr Arg Asp Gly Lye Tyr Ala Trp Ala Met Phe Leu Asp Arg385 390 395 400Pro Gln Gln Trp Leu Gln Leu Val Leu Leu Pro Pro Ala Leu Phe Ile405 410 415Pro Ser Thr Glu Asn Glu Glu Gln Arg Leu Ala Ser Ala Arg Ala Val420 425 430Pro Arg Asn Val Gln Pro Tyr Val Val Tyr Glu Glu Val Thr Asn Val435 440 445Trp Ile Asn Val His Asp Ile Phe Tyr Pro Phe Pro Gln Ser Glu Gly450 455 460Glu Asp Glu Leu Cys Phe Leu Arg Ala Asn Glu Cys Lys Thr Gly Phe465 470 475 480Cys His Leu Tyr Lys Val Thr Ala Val Leu Lys Ser Gln Gly Tyr Asp485 490 495Trp Ser Glu Pro Phe Ser Pro Gly Glu Asp Glu Phe Lys Cys Pro Ile500 505 510Lys Glu Glu Ile Ala Leu Thr Ser Gly Glu Trp Glu Val Leu Ala Arg515 520 525His Gly Ser Lys Gly Thr Lys Asp Thr Pro Leu Glu His His Leu Tyr530 535 540Val Val Ser Tyr Glu Ala Ala Gly Glu Ile Val Arg Leu Thr Thr Pro545 550 555 560Gly Phe Ser His Ser Cya Ser Met Ser Gln Asn Phe Asp Met Phe Val565 570 575Ser His Tyr Ser Ser Val Ser Thr Pro Pro Cys Val His Val Tyr Lys580 585 590Leu Ser Gly Pro Asp Asp Asp Pro Leu His Lys Gln Pro Arg Phe Trp595 600 605Ala Ser Met Met Glu Ala Ala Ser Cys Pro Pro Asp Tyr Val Pro Pro610 615 620Glu Ile Phe His Phe His Thr Arg Ser Asp Val Arg Leu Tyr Gly Met625 630 635 640Ile Tyr Lys Pro His Ala Leu Gln Pro Gly Lys Lys His Pro Thr Val645 650 655Leu Phe Val Tyr Gly Gly Pro Gln Val Gln Leu Val Asn Asn Ser Phe660 665 670Lys Gly Ile Lys Tyr Leu Arg Leu Asn Thr Leu Ala Ser Leu Gly Tyr675 680 685Ala Val Val Val Ile Asp Gly Arg Gly Ser Cys Gln Arg Gly Leu Arg690 695 700Phe Glu Gly Ala Leu Lys Asn Gln Met Gly Gln Val Glu Ile Glu Asp705 710 715 720Gln Val Glu Gly Leu Gln Phe Val Ala Glu Lys Tyr Gly Phe Ile Asp725 730 735
Leu Ser Arg Val Ala Ile His Gly Trp Ser Tyr Gly Gly Phe Leu Ser740 745 750Leu Met Gly Leu Ile His Lys Pro Gln Val Phe Lys Ala Gln Pro Leu755 760 765Ala Tyr Pro Pro Arg Leu Pro Gly Arg Lys Arg Ala Leu Phe Pro His770 775 780Lys Leu Pro Arg Leu Pro Thr Asp Pro Ser Arg Glu Thr Leu Pro Ala785 790 795 800Pro Asp Leu Pro Gln Arg Glu Thr Gln Tyr Ser Leu Pro Arg Val Gly805 810 815Arg Ala Leu<210>38<211>4120<212>DNA<213>智人(Homo sapiens)<400>38caggccgccg cctgggtcgc tcaacttccg ggtcaaaggt gcctgagccg gcgggtcccc 60tgtgtccgcc gcggctgtcg tcccccgctc ccgccacttc cggggtcgca gtcccgggca120tggagccgcg accgtgaggc gccgctggac ccgggacgac ctgcccagtc cggccgccgc180cccacgtccc ggtctgtgtc ccacgcctgc agctggaatg gaggctctct ggacccttta240gaaggcaccc ctgccctcct gaggtcagct gagcggttaa tgcggaaggt taagaaactg300cgcctggaca aggagaacac cggaagttgg agaagcttct cgctgaattc cgagggggct360gagaggatgg ccaccaccgg gaccccaacg gccgaccgag gcgacgcagc cgccacagat420gacccggccg cccgcttcca ggtgcagaag cactcgtggg acgggctccg gagcatcatc480cacggcagcc gcaagtactc gggcctcatt gtcaacaagg cgccccacga cttccagttt540gtgcagaaga cggatgagtc tgggccccac tcccaccgcc tctactacct gggaatgcca600tatggcagcc gagagaactc cctcctctac tctgagattc ccaagaaggt ccggaaagag660gctctgctgc tcctgtcctg gaagcagatg ctggatcatt tccaggccac gccccaccat720ggggtctact ctcgggagga ggagctgctg agggagcgga aacgcctggg ggtcttcggc780atcacctcct acgacttcca cagcgagagt ggcctcttcc tcttccaggc cagcaacagc840ctcttccact gccgcgacgg cggcaagaac ggcttcatgg tgtcccctat gaaaccgctg900gaaatcaaga cccagtgctc agggccccgg atggacccca aaatctgccc tgccgaccct960gccttcttct ccttcatcaa taacagcgac ctgtgggtgg ccaacatcga gacaggcgag 1020gagcggcggc tgaccttctg ccaccaaggt ttatccaatg tcctggatga ccccaagtct 1080gcgggtgtgg ccaccttcgt catacaggaa gagttcgacc gcttcactgg gtactggtgg 1140tgccccacag cctcctggga aggttcagag ggcctcaaga cgctgcgaat cctgtatgag 1200gaagtcgatg agtccgaggt ggaggtcatt cacgtcccct ctcctgcgct agaagaaagg 1260aagacggact cgtatcggta ccccaggaca ggcagcaaga atcccaagat tgccttgaaa 1320ctggctgagt tccagactga cagccagggc aagatcgtct cgacccagga gaaggagctg 1380gtgcagccct tcagctcgct gttcccgaag gtggagtaca tcgccagggc cgggtggacc 1440cgggatggca aatacgcctg ggccatgttc ctggaccggc cccagcagtg gctccagctc 1500gtcctcctcc ccccggccct gttcatcccg agcacagaga atgaggagca gcggctagcc 1560tctgccagag ctgtccccag gaatgtccag ccgtatgtgg tgtacgagga ggtcaccaac 1620gtctggatca atgttcatga catcttctat cccttccccc aatcagaggg agaggacgag 1680ctctgctttc tccgcgccaa tgaatgcaag accggcttct gccatttgta caaagtcacc 1740gccgttttaa aatcccaggg ctacgattgg agtgagccct tcagccccgg ggaagatgaa 1800tttaagtgcc ccattaagga agagattgct ctgaccagcg gtgaatggga ggttttggcg 1860aggcacggct ccaagggcac caaggacacg ccgctggagc accacctcta cgtggtcagc 1920tatgaggcgg ccggcgagat cgtacgcctc accacgcccg gcttctccca tagctgctcc 1980atgagccaga acttcgacat gttcgtcagc cactacagca gcgtgagcac gccgccctgc 2040gtgcacgtct acaagctgag cggccccgac gacgaccccc tgcacaagca gccccgcttc 2100tgggctagca tgatggaggc agccagctgc cccccggatt atgttcctcc agagatcttc 2160catttccaca cgcgctcgga tgtgcggctc tacggcatga tctacaagcc ccacgccttg 2220cagccaggga agaagcaccc caccgtcctc tttgtatatg gaggccccca ggtgcagctg 2280gtgaataact ccttcaaagg catcaagtac ttgcggctca acacactggc ctccctgggc 2340tacgccgtgg ttgtgattga cggcaggggc tcctgtcagc gagggcttcg gttcgaaggg 2400gccctgaaaa accaaatggg ccaggtggag atcgaggacc aggtggaggg cctgcagttc 2460
gtggccgaga agtatggctt catcgacctg agccgagttg ccatccatgg ctggtcctac 2520gggggcttcc tctcgctcat ggggctaatc cacaagcccc aggtgttcaa ggcccaaccg 2580cttgcttatc ctccacggct tcctggacga aaacgtgcac tttttccaca caaacttcct 2640cgtctcccaa ctgatccgag cagggaaacc ttaccagctc cagatctacc ccaacgagag 2700acacagtatt cgctgccccg agtcgggcga gcactatgaa gtcacgttgc tgcactttct 2760acaggaatac ctctgagcct gcccaccggg agccgccaca tcacagcaca agtggctgca 2820gcctccgcgg ggaaccaggc gggagggact gagtggcccg cgggccccag tgaggcactt 2880tgtcccgccc agcgctggcc agccccgagg agccgctgcc ttcaccgccc cgacgccttt 2940tatccttttt taaacgctct tgggttttat gtccgctgct tcttggttgc cgagacagag 3000agatggtggt ctcgggccag cccctcctct ccccgccttc tgggaggagg aggtcacacg 3060ctgatgggca ctggagaggc cagaagagac tcagaggagc gggctgcctt ccgcctgggg 3120ctccctgtga cctctcagtc ccctggcccg gccagccacc gtccccagca cccaagcatg 3180caattgcctg tcccccccgg ccagcctccc caacttgatg tttgtgtttt gtttgggggg 3240atatttttca taattattta aaagacaggc cgggcgcggt ggctcacgtc tgtaatccca 3300gcactttggg aggctgaggc gggcggatca cctgaggttg ggagttcaag accagcctgg 3360ccaacatggg gaaaccccgt ctctactaaa aatacaaaaa attagccggg tgtggtggcg 3420cgtgcctata atcccagcta ctcgggaggc tgaggcagga gaatcgcttg aacccgggag 3480gtggaggttg cggtgagcca agatcgcacc attgcactcc agcctgggca acaagagcga 3540aactctgtct caaaataaat aaaaaataaa agacagaaag caaggggtgc ctaaatctag 3600acttggggtc cacaccgggc agcggggttg caacccagca cctggtaggc tccatttctt 3660cccaagcccg agcagagggt catgcgggcc ccacaggaga agcggccagg gcccgcgggg 3720ggcaccacct gtggacagcc ctcctgtccc caagctttca ggcaggcact gaaacgcacc 3780gaacttccac gctctgctgg tcagtggcgg ctgtcccctc cccagcccag ccgcccagcc 3840acatgtgtct gcctgacccg tacacaccag gggttccggg gttgggagct gaaccatccc 3900cacctcaggg ttatatttcc ctctcccctt ccctccccgc caagagctct gccaggggcg 3960ggcaaaaaaa aaagtaaaaa gaaaagaaaa aaaaaaaaaa gaaacaaacc acctctacat 4020attatggaaa gaaaatattt ttgtcgattc ttattctttt ataattatgc gtggaagaag 4080tagacacatt aaacgattcc agttggaaac atgtcacctg 4120<210>39<211>819<212>PRT<213>智人(Homo sapiens)<400>39Met Arg Lys Val Lys Lys Leu Arg Leu Asp Lys Glu Asn Thr Gly Ser1 5 10 15Trp Arg Ser Phe Ser Leu Asn Ser Glu Gly Ala Glu Arg Met Ala Thr20 25 30Thr Gly Thr Pro Thr Ala Asp Arg Gly Asp Ala Ala Ala Thr Asp Asp35 40 45Pro Ala Ala Arg Phe Gln Val Gln Lys His Ser Trp Asp Gly Leu Arg50 55 60Ser Ile Ils His Gly Ser Arg Lys Tyr Ser Gly Leu Ile Val Asn Lys65 70 75 80Ala Pro His Asp Phe Gln Phe Val Gln Lys Thr Asp Glu Ser Gly Pro85 90 95His Ser His Arg Leu Tyr Tyr Leu Gly Met Pro Tyr Gly Ser Arg Glu100 105 110Asn Ser Leu Leu Tyr Ser Glu Ile Pro Lys Lys Val Arg Lys Glu Ala115 120 125Leu Leu Leu Leu Ser Trp Lys Gln Met Leu Asp His Phe Gln Ala Thr130 135 140Pro His His Gly Val Tyr Ser Arg Glu Glu Glu Leu Leu Arg Glu Arg145 150 155 160Lys Arg Leu Gly Val Phe Gly Ile Thr Ser Tyr Asp Phe His Ser Glu165 170 175Ser Gly Leu Phe Leu Phe Gln Ala Ser Asn Ser Leu Phe His Cys Arg180 185 190
Asp Gly Gly Lys Asn Gly Phe Met Val Ser Pro Met Lys Pro Leu Glu195 200 205Ile Lys Thr Gln Cys Ser Gly Pro Arg Met Asp Pro Lys Ile Cys Pro210 215 220Ala Asp Pro Ala Phe Phe Ser Phe Ile Asn Asn Ser Asp Leu Trp Val225 230 235 240Ala Asn Ile Glu Thr Gly Glu Glu Arg Arg Leu Thr Phe Cys His Gln245 250 255Gly Leu Ser Asn Val Leu Asp Asp Pro Lys Ser Ala Gly Val Ala Thr260 265 270Phe Val Ile Gln Glu Glu Phe Asp Arg Phe Thr Gly Tyr Trp Trp Cys275 280 285Pro Thr Ala Ser Trp Glu Gly Ser Glu Gly Leu Lys Thr Leu Arg Ile290 295 300Leu Tyr Glu Glu Val Asp Glu Ser Glu Val Glu Val Ile His Val Pro305 310 315 320Ser Pro Ala Leu Glu Glu Arg Lys Thr Asp Ser Tyr Arg Tyr Pro Arg325 330 335Thr Gly Ser Lys Asn Pro Lys Ile Ala Leu Lys Leu Ala Glu Phe Gln340 345 350Thr Asp Ser Gln Gly Lys Ile Val Ser Thr Gln Glu Lys Glu Leu Val355 360 365Gln Pro Phe Ser Ser Leu Phe Pro Lys Val Glu Tyr Ile Ala Arg Ala370 375 380Gly Trp Thr Arg Asp Gly Lys Tyr Ala Trp Ala Met Phe Leu Asp Arg385 390 395 400Pro Gln Gln Trp Leu Gln Leu Val Leu Leu Pro Pro Ala Leu Phe Ile405 410 415Pro Ser Thr Glu Asn Glu Glu Gln Arg Leu Ala Ser Ala Arg Ala Val420 425 430Pro Arg Asn Val Gln Pro Tyr Val Val Tyr Glu Glu Val Thr Asn Val435 440 445Trp Ile Asn Val His Asp Ile Phe Tyr Pro Phe Pro Gln Ser Glu Gly450 455 460Glu Asp Glu Leu Cys Phe Leu Arg Ala Asn Glu Cys Lys Thr Gly Phe465 470 475 480Cys His Leu Tyr Lys Val Thr Ala Val Leu Lys Ser Gln Gly Tyr Asp485 490 495Trp Ser Glu Pro Phe Ser Pro Gly Glu Asp Glu Phe Lys Cys Pro Ile500 505 510Lys Glu Glu Ile Ala Leu Thr Ser Gly Glu Trp Glu Val Leu Ala Arg515 520 525His Gly Ser Lys Gly Thr Lys Asp Thr Pro Leu Glu His His Leu Tyr530 535 540Val Val Ser Tyr Glu Ala Ala Gly Glu Ile Val Arg Leu Thr Thr Pro545 550 555 560Gly Phe Ser His Ser Cys Ser Met Ser Gln Asn Phe Asp Met Phe Val565 570 575Ser His Tyr Ser Ser Val Ser Thr Pro Pro Cys Val His Val Tyr Lys580 585 590Leu Ser Gly Pro Asp Asp Asp Pro Leu His Lys Gln Pro Arg Phe Trp595 600 605Ala Ser Met Met Glu Ala Ala Ser Cys Pro Pro Asp Tyr Val Pro Pro610 615 620Glu Ile Phe His Phe His Thr Arg Ser Asp Val Arg Leu Tyr Gly Met625 630 635 640Ile Tyr Lys Pro His Ala Leu Gln Pro Gly Lys Lys His Pro Thr Val645 650 655
Leu Phe Val Tyr Gly Gly Pro Gln Val Gln Leu Val Asn Asn Ser Phe660 665 670Lys Gly Ile Lys Tyr Leu Arg Leu Asn Thr Leu Ala Ser Leu Gly Tyr675 680 685Ala Val Val Val Ile Asp Gly Arg Gly Ser Cys Gln Arg Gly Leu Arg690 695 700Phe Glu Gly Ala Leu Lys Asn Gln Met Gly Gln Val Glu Ile Glu Asp705 710 715 720Gln Val Glu Gly Leu Gln Phe Val Ala Glu Lys Tyr Gly Phe Ile Asp725 730 735Leu Ser Arg Val Ala Ile His Gly Trp Ser Tyr Gly Gly Phe Leu Ser740 745 750Leu Met Gly Leu Ile His Lys Pro Gln Val Phe Lys Ala Gln Pro Leu755 760 765Ala Tyr Pro Pro Arg Leu Pro Gly Arg Lys Arg Ala Leu Phe Pro His770 775 780Lys Leu Pro Arg Leu Pro Thr Asp Pro Ser Arg Glu Thr Leu Pro Ala785 790 795 800Pro Asp Leu Pro Gln Arg Glu Thr Gln Tyr Ser Leu Pro Arg Val Gly805 810 815Arg Ala Leu<210>40<211>4037<212>DNA<213>智人(Homo sapiens)<400>40caggccgccg cctgggtcgc tcaacttccg ggtcaaaggt gcctgagccg gcgggtcccc 60tgtgtccgcc gcggctgtcg tcccccgctc ccgccacttc cggggtcgca gtcccgggca120tggagccgcg accgtgaggc gccgctggac ccgggacgac ctgcccagtc cggccgccgc180cccacgtccc ggtctgtgtc ccacgcctgc agctggaatg gaggctctct ggacccttta240gaaggcaccc ctgccctcct gaggtcagct gagcggttaa tgcggaaggt taagaaactg300cgcctggaca aggagaacac cggaagttgg agaagcttct cgctgaattc cgagggggct360gagaggatgg ccaccaccgg gaccccaacg gccgaccgag gcgacgcagc cgccacagat420gacccggccg cccgcttcca ggtgcagaag cactcgtggg acgggctccg gagcatcatc480cacggcagcc gcaagtactc gggcctcatt gtcaacaagg cgccccacga cttccagttt540gtgcagaaga cggatgagtc tgggccccac tcccaccgcc tctactacct gggaatgcca600tatggcagcc gagagaactc cctcctctac tctgagattc ccaagaaggt ccggaaagag660gctctgctgc tcctgtcctg gaagcagatg ctggatcatt tccaggccac gccccaccat720ggggtctact ctcgggagga ggagctgctg agggagcgga aacgcctggg ggtcttcggc780atcacctcct acgacttcca cagcgagagt ggcctcttcc tcttccaggc cagcaacagc840ctcttccact gccgcgacgg cggcaagaac ggcttcatgg tgtcccctat gaaaccgctg900gaaatcaaga cccagtgctc agggccccgg atggacccca aaatctgccc tgccgaccct960gccttcttct ccttcatcaa taacagcgac ctgtgggtgg ccaacatcga gacaggcgag 1020gagcggcggc tgaccttctg ccaccaaggt ttatccaatg tcctggatga ccccaagtct 1080gcgggtgtgg ccaccttcgt catacaggaa gagttcgacc gcttcactgg gtactggtgg 1140tgccccacag cctcctggga aggttcagag ggcctcaaga cgctgcgaat cctgtatgag 1200gaagtcgatg agtccgaggt ggaggtcatt cacgtcccct ctcctgcgct agaagaaagg 1260aagacggact cgtatcggta ccccaggaca ggcagcaaga atcccaagat tgccttgaaa 1320ctggctgagt tccagactga cagccagggc aagatcgtct cgacccagga gaaggagctg 1380gtgcagccct tcagctcgct gttcccgaag gtggagtaca tcgccagggc cgggtggacc 1440cgggatggca aatacgcctg ggccatgttc ctggaccggc cccagcagtg gctccagctc 1500gtcctcctcc ccccggccct gttcatcccg agcacagaga atgaggagca gcggctagcc 1560tctgccagag ctgtccccag gaatgtccag ccgtatgtgg tgtacgagga ggtcaccaac 1620gtctggatca atgttcatga catcttctat cccttccccc aatcagaggg agaggacgag 1680ctctgctttc tccgcgccaa tgaatgcaag accggcttct gccatttgta caaagtcacc 1740gccgttttaa aatcccaggg ctacgattgg agtgagccct tcagccccgg ggaagatgaa 1800tttaagtgcc ccattaagga agagattgct ctgaccagcg gtgaatggga ggttttggcg 1860
aggcacggct ccaagggcac caaggacacg ccgctggagc accacctcta cgtggtcagc 1920tatgaggcgg ccggcgagat cgtacgcctc accacgcccg gcttctccca tagctgctcc 1980atgagccaga acttcgacat gttcgtcagc cactacagca gcgtgagcac gccgccctgc 2040gtgcacgtct acaagctgag cggccccgac gacgaccccc tgcacaagca gccccgcttc 2100tgggctagca tgatggaggc agccagctgc cccccggatt atgttcctcc agagatcttc 2160catttccaca cgcgctcgga tgtgcggctc tacggcatga tctacaagcc ccacgccttg 2220cagccaggga agaagcaccc caccgtcctc tttgtatatg gaggccccca ggtgcagctg 2280gtgaataact ccttcaaagg catcaagtac ttgcggctca acacactggc ctccctgggc 2340tacgccgtgg ttgtgattga cggcaggggc tcctgtcagc gagggcttcg gttcgaaggg 2400gccctgaaaa accaaatggg ccaggtggag atcgaggacc aggtggaggg cctgcagttc 2460gtggccgaga agtatggctt catcgacctg agccgagttg ccatccatgg ctggtcctac 2520gggggcttcc tctcgctcat ggggctaatc cacaagcccc aggtgttcaa ggcccaaccg 2580cttgcttatc ctccacggct tcctggacga aaacgtgcac tttttccaca caaacttcct 2640cgtctcccaa ctgatccgag cagggaaacc ttaccagctc cagatctacc ccaacgagag 2700acacagtatt cgctgccccg agtcgggcga gcactatgaa gtcacgttgc tgcactttct 2760acaggaatac ctctgagcct gcccaccggg agccgccaca tcacagcaca agtggctgca 2820gcctccgcgg ggaaccaggc gggagggact gagtggcccg cgggccccag tgaggcactt 2880tgtcccgccc agcgctggcc agccccgagg agccgctgcc ttcaccgccc cgacgccttt 2940tatccttttt taaacgctct tgggttttat gtccgctgct tcttggttgc cgagacagag 3000agatggtggt ctcgggccag cccctcctct ccccgccttc tgggaggagg aggtcacacg 3060ctgatgggca ctggagaggc cagaagagac tcagaggagc gggctgcctt ccgcctgggg 3120ctccctgtga cctctcagtc ccctggcccg gccagccacc gtccccagca cccaagcatg 3180caattgcctg tcccccccgg ccagcctccc caacttgatg tttgtgtttt gtttgggggg 3240atatttttca taattattta aaagacaggc cgggcgcggt ggctcacgtc tgtaatccca 3500gcactttggg aggctgaggc gggcggatca cctgaggttg ggagttcaag accagcctgg 3360ccaacatggg gaaaccccgt ctctactaaa aatacaaaaa attagccggg tgtggtggcg 3420cgtgcctata atcccagcta ctcgggaggc tgaggcagga gaatcgcttg aacccgggag 3480gtggaggttg cggtgagcca agatcgcacc attgcactcc agcctgggca acaagagcga 3540aactctgtct caaaataaat aaaaaataaa agacagaaag caaggggtgc ctaaatctag 3600acttggggtc cacaccgggc agcggggttg caacccagca cctggtaggc tccatttctt 3660cccaagcccg actttcaggc aggcactgaa acgcaccgaa cttccacgct ctgctggtca 3720gtggcggctg tcccctcccc agcccagccg cccagccaca tgtgtctgcc tgacccgtac 3780acaccagggg ttccggggtt gggagctgaa ccatccccac ctcagggtta tatttccctc 3840tccccttccc tccccgccaa gagctctgcc aggggcgggc aaaaaaaaaa gtaaaaagaa 3900aagaaaaaaa aaaaaaagaa acaaaccacc tctacatatt atggaaagaa aatatttttg 3960tcgattctta ttcttttata attatgcgtg gaagaagtag acacattaaa cgattccagt 4020tggaaacatg tcacctg 4037<210>41<211>706<212>PRT<213>智人(Homo sapiens)<400>41Asp Thr Asp Val Val Tyr Lys Ser Glu Asn Gly His Val Ile Lys Leu1 5 10 15Asn Ile Glu Thr Asn Ala Thr Thr Leu Leu Leu Glu Asn Thr Thr Phe20 25 30Val Thr Phe Lys Ala Ser Arg His Ser Val Ser Pro Asp Leu Lys Tyr35 40 45Val Leu Leu Ala Tyr Asp Val Lys Gln Ile Phe His Tyr Ser Tyr Thr50 55 60Ala Ser Tyr Val Ile Tyr Asn Ile His Thr Arg Glu Val Trp Glu Leu65 70 75 80Asn Pro Pro Glu Val Glu Asp Ser Val Leu Gln Tyr Ala Ala Trp Gly85 90 95Val Gln Gly Gln Gln Leu Ile Tyr Ile Phe Glu Asn Asn Ile Tyr Tyr100 105 110
Gln Pro Asp Ile Lys Ser Ser Ser Leu Arg Leu Thr Ser Ser Gly Lys115 120 125Glu Glu Ile Ile Phe Asn Gly Ile Ala Asp Trp Leu Tyr Glu Glu Glu130 135 140Leu Leu His Ser His Ile Ala His Trp Trp Ser Pro Asp Gly Glu Arg145 150 155 160Leu Ala Phe Leu Met Ile Asn Asp Ser Leu Val Pro Thr Met Val Ile165 170 175Pro Arg Phe Thr Gly Ala Leu Tyr Pro Lys Gly Lys Gln Tyr Pro Tyr180 185 190Pro Lys Ala Gly Gln Val Asn Pro Thr Ile Lys Leu Tyr Val Val Asn195 200 205Leu Tyr Gly Pro Thr His Thr Leu Glu Leu Met Pro Pro Asp Ser Phe210 215 220Lys Ser Arg Glu Tyr Tyr Ile Thr Met Val Lys Trp Val Ser Asn Thr225 230 235 240Lys Thr Val Val Arg Trp Leu Asn Arg Pro Gln Asn Ile Ser Ile Leu245 250 255Thr Val Cys Glu Thr Thr Thr Gly Ala Cys Ser Lys Lys Tyr Glu Met260 265 270Thr Ser Asp Thr Trp Leu Ser Gln Gln Asn Glu Glu Pro Val Phe Ser275 280 285Arg Asp Gly Ser Lys Phe Phe Met Thr Val Pro Val Lys Gln Gly Gly290 295 300Arg Gly Glu Phe His His Ile Ala Met Phe Leu Ile Gln Ser Lys Ser305 310 315 320Glu Gln Ile Thr Val Arg His Leu Thr Ser Gly Asn Trp Glu Val Ile325 330 335Lys Ile Leu Ala Tyr Asp Glu Thr Thr Gln Lys Ile Tyr Phe Leu Ser340 345 350Thr Glu Ser Ser Pro Arg Gly Arg Gln Leu Tyr Ser Ala Ser Thr Glu355 360 365Gly Leu Leu Asn Arg Gln Cys Ile Ser Cys Asn Phe Met Lys Glu Gln370 375 380Cys Thr Tyr Phe Asp Ala Ser Phe Ser Pro Met Asn Gln His Phe Leu385 390 395 400Leu Phe Cys Glu Gly Pro Arg Val Pro Val Val Ser Leu His Ser Thr405 410 415Asp Asn Pro Ala Lys Tyr Phe Ile Leu Glu Ser Asn Ser Met Leu Lys420 425 430Glu Ala Ile Leu Lys Lys Lys Ile Gly Lys Pro Glu Ile Lys Ile Leu435 440 445His Ile Asp Asp Tyr Glu Leu Pro Leu Gln Leu Ser Leu Pro Lys Asp450 455 460Phe Met Asp Arg Asn Gln Tyr Ala Leu Leu Leu Ile Met Asp Glu Glu465 470 475 480Pro Gly Gly Gln Leu Val Thr Asp Lys Phe His Ile Asp Trp Asp Ser485 490 495Val Leu Ile Asp Met Asp Asn Val Ile Val Ala Arg Phe Asp Gly Arg500 505 510Gly Ser Gly Phe Gln Gly Leu Lys Ile Leu Gln Glu Ile His Arg Arg515 520 525Leu Gly Ser Val Glu Val Lys Asp Gln Ile Thr Ala Val Lys Phe Leu530 535 540Leu Lys Leu Pro Tyr Ile Asp Ser Lys Arg Leu Ser Ile Phe Gly Lys545 550 555 560Gly Tyr Gly Gly Tyr Ile Ala Ser Met Ile Leu Lys Ser Asp Glu Lys565 570 575
Leu Phe Lys Cys Gly Ser Val Val Ala Pro Ile Thr Asp Leu Lys Leu580 585 590Tyr Ala Ser Ala Phe Ser Glu Arg Tyr Leu Gly Met Pro Ser Lys Glu595 600 605Glu Ser Thr Tyr Gln Ala Ala Ser Val Leu His Asn Val His Gly Leu610 615 620Lys Glu Glu Asn Ile Leu Ile Ile His Gly Thr Ala Asp Thr Lys Val625 630 635 640His Phe Gln His Ser Ala Glu Leu Ile Lys His Leu Ile Lys Ala Gly645 650 655Val Asn Tyr Thr Met Gln Val Tyr Pro Asp Glu Gly His Asn Val Ser660 665 670Glu Lys Ser Lys Tyr His Leu Tyr Ser Thr Ile Leu Lys Phe Phe Ser675 680 685Asp Cys Leu Lys Glu Glu Ile Ser Val Leu Pro Gln Glu Pro Glu Glu690 695 700Asp Glu705<210>42<211>4541<212>DNA<213>智人(Homo sapiens)<400>42gkctykgtkg wtsmagatac agatgtggtg tataaaagcg agaatggaca tgtcattaaa 60ctgaatatag aaacaaatgc taccacatta ttattggaaa acacaacttt tgtaaccttc120aaagcatcaa gacattcagt ttcaccagat ttaaaatatg tccttctggc atatgatgtc180aaacagattt ttcattattc gtatactgct tcatatgtga tttacaacat acacactagg240gaagtttggg agttaaatcc tccagaagta gaggactccg tcttgcagta cgcggcctgg300ggtgtccaag ggcagcagct gatttatatt tttgaaaata atatctacta tcaacctgat360ataaagagca gttcattgcg actgacatct tctggaaaag aagaaataat ttttaatggg420attgctgact ggttatatga agaggaactc ctgcattctc acatcgccca ctggtggtca480ccagatggag aaagacttgc cttcctgatg ataaatgact ctttggtacc caccatggtt540atccctcggt ttactggagc gttgtatccc aaaggaaagc agtatccgta tcctaaggca600ggtcaagtga acccaacaat aaaattatat gttgtaaacc tgtatggacc aactcacact660ttggagctca tgccacctga cagctttaaa tcaagagaat actatatcac tatggttaaa720tgggtaagca ataccaagac tgtggtaaga tggttaaacc gacctcagaa catctccatc780ctcacagtct gtgagaccac tacaggtgct tgtagtaaaa aatatgagat gacatcagat840acgtggctct ctcagcagaa tgaggagccc gtgttttcta gagacggcag caaattcttt900atgacagtgc ctgttaagca agggggacgt ggagaatttc accacatagc tatgttcctc960atccagagta aaagtgagca aattaccgtg cggcatctga catcaggaaa ctgggaagtg 1020ataaagatct tggcatacga tgaaactact caaaaaattt actttctgag cactgaatct 1080tctcccagag gaaggcagct gtacagtgct tctactgaag gattattgaa tcgccaatgc 1140atttcatgta atttcatgaa agaacaatgt acatattttg atgccagttt tagtcccatg 1200aatcaacatt tcttattatt ctgtgaaggt ccaagggtcc cagtggtcag cctacatagt 1260acggacaacc cagcaaaata ttttatattg gaaagcaatt ctatgctgaa ggaagctatc 1320ctgaagaaga agataggaaa gccagaaatt aaaatccttc atattgacga ctatgaactt 1380cctttacagt tgtcccttcc caaagatttt atggaccgaa accagtatgc tcttctgtta 1440ataatggatg aagaaccagg aggccagctg gttacagata agttccatat tgactgggat 1500tccgtactca ttgacatgga taatgtcatt gtagcaagat ttgatggcag aggaagtgga 1560ttccagggtc tgaaaatttt gcaggagatt catcgaagat taggttcagt agaagtaaag 1620gaccaaataa cagctgtgaa atttttgctg aaactgcctt acattgactc caaaagatta 1680agcatttttg gaaagggtta tggtggctat attgcatcaa tgatcttaaa atcagatgaa 1740aagcttttta aatgtggatc cgtggttgca cctatcacag acttgaaatt gtatgcctca 1800gctttctctg aaagatacct tgggatgcca tctaaggaag aaagcactta ccaggcagcc 1860agtgtgctac ataatgttca tggcttgaaa gaagaaaata tattaataat tcatggaact 1920gctgacacaa aagttcattt ccaacactca gcagaattaa tcaagcacct aataaaagct 1980ggagtgaatt atactatgca ggtctaccca gatgaaggtc ataacgtatc tgagaagagc 2040
aagtatcatc tctacagcac aatcctcaaa ttcttcagtg attgtttgaa ggaagaaata 2100tctgtgctac cacaggaacc agaagaagat gaataatgga ccgtatttat acagaactga 2160agggaatatt gaggctcaat gaaacctgac aaagagactg taatattgta gttgctccag 2220aatgtcaagg gcagcttacg gagatgtcac tggagcagca cgctcagaga cagtgaacta 2280gcatttgaat acacaagtcc aagtctactg tgttgctagg ggtgcagaac ccgtttcttt 2340gtatgagaga ggtcaaaggg ttggtttcct gggagaaatt agttttgcat taaagtagga 2400gtagtgcatg ttttcttctg ttatccccct gtttgttctg taactagttg ctctcatttt 2460aatttcactg gccaccatca tctttgcata taatgcacaa tctatcatct gtcctacagt 2520ccctgatctt tcatggctga gctgcaatct aacactttac tgtaccttta taataagtgc 2580aattctttca ttgtctatta ttatgcttaa gaaaatattc agttaataaa aaacagagta 2640ttttatgtaa tttctgtttt taaaaagaca ttattaaatg ggtcaaagga catatagaaa 2700tgtggatttc agcaccttcc aaagttcagc cagttatcag tagatacaat atctttaaat 2760gaacacacga gtgtatgtct cacaatatat atacacaagt gtgcatatac agttaatgaa 2820actatcttta aatgttattc atgctataaa gagtaaacgt ttgatgaatt agaagagatg 2880ctcttttcca agctataatg gatgctttgt ttaatgagcc aaatatgatg aaacattttt 2940tccaattcaa attctagcta ttgctttcct ataaatgttt gggttgtgtt tggtattgtt 3000tttagtggtt aatagttttc cagttgcatt taattttttg aatatgatac cttgtcacat 3060gtaaattaga tacttaaata ttaaattata gtttctgata aagaaatttt gttaacaatg 3120caatgccact gagtgctatt ttgctctttt ggtggagaag gcttttttca aaactcttgg 3180tccttttact tctttctctc agtgcagaat caattctcat tttcatcgta aaagcaaata 3240gctggattat ttcatttgcc agtttctatt tagtattcca tgcctgccca attcatctgt 3300tactgtttaa tttcaattct tctggtgaga attagaaatg aaatattttt tattcattgg 3360ccaaaaagtt cacagacagc agtgtttgct atttactttg aattgaaggc acaaaatgca 3420tcaattcctg tgctgtgttg acttgcagta gtaagtaact gagagcataa aataaacctg 3480actgtatgaa gtcaatttaa gtgatgagaa catttaactt tggtgactaa agtcagaata 3540tcttctcact tcacttaagg gatcttccag aagatatcta aaagtctgta ataagcttag 3600aagttcagat aaatctaggc aggatactgc atttttgtgg ttttaaaaaa gtccttagga 3660cagactgaat tatcataact tatggcatca ggaggaaact ttaaaatatc aaggaatcac 3720tcagtcaccc tcctgttttg ttgaaggatc aaccccaaat tctgggtatt tgagtacatg 3780tgaatcatgg atttggtatt caactttttc cctggatgct ttggaatcgt gtcttccatg 3840ctccactggg ttcaatttaa aataggagag gctttctctt ctgaaagatc cattttaggt 3900ctttttcaag aatagtgaac acatttttta acaaaataag ttgtaatttt aaaaggaaag 3960ttttgcctat tttattaaga tggaaatttc tttttaggct aatttgaaat ccaactgaag 4020ctttttaacc aatattttaa atttgaacca ctagagtttt ttatgatgca aatgattatg 4080ttgtctgaaa ggtgtggttt tattgaatgt ctatttgagt atcatttaaa aagtatttgc 4140cttttactgt catcatttct cttgttttat tattattatc aatgtttatc tatttttcaa 4200ttaatttaat acagtttcta atgtgaaaga catttttctg gaacccgttt tccccttaaa 4260cactaaagag acctcaagtg aaagcatatt gcttagtagg aaggtagaaa atgttaatcc 4320ctgcgattct ttgagtttta atgacagggt cattttcagt aaaggaaatg ctcaccaaca 4380catagtcacc aactattaaa ggaatcatgt gattggattt tcccctgtat acatgtaccc 4440ttggtcataa tcccactatt tcatacatat ttatgcattg ctagattttc ctaggactcc 4500aatagcatgc tttccaagtg ttattattcc cttaatgtta a 4541<210>43<211>691<212>PRT<213>智人(Homo sapiens)<400>43Asp Thr Asp Val Val Tyr Lys Ser Glu Asn Gly His Val Ile Lys Leu1 5 10 15Asn Ile Glu Thr Asn Ala Thr Thr Leu Leu Leu Glu Asn Thr Thr Phe20 25 30Val Thr Phe Lys Ala Ser Arg His Ser Val Ser Pro Asp Leu Lys Tyr35 40 45Val Leu Leu Ala Tyr Asp Val Lys Gln Ile Phe His Tyr Ser Tyr Thr50 55 60Ala Ser Tyr Val Ile Tyr Asn Ile His Thr Arg Glu Val Trp Glu Leu65 70 75 80
Asn Pro Pro Glu Val Glu Asp Ser Val Leu Gln Tyr Ala Ala Trp Gly85 90 95Val Gln Gly Gln Gln Leu Ile Tyr Ile Phe Glu Asn Asn Ile Tyr Tyr100 105 110Gln Pro Asp Ile Lys Ser Ser Ser Leu Arg Leu Thr Ser Ser Gly Lys115 120 125Glu Glu Ile Ile Phe Asn Gly Ile Ala Asp Trp Leu Tyr Glu Glu Glu130 135 140Leu Leu His Ser His Ile Ala His Trp Trp Ser Pro Asp Gly Glu Arg145 150 155 160Leu Ala Phe Leu Met Ile Asn Asp Ser Leu Val Pro Thr Met Val Ile165 170 175Pro Arg Phe Thr Gly Ala Leu Tyr Pro Lys Gly Lys Gln Tyr Pro Tyr180 185 190Pro Lys Ala Gly Gln Val Asn Pro Thr Ile Lys Leu Tyr Val Val Asn195 200 205Leu Tyr Gly Pro Thr His Thr Leu Glu Leu Met Pro Pro Asp Ser Phe210 215 220Lys Ser Arg Glu Tyr Tyr Ile Thr Met Val Lys Trp Val Ser Asn Thr225 230 235 240Lys Thr Val Val Arg Trp Leu Asn Arg Pro Gln Asn Ile Ger Ile Leu245 250 255Thr Val Cys Glu Thr Thr Thr Gly Ala Cys Ser Lys Lys Tyr Glu Met260 265 270Thr Ser Asp Thr Trp Leu Ser Gln Gln Asn Glu Glu Pro Val Phe Ser275 280 285Arg Asp Gly Ser Lys Phe Phe Met Thr Val Pro Val Lys Gln Gly Gly290 295 300Arg Gly Glu Phe His His Ile Ala Met Phe Leu Ile Gln Ser Lys Ser305 310 315 320Glu Gln Ile Thr Val Arg His Leu Thr Ser Gly Asn Trp Glu Val Ile325 330 335Lys Ile Leu Ala Tyr Asp Glu Thr Thr Gln Lys Ile Ser Ala Ser Thr340 345 350Glu Gly Leu Leu Asn Arg Gln Cys Ile Ser Cys Asn Phe Met Lys Glu355 360 365Gln Cys Thr Tyr Phe Asp Ala Ser Phe Ser Pro Met Asn Gln His Phe370 375 380Leu Leu Phe Cys Glu Gly Pro Arg Val Pro Val Val Ser Leu His Ser385 390 395 400Thr Asp Asn Pro Ala Lys Tyr Phe Ile Leu Glu Ser Asn Ser Met Leu405 410 415Lys Glu Ala Ile Leu Lys Lys Lys Ile Gly Lys Pro Glu Ile Lys Ile420 425 430Leu His Ile Asp Asp Tyr Glu Leu Pro Leu Gln Leu Ser Leu Pro Lys435 440 445Asp Phe Met Asp Arg Asn Gln Tyr Ala Leu Leu Leu Ile Met Asp Glu450 455 460Glu Pro Gly Gly Gln Leu Val Thr Asp Lys Phe His Ile Asp Trp Asp465 470 475 480Ser Val Leu Ile Asp Met Asp Asn Val Ile Val Ala Arg Phe Asp Gly485 490 495Arg Gly Ser Gly Phe Gln Gly Leu Lys Ile Leu Gln Glu Ile His Arg500 505 510Arg Leu Gly Ser Val Glu Val Lys Asp Gln Ile Thr Ala Val Lys Phe515 520 525Leu Leu Lys Leu Pro Tyr Ile Asp Ser Lys Arg Leu Ser Ile Phe Gly530 535 540
Lys Gly Tyr Gly Gly Tyr Ile Ala Ser Met Ile Leu Lys Ser Asp Glu545 550 555 560Lys Leu Phe Lys Cys Gly Ser Val Val Ala Pro Ile Thr Asp Leu Lys565 570 575Leu Tyr Ala Ser Ala Phe Ser Glu Arg Tyr Leu Gly Met Pro Ser Lys580 585 590Glu Glu Ser Thr Tyr Gln Ala Ala Ser Val Leu His Asn Val His Gly595 600 605Leu Lys Glu Glu Asn Ile Leu Ile Ile His Gly Thr Ala Asp Thr Lys610 615 620Val His Phe Gln His Ser Ala Glu Leu Ile Lys His Leu Ile Lys Ala625 630 635 640Gly Val Asn Tyr Thr Met Gln Val Tyr Pro Asp Glu Gly His Asn Val645 650 655Ser Glu Lys Ser Lys Tyr His Leu Tyr Ser Thr Ile Leu Lys Phe Phe660 665 670Ser Asp Cys Leu Lys Glu Glu Ile Ser Val Leu Pro Gln Glu Pro Glu675 680 685Glu Asp Glu690<210>44<211>4496<212>DNA<213>智人(Homo sapiens)<400>44gkctykgtkg wtsmagatac agatgtggtg tataaaagcg agaatggaca tgtcattaaa 60ctgaatatag aaacaaatgc taccacatta ttattggaaa acacaacttt tgtaaccttc120aaagcatcaa gacattcagt ttcaccagat ttaaaatatg tccttctggc atatgatgtc180aaacagattt ttcattattc gtatactgct tcatatgtga tttacaacat acacactagg240gaagtttggg agttaaatcc tccagaagta gaggactccg tcttgcagta cgcggcctgg300ggtgtccaag ggcagcagct gatttatatt tttgaaaata atatctacta tcaacctgat360ataaagagca gttcattgcg actgacatct tctggaaaag aagaaataat ttttaatggg420attgctgact ggttatatga agaggaactc ctgcattctc acatcgccca ctggtggtca480ccagatggag aaagacttgc cttcctgatg ataaatgact ctttggtacc caccatggtt540atccctcggt ttactggagc gttgtatccc aaaggaaagc agtatccgta tcctaaggca600ggtcaagtga acccaacaat aaaattatat gttgtaaacc tgtatggacc aactcacact660ttggagctca tgccacctga cagctttaaa tcaagagaat actatatcac tatggttaaa720tgggtaagca ataccaagac tgtggtaaga tggttaaacc gacctcagaa catctccatc780ctcacagtct gtgagaccac tacaggtgct tgtagtaaaa aatatgagat gacatcagat840acgtggctct ctcagcagaa tgaggagccc gtgttttcta gagacggcag caaattcttt900atgacagtgc ctgttaagca agggggacgt ggagaatttc accacatagc tatgttcctc960atccagagta aaagtgagca aattaccgtg cggcatctga catcaggaaa ctgggaagtg 1020ataaagatct tggcatacga tgaaactact caaaaaatca gtgcttctac tgaaggatta 1080ttgaatcgcc aatgcatttc atgtaatttc atgaaagaac aatgtacata ttttgatgcc 1140agttttagtc ccatgaatca acatttctta ttattctgtg aaggtccaag ggtcccagtg 1200gtcagcctac atagtacgga caacccagca aaatatttta tattggaaag caattctatg 1260ctgaaggaag ctatcctgaa gaagaagata ggaaagccag aaattaaaat ccttcatatt 1320gacgactatg aacttccttt acagttgtcc cttcccaaag attttatgga ccgaaaccag 1380tatgctcttc tgttaataat ggatgaagaa ccaggaggcc agctggttac agataagttc 1440catattgact gggattccgt actcattgac atggataatg tcattgtagc aagatttgat 1500ggcagaggaa gtggattcca gggtctgaaa attttgcagg agattcatcg aagattaggt 1560tcagtagaag taaaggacca aataacagct gtgaaatttt tgctgaaact gccttacatt 1620gactccaaaa gattaagcat ttttggaaag ggttatggtg gctatattgc atcaatgatc 1680ttaaaatcag atgaaaagct ttttaaatgt ggatccgtgg ttgcacctat cacagacttg 1740aaattgtatg cctcagcttt ctctgaaaga taccttggga tgccatctaa ggaagaaagc 1800acttaccagg cagccagtgt gctacataat gttcatggct tgaaagaaga aaatatatta 1860ataattcatg gaactgctga cacaaaagtt catttccaac actcagcaga attaatcaag 1920
cacctaataa aagctggagt gaattatact atgcaggtct acccagatga aggtcataac 1980gtatctgaga agagcaagta tcatctctac agcacaatcc tcaaattctt cagtgattgt 2040ttgaaggaag aaatatctgt gctaccacag gaaccagaag aagatgaata atggaccgta 2100tttatacaga actgaaggga atattgaggc tcaatgaaac ctgacaaaga gactgtaata 2160ttgtagttgc tccagaatgt caagggcagc ttacggagat gtcactggag cagcacgctc 2220agagacagtg aactagcatt tgaatacaca agtccaagtc tactgtgttg ctaggggtgc 2280agaacccgtt tctttgtatg agagaggtca aagggttggt ttcctgggag aaattagttt 2340tgcattaaag taggagtagt gcatgttttc ttctgttatc cccctgtttg ttctgtaact 2400agttgctctc attttaattt cactggccac catcatcttt gcatataatg cacaatctat 2460catctgtcct acagtccctg atctttcatg gctgagctgc aatctaacac tttactgtac 2520ctttataata agtgcaattc tttcattgtc tattattatg cttaagaaaa tattcagtta 2580ataaaaaaca gagtatttta tgtaatttct gtttttaaaa agacattatt aaatgggtca 2640aaggacatat agaaatgtgg atttcagcac cttccaaagt tcagccagtt atcagtagat 2700acaatatctt taaatgaaca cacgagtgta tgtctcacaa tatatataca caagtgtgca 2760tatacagtta atgaaactat ctttaaatgt tattcatgct ataaagagta aacgtttgat 2820gaattagaag agatgctctt ttccaagcta taatggatgc tttgtttaat gagccaaata 2880tgatgaaaca ttttttccaa ttcaaattct agctattgct ttcctataaa tgtttgggtt 2940gtgtttggta ttgtttttag tggttaatag ttttccagtt gcatttaatt ttttgaatat 3000gataccttgt cacatgtaaa ttagatactt aaatattaaa ttatagtttc tgataaagaa 3060attttgttaa caatgcaatg ccactgagtg ctattttgct cttttggtgg agaaggcttt 3120tttcaaaact cttggtcctt ttacttcttt ctctcagtgc agaatcaatt ctcattttca 3180tcgtaaaagc aaatagctgg attatttcat ttgccagttt ctatttagta ttccatgcct 3240gcccaattca tctgttactg tttaatttca attcttctgg tgagaattag aaatgaaata 3300ttttttattc attggccaaa aagttcacag acagcagtgt ttgctattta ctttgaattg 3360aaggcacaaa atgcatcaat tcctgtgctg tgttgacttg cagtagtaag taactgagag 3420cataaaataa acctgactgt atgaagtcaa tttaagtgat gagaacattt aactttggtg 3480actaaagtca gaatatcttc tcacttcact taagggatct tccagaagat atctaaaagt 3540ctgtaataag cttagaagtt cagataaatc taggcaggat actgcatttt tgtggtttta 3600aaaaagtcct taggacagac tgaattatca taacttatgg catcaggagg aaactttaaa 3660atatcaagga atcactcagt caccctcctg ttttgttgaa ggatcaaccc caaattctgg 3720gtatttgagt acatgtgaat catggatttg gtattcaact ttttccctgg atgctttgga 3780atcgtgtctt ccatgctcca ctgggttcaa tttaaaatag gagaggcttt ctcttctgaa 3840agatccattt taggtctttt tcaagaatag tgaacacatt ttttaacaaa ataagttgta 3900attttaaaag gaaagttttg cctattttat taagatggaa atttcttttt aggctaattt 3960gaaatccaac tgaagctttt taaccaatat tttaaatttg aaccactaga gttttttatg 4020atgcaaatga ttatgttgtc tgaaaggtgt ggttttattg aatgtctatt tgagtatcat 4080ttaaaaagta tttgcctttt actgtcatca tttctcttgt tttattatta ttatcaatgt 4140ttatctattt ttcaattaat ttaatacagt ttctaatgtg aaagacattt ttctggaacc 4200cgttttcccc ttaaacacta aagagacctc aagtgaaagc atattgctta gtaggaaggt 4260agaaaatgtt aatccctgcg attctttgag ttttaatgac agggtcattt tcagtaaagg 4320aaatgctcac caacacatag tcaccaacta ttaaaggaat catgtgattg gattttcccc 4380tgtatacatg tacccttggt cataatccca ctatttcata catatttatg cattgctaga 4440ttttcctagg actccaatag catgctttcc aagtgttatt attcccttaa tgttaa 4496<210>45<211>29<212>DNA<213>智人(Homo sapiens)<400>45cggtaccatg gcagcagcaa tggaaacag 29<210>46<211>39<212>DNA<213>智人(Homo sapiens)<400>46ggagctcgcg gccgctcata tcacttttag agcagcaat39
<210>47<211>27<212>DNA<213>智人(Homo sapiens)<400>47caagctttat cacttttaga gcagcaa 27<210>48<211>22<212>DNA<213>智人(Homo sapiens)<400>48cacattcttg ctgcatcagt ca 22<210>49<211>22<212>DNA<213>智人(Homo sapiens)<400>49ttgggtcatc ttcaggactt ga 22<210>50<211>27<212>DNA<213>智人(Homo sapiens)<400>50caagcttacc atggccacca ccgggac 27<210>51<211>37<212>DNA<213>智人(Homo sapiens)<400>51cggatccgcg gccgctcaga ggtattcctg tagaaag 37<210>52<211>27<212>DNA<213>智人(Homo sapiens)<400>52cggatccagg tattcctgta gaaagtg 27<210>53<211>20<212>DNA<213>智人(Homo sapiens)<400>53tacgccgtgg ttgtgattga 20<210>54<211>20<212>DNA
<213>智人(Homo sapiens)<400>54ccatacttct cggccacgaa 20<210>55<211>19<212>DNA<213>智人(Homo sapiens)<400>55gcctgggatt gtgcactgt 19<210>56<211>29<212>DNA<213>智人(Homo sapiens)<400>56gtgtattcaa atgctagttc actgtctct 29<210>57<211>22<212>DNA<213>智人(Homo sapiens)<400>57agctagcact gtccagggtc ct 22<210>58<211>25<212>DNA<213>智人(Homo sapiens)<400>58agggcccttc atcttcttct ggttc 25<210>59<211>19<212>PRT<213>智人(Homo sapiens)<400>59Val Glu Asp Asp Val Met Glu Arg Gln Arg Leu Ile Glu Ser Val Pro1 5 10 15Asp Ser Val<210>60<211>19<212>PRT<213>智人(Homo sapiens)<400>60Ser Thr Glu Asn Glu Glu Gln Arg Leu Ala Ser Ala Arg Ala Val Pro1 5 10 15Arg Asn Val<210>61<211>15<212>PRT<213>智人(Homo sapiens)<400>61Lys Glu Ala Ile Leu Lys Lys Lys Ile Gly Lys Pro Glu Ile Lys1 5 10 1權(quán)利要求
1.一種分離的核酸，其特征在于，該核酸編碼(a)包含SEQ ID NO1、3和5之一的氨基酸序列的多肽，或(b)具有與SEQ ID NO1、3和5之一的氨基酸序列至少約70％的相似性的氨基酸序列，并顯示同樣的生物功能的多肽；或該核酸是SEQ ID NOS；2、4和6之一的交替剪接變體；或該核酸是含有編碼(a)或(b)的所述核酸的至少14個連續(xù)核苷酸的探針；或該核酸與上述任何一種序列互補。
2.如權(quán)利要求1所述的分離的核酸，其特征在于，所述核酸是DNA或RNA。
3.如權(quán)利要求1所述的分離的核酸，其特征在于，所述核酸是一種DNA轉(zhuǎn)錄物，該轉(zhuǎn)錄物包含SEQ ID NO2、4和6之一的全長序列，或與SEQ ID NO2、4和6之一的整個編碼區(qū)互補。
4.一種針對權(quán)利要求3所述的DNA的反義寡核苷酸。
5.如權(quán)利要求1所述的分離的核酸，其特征在于，所述核酸是一種RNA轉(zhuǎn)錄物，該轉(zhuǎn)錄物包含SEQ ID NO2、4和6之一的全長序列。
6.如權(quán)利要求1所述的分離的核酸，其特征在于，所述核酸是SEQ ID NO2、4和6之一的交替剪接變體。
7.一種權(quán)利要求6所述的核酸編碼的多肽。
8.如權(quán)利要求1所述的分離的核酸，其特征在于，所述核酸編碼一種多肽，該多肽具有與SEQ ID NO1、3和5之一至少90％相似的氨基酸。
9.如權(quán)利要求1所述的分離的核酸，其特征在于，所述核酸編碼一種多肽，該多肽具有與SEQ ID NO1、3和5之一至少95％相似的氨基酸。
10.如權(quán)利要求1所述的分離的核酸，其特征在于，所述核酸編碼一種多肽，該多肽具有與SEQ ID NO1、3和5之一至少90％相同的氨基酸。
11.如權(quán)利要求1所述的核酸探針，其特征在于，所述核酸探針含有SEQ IDNO2、4和6之一的至少14個連續(xù)核苷酸。
12.一種分離的重組多核苷酸分子，其特征在于，該分子含有權(quán)利要求1所述的核酸加上與所述核酸可操縱性連接的表達控制元件，以驅(qū)動其表達。
13.一種表達載體，其特征在于，該載體含有權(quán)利要求1所述的核酸，該核酸編碼具有SEQ ID NO1、3和5之一的整個氨基酸序列的多肽，所述核酸與啟動子可操縱性連接，所述表達載體存在于相容的宿主細胞中。
14.一種哺乳動物、昆蟲或細菌宿主細胞，其特征在于，該細胞已被權(quán)利要求1所述的核酸的插入而經(jīng)過基因工程改造，所述核酸編碼SEQ ID NO1、3或5的氨基酸序列的至少成熟蛋白質(zhì)部分。
15.一種產(chǎn)生含有SEQ ID NO1、3或5之一的成熟蛋白質(zhì)部分的多肽的方法，其特征在于，該方法包括將權(quán)利要求11所述的宿主細胞在生產(chǎn)所述多肽的足夠條件下培養(yǎng)。
16.如權(quán)利要求15所述的方法，其特征在于，所述多肽在所述細胞表面表達，并且還包括從培養(yǎng)物中回收多肽或其片段的步驟。
17.一種多肽，其特征在于，該多肽可任選糖基化，和它(a)具有SEQ ID NO1、3和5之一列出的成熟蛋白的氨基酸序列；(b)具有與(a)的成熟蛋白質(zhì)之一至少70％相似性的成熟蛋白質(zhì)的氨基酸序列，并顯示相同的生物學功能；(c)具有與SEQ ID NO1、3和5之一的成熟蛋白質(zhì)至少約90％相同性的成熟蛋白質(zhì)的氨基酸序列；或(d)是(a)的免疫反應性片段。
18.如權(quán)利要求14所述的多肽，其特征在于，該多肽是與(a)的成熟蛋白質(zhì)具有至少約95％相似性的成熟蛋白質(zhì)。
19.如權(quán)利要求14所述的多肽，其特征在于，該多肽是與(a)的成熟蛋白質(zhì)具有至少約95％相似性的成熟蛋白質(zhì)。
20.如權(quán)利要求14所述的多肽，其特征在于，該多肽具有SEQ ID NO1、3和5之一的成熟蛋白質(zhì)的氨基酸序列，或者作為代表性成熟蛋白質(zhì)是其顯示相同生物功能的片段。
21.一種DPRP拮抗劑，其特征在于，該拮抗劑抑制權(quán)利要求17、18和19所述的成熟蛋白質(zhì)之一的生物學功能。
22.一種抗體，其特征在于，該抗體識別權(quán)利要求17所述的多肽或片段。
23.如權(quán)利要求22所述的抗體，其特征在于，該抗體識別具有SEQ ID NO1、3或5的氨基酸序列的多肽。
24.一種篩選能抑制權(quán)利要求17所述的至少一種成熟蛋白質(zhì)的酶活性的化合物的方法，其特征在于，該方法包括將所述成熟蛋白質(zhì)和所述成熟蛋白質(zhì)的合適底物，在一種或多種測試化合物或其鹽的存在下溫育，測定所述成熟蛋白質(zhì)的酶活性，與缺乏測試化合物的情況下測定的活性比較，并選擇降低酶活性的測試化合物。
25.一種篩選能抑制DPPIV活性，而不抑制權(quán)利要求20所述的至少一種成熟蛋白質(zhì)的酶活性的化合物的方法，其特征在于，該方法包括將所述成熟蛋白質(zhì)和所述成熟蛋白質(zhì)的合適底物，在一種或多種DPPIV抑制劑或其鹽的存在下溫育，測定所述成熟蛋白質(zhì)的酶活性，與缺乏DPPIV抑制劑的情況下測定的活性比較，并選擇不降低所述成熟蛋白質(zhì)的酶活性的化合物。
全文摘要
要提供了與DPPIV具有顯著序列同源性的新穎蛋白質(zhì)或多肽，其編碼核酸、用這些核酸修飾的能表達這些蛋白質(zhì)的細胞，這些蛋白質(zhì)的抗體，發(fā)現(xiàn)新治療劑的篩選方法，這些新治療劑是這些蛋白質(zhì)或相關(guān)蛋白質(zhì)活性的抑制劑，和這些篩選方法發(fā)現(xiàn)的治療劑，以及新治療方法。
文檔編號C12N5/10GK1636061SQ01817312
公開日2005年7月6日 申請日期2001年10月12日 優(yōu)先權(quán)日2000年10月12日
發(fā)明者S·威, K·O·埃金桑亞, P·J·-M·里弗, J·-L·朱尼英 申請人:凡林有限公司