利用IL-1拮抗剂治疗自身炎症性疾病的方法
背景
发明领域
本发明涉及利用白细胞介素-1(IL-1)拮抗剂治疗自身炎症性疾 病的方法，所述自身炎症性疾病例如包括家族性地中海热(FMF)、 NOMID/CINCA、穆-韦综合征、FCAS以及肿瘤坏死因子受体相关的周期 性发热综合征(TRAPS)。
相关领域的描述
重要的一组自身炎症性疾病包括与CIAS-1中突变相关的常染色 体显性疾病，所述CIAS-1是编码被称为“cryopyrin”的pyrin相关 蛋白的基因(Feldmann等人，(2002)Am.J.Hum.Genet.71：198-203； Hoffman等人，(2001)Nat.Genet.29：301-305)。这些病症包括 新生儿期起病的多系统炎性病症(NOMID/CINCA)、穆-韦综合征(MWS) 和家族性寒冷型自身炎症性综合征(FCAS)。这些病症呈现出从最轻 微的FCAS到严重的残疾疾病NOMID/CINCA的一系列临床表现。荨麻 疹样皮疹是整个范围的这些疾病所共有的。在FCAS患者中，这种皮疹 由寒冷暴露诱导，而在大部分MWS或NOMID患者中存在一向由各种不 同的刺激引起的日常皮疹。结膜炎存在于所有形式的疾病表现中，然 而，听力丧失、无菌性脑膜炎和关节炎主要见于MWS和NOMID/CINCA 患者。在骨骺和髌骨处的损形性和致残性骨过度生长仅见于 NOMID/CINCA患者。
FMF是以发热和浆膜炎或滑膜炎的发作为特征的隐性遗传疾病； 某些受试者还发展为全身性淀粉样变性(Balow等人，(1997) Genomics44：280-291)。FMF基因编码被称为pyrin的新型蛋白，所 述pyrin蛋白是与凋亡(细胞死亡)和炎症调节有关的分子家族的原 型。这些蛋白起作用以及突变导致疾病的精确的生物化学机制仍是未 知的。
斯蒂尔病(全身性发作的青少年特发性关节炎)表现为峰热、渐 失性橙红色皮疹、关节炎、关节痛和肝脾肿大(Masson等人，(1995) Rev.Rhum.Engl.Ed.62：748-757；Spiegel等人，(2000)Arthritis Rheum.43：2402-2409)。迄今仍没有与斯蒂尔病的确定遗传联系而且 发病机理知之甚少。有趣的是，斯蒂尔病的许多体征和症状与自身炎 症性疾病的那些类似。斯蒂尔病一般首先在儿童期发生，但也可以在 成人期发作。
类似地，川崎病是侵袭儿童的疾病，它伴随发热、肿胀和关节炎 性关节以及皮疹，还有血管炎症，所述血管炎症可在大约15-25％的 受侵袭儿童中导致永久性冠状动脉损伤。其他两种类似的疾病是Blau 综合征和早发型结节病(Early Onset Sarcoidosis)(EOS)，这两 种疾病均由NOD2中的功能突变的获得而引起，并引起皮疹、肉芽肿、 关节炎和葡萄膜炎，所述NOD2是与Pyrin类似的蛋白。也已被认为是 自身炎症性的其他疾病包括化脓性汗腺炎、贝切特综合征、具有周期 性发热综合征(HIDS)的高免疫球蛋白血症D、肿瘤坏死因子受体相 关的周期性发热综合征(TRAPS)和脓性无菌性关节炎、坏疽性脓皮症 和痤疮(PAPA综合征)。
自身炎症性疾病的发病机理还未完全了解。有一批增长中的证据 表明白细胞介素-1(IL-1)在许多这种疾病中起作用并且这种细胞因 子的靶向可以提供重大利益(Hoffman等人，(2004)Arthritis.Rheum. 50：345-349)。显然需要开发这些自身炎症性疾病的改良的治疗处理。
发明概述
在第一个方面，本发明以治疗、抑制或改善自身炎症性病症的方 法为特征，所述方法包括在需要时对受试者施用白细胞介素-1(IL-1) 拮抗剂。IL-1拮抗剂是能够阻断或抑制IL-1的生物作用的化合物， 包括IL-1结合性融合蛋白。在一个优选实施方案中，IL-1拮抗剂是 包括两个受体组分和多聚化组分的IL-1特异性融合蛋白，例如，2003 年7月31日公布的美国专利公开号2003/0143697中描述的IL-1融合 蛋白捕获拮抗剂(“IL-1捕获剂”)。在一个具体实施方案中，IL-1 拮抗剂是SEQ ID NO：4、6、8、10、12、14、16、18、20、22、24、 26中显示的融合蛋白。优选的融合蛋白显示于SEQ ID NO：10中。本 发明包括IL-1结合性融合蛋白的用途，所述IL-1结合性融合蛋白与 SEQ ID NO：4、6、8、10、12、14、16、18、20、22、24、26的蛋白 基本上相同，即，与SEQ ID NO：4、6、8、10、12、14、16、18、20、 22、24、26的蛋白具有至少95％的同一性、至少97％的同一性、至 少98％的同一性，并且能够结合和抑制IL-1的蛋白。进一步地，在 具体实施方案中，该IL-1拮抗剂是包括一个或多个免疫球蛋白衍生组 分的融合蛋白，所述免疫球蛋白衍生组分代替一个或多个受体组分。 在具体实施方案中，该IL-1拮抗剂包括一个或多个对于IL-1和/或 IL-1受体特异的免疫球蛋白衍生组分。
被治疗的受试者最优选是被诊断为患自身炎症性病症的人。更具 体而言，患者是被诊断有与CIAS-1中突变相关的自身炎症性病症的成 人或儿童，所述自身炎症性病症例如为新生儿期起病的多系统炎性病 症(NOMID/CINCA)、穆-韦综合征(MWS)、家族性寒冷型自身炎症性 综合征(FCAS)；家族性地中海热(FMF)；全身性发作的青少年特发 性关节炎(斯蒂尔病)、肿瘤坏死因子受体相关的周期性发热综合征 (TRAPS)或川崎病。
本发明的方法包括通过本领域已知的任何方法施用IL-1拮抗剂， 所述方法例如皮下、肌内、鼻内、静脉内、经皮肤给药或口服给药。 优选皮下或静脉内给药。
在第二个方面，本发明以治疗、抑制或改善疾病或病状的方法为 特征，所述疾病或病状选自NOMID/CINCA、MWS、FCAS、FMP、斯蒂尔 病、TRAPS和川崎病，所述方法包括在需要时对受试者施用白细胞介 素-1(IL-1)拮抗剂。在一个优选实施方案中，该IL-1拮抗剂是能够 捕获IL-1的融合蛋白。在一个具体实施方案中，该IL-1拮抗剂是SEQ ID NO：4、6、8、10、12、14、16、18、20、22、24、26中显示的融 合蛋白，或能够结合并抑制IL-1的基本上相同的蛋白。优选的IL-1 拮抗剂显示于SEQ ID NO：10中。优选地，被治疗的受试者是被诊断 有该疾病或病状的儿童或成人。
在第三个方面，本发明以治疗、抑制或改善新生儿期起病的多系 统炎性病症(NOMID/CINCA)的方法为特征，所述方法包括在需要时对 受试者施用白细胞介素-1(IL-1)拮抗剂。在一个优选实施方案中， 该IL-1拮抗剂是能够捕获IL-1的融合蛋白。在一个具体实施方案中， 该IL-1拮抗剂是SEQ ID NO：4、6、8、10、12、14、16、18、20、 22、24、26中显示的融合蛋白，或能够结合并抑制IL-1的基本上相 同的蛋白。优选的IL-1拮抗剂显示于SEQ ID NO：10中。
在第四个方面，本发明以治疗、抑制或改善穆-韦综合征(MWS) 的方法为特征，所述方法包括在需要时对受试者施用白细胞介素-1 (IL-1)拮抗剂。在一个优选实施方案中，该IL-1拮抗剂是能够捕获 IL-1的融合蛋白。在一个具体实施方案中，该IL-1拮抗剂是SEQ ID NO： 4、6、8、10、12、14、16、18、20、22、24、26中显示的融合蛋白， 或能够结合并抑制IL-1的基本上相同的蛋白。优选的IL-1拮抗剂显 示于SEQ ID NO：10中。
在第五个方面，本发明以治疗、抑制或改善家族性寒冷型自身炎 症性综合征(FCAS)的方法为特征，所述方法包括在需要时对受试者 施用白细胞介素-1(IL-1)拮抗剂。在一个优选实施方案中，该IL-1 拮抗剂是能够捕获IL-1的融合蛋白。在一个具体实施方案中，该IL-1 拮抗剂是SEQ ID NO：4、6、8、10、12、14、16、18、20、22、24、 26中显示的融合蛋白，或能够结合并抑制IL-1的基本上相同的蛋白。 优选的IL-1拮抗剂显示于SEQ ID NO：10中。
在第六个方面，本发明以治疗、抑制或改善家族性地中海热(FMF) 的方法为特征，该方法包括在需要时对受试者施用白细胞介素-1 (IL-1)拮抗剂。在一个优选实施方案中，该IL-1拮抗剂是能够捕获 IL-1的融合蛋白。在一个具体实施方案中，该IL-1捕获剂是SEQ ID NO： 4、6、8、10、12、14、16、18、20、22、24、26中显示的融合蛋白， 或能够结合并抑制IL-1的基本上相同的蛋白。优选的IL-1捕获剂显 示于SEQ ID NO：10中。
在第七个方面，本发明以治疗、抑制或改善全身性发作的青少年 特发性关节炎(斯蒂尔病)的方法为特征，所述方法包括在需要时对 受试者施用白细胞介素-1(IL-1)拮抗剂。在一个优选实施方案中， 该IL-1拮抗剂是能够捕获IL-1的融合蛋白。在一个具体实施方案中， 该IL-1拮抗剂是SEQ ID NO：4、6、8、10、12、14、16、18、20、 22、24、26中显示的融合蛋白，或能够结合并抑制IL-1的基本上相 同的蛋白。优选的IL-1捕获剂显示于SEQ ID NO：10中。
在第八个方面，本发明以治疗、抑制或改善肿瘤坏死因子受体相 关的周期性发热综合征(TRAPS)的方法为特征，所述方法包括在需要 时对受试者施用IL-1拮抗剂。在一个优选实施方案中，该IL-1拮抗 剂是能够捕获IL-1的融合蛋白。在一个具体实施方案中，该IL-1拮 抗剂是SEQ ID NO：4、6、8、10、12、14、16、18、20、22、24、26 中显示的融合蛋白，或能够结合并抑制IL-1的基本上相同的蛋白。优 选的IL-1捕获剂显示于SEQ ID NO：10中。
在本发明治疗方法的具体实施方案中，用第一种IL-1结合性融合 蛋白捕获分子和第二种治疗剂的组合来治疗受试者。第二种治疗剂可 以是第二种IL-1拮抗剂，例如，第二种IL-1结合性融合蛋白捕获剂， 阿那白滞素(Kineret，Amgen)、重组非糖基化形式的人IL-1受体 拮抗剂(IL1Ra)，或抗IL-18药物例如IL-18BP或衍生物、IL-18结 合性融合蛋白捕获剂(IL-18捕获剂)、抗IL-18、抗IL-18R1、或抗 IL-18Racp抗体或抗体片段。其他协同疗法包括对于FMF的低剂量的 秋水仙碱，阿司匹林或其他NSAIDs，类固醇例如泼尼松龙，甲氨蝶呤， 低剂量的环孢菌素A，TNF抑制剂例如Enbrel或Humira，其他炎症 抑制剂例如胱天蛋白酶-1的抑制剂、p38、IKK1/2、CTLA-4Ig、抗IL-6 或抗IL6Ra等。
在第九个方面，本发明以治疗自身炎症性疾病或病状的治疗方法 为特征，所述方法包括施用包含IL-1结合性融合蛋白捕获剂和药物学 上可接受载体的药物组合物。在一个实施方案中，在1周到1年或更 长的治疗时期内在每周一次的基础上以1-20mg/kg的剂量范围施用 IL-1结合性融合蛋白捕获剂。在另一实施方案中，总IL-1结合性融 合蛋白的施用范围为50-2000mg，它可以以单剂量形式或以连续剂 量形式在例如数周或数月的时间段内被提供。
其他目的和优点经参阅随后的详细描述将是显而易见的。
发明详述
在描述本方法之前，应当理解本发明不限于所描述的具体方法和 实验条件，因为此类方法和条件可以改变。还应当理解本文所使用的 术语仅用于描述具体实施方案，并不希望用于限制，因为本发明的范 围将仅由所附的权利要求来限定。
如本说明书和所附权利要求中所使用的，除非上下文明确说明否 则单数形式的“a”、“an”和“the”包括复数。因此例如提及“一 种方法”包括本文所描述的和/或阅读本公开内容等后对于本领域技术 人员将是显而易见的类型的一种或多种方法和/或步骤。
除非另外定义，本文所使用的所有技术和科学术语具有与本发明 所属领域普通技术人员通常理解相同的含义。尽管与本文所述那些类 似或等同的任何方法和材料均可用于本发明的实践或测试中，现在还 是描述优选的方法和材料。
一般描述
现在认识到基因CIAS1中的突变负责三种罕见的遗传综合征：新 生儿期起病的多系统炎性病症(NOMID)、穆-韦综合征(MWS)和家族 性寒冷型自身炎症性综合征(FCAS)(Hoffman等人，2001 Naure 29：301-305；Feldmann等人，2002 Am J Hum Genet 71：198-203； Aksentijevich等人，2002 Arthritis Rheum 46：3340-3348)。总 的说来，这些病状被称为“CAPS”，“CIAS1相关的周期性综合征” 的首字母缩写。CAPS病症非常罕见：在美国大约200-300位有FCAS 的成人和儿童并且明显更少的有NOMID或MWS的成人已知有这些疾病。 这些病状特别是NOMID和MWS的稀少，很可能是由于疾病严重度对生 存或生殖适合度的影响。
CAPS是以常染色体显性方式遗传的，具有单个发生或家族模式。 CIAS1编码被称为NALP3的蛋白，所述NALP3是“inflammasome”的 组分，所述“inflammasome”是调节胱天蛋白酶1活性的亚细胞酶复 合体。胱天蛋白酶1是将促炎细胞因子IL-1的无活性前体形式 (pro-form)裂解成其生物学活性形式的酶(Agostini等人，2004， 同上)。CIAS1中的突变导致IL-1产生增加以及众多的病理学后果 (Aksentijevich等人，2002，同上)。IL-1强烈诱导肝脏中产生急 性期反应物，例如C-反应性蛋白(CRP)和血清淀粉样A(SAA)。
CAPS的遗传学的有趣之处在于CIAS1中可以有许多不同的点突变 与这些综合征相关(Sarrauste de Menthiere等人，2003 Nucleic Acids Res 31：282-285；Aksentijevich等人，2002，同上)。这些 突变中的一些仅与一种综合征相关；其他的与两种综合征相关。例如， 某些突变可以与FCAS和MWS相关；其他突变可以与MWS和NOMID相关。 大约50％的NOMID患者在CIAS1编码区中没有可识别的突变。在这些 患者中，该疾病可以归因于在CIAS1的调节区或蛋白中，或在编码该 途径中的紧密相关蛋白的另一基因中迄今仍未识别的突变。FCAS在遗 传学上比NOMID更同源：几乎所有的FCAS患者分享共同的突变 (Sarrauste de Menthiere等人，2003，同上；Hoffman等人，2001， 同上)。
CAPS病症分享共同的临床特征并且呈现为一系列的临床严重度。 NOMID是最严重的残疾，MWS稍微轻些而FCAS最不严重。CAPS病症具 有重叠的特征并且存在具有独特集群的体征和症状的个人和家族。所 有这些症状的共同特征包括发热、荨麻疹样皮疹、关节炎或关节痛、 肌痛、不舒服和结膜炎。然而，对于任何有CAPS病症的患者，这系列 的症状可以不同于有相同病症的另一患者。活跃的CAPS疾病的普遍特 征是急性期反应物的实验室检验上升，所述急性期反应物例如为CRP、 SAA和/或红细胞沉降率(ESR)。
在NOMID中，慢性无菌性脑膜炎可以导致智力发育迟缓并且这些 患者还可能遭受在骨骺和髌骨处的损形性和致残性骨过度生长。这些 患者还可能由于视神经萎缩而遭受失明，所述视神经萎缩由颅内压升 高引起。MWS和NOMID通常与重度炎症相关，所述重度炎症可以包括 听觉系统、脑膜和关节。这些患者可能遭受每日高的峰热以及经常改 变分布和强度的慢性皮疹。患者可能遭受听力丧失或耳聋。经常观察 到结膜炎和视神经乳头水肿。由于慢性炎症和急性期反应物(特别是 SAA)的过度产生，淀粉样变性可以发展并导致肾衰竭。MWS也被称为 “淀粉样变性-耳聋综合征”。
FCAS的临床体征和症状通过暴露于适度冷的空气诱导(例如，季 节性温度改变、空调)。在寒冷的月份时或在空调盛行的场所患者可 以经常(有时是每日)发作疼痛的或痒的皮疹、发热、疲劳、不舒服、 头痛、恶心和口渴。在许多场所，这可以包括大多数工作场所。FCAS 是患者频繁疼痛的来源并可限制他们的工作、社交和娱乐机会。高达 2％的FCAS患者发展出淀粉样变性，这是危及生命的病状。这个频率基 本上高于一般公众中淀粉样变性的比率。FCAS的遗传学和自然历史 的详细描述见于Hoffman等人，2001 Nature 29：301-305和Hoffman 等人，2001 J Allergy clin Immunol 108：615-620。
定义
术语“阻滞剂”、“抑制剂”或“拮抗剂”是指延缓或阻止化学 或生理反应或应答的物质。通常的阻滞剂或抑制剂包括但不限于反义 分子、抗体、拮抗剂及其衍生物。更具体而言，IL-1的阻滞剂或抑制 剂的实例为IL-1拮抗剂，包括但不限于，IL-1融合蛋白捕获拮抗剂， 它可以结合并抑制IL-1。
术语“治疗上有效的剂量”是指产生施用预期效应的剂量。确切 的剂量将取决于治疗的目的，并且将由本领域技术人员利用已知技术 确定(参见，例如Lloyd(1999)The Art，Science and Technology of Pharmaceutical Compounding)。
术语“基本上相同”是指与氨基酸序列具有至少95％的同一性并 且能够结合IL-1并抑制IL-1生物活性的蛋白质序列，所述氨基酸序 列选自氨基酸SEQ ID NO：4、6、8、10、12、14、16、18、20、22、 24和26。
术语“同一性”或“同源性”被解释为指比对序列后，候选序列 中与进行比较的对应序列的残基相同的氨基酸残基的百分比，在比对 过程中如果需要引入缺口以达到整个序列的最大百分比同一性，并且 不考虑任何保守置换作为序列同一性的一部分。N-或C-末端延伸以及 插入将均不解释为降低同一性或同源性。关于比对的方法和计算机程 序是本领域众所周知的。序列同一性可以利用序列分析软件(例如 Sequence Analysis Software Package，Genetics Computer Group， University of Wisconsin Biotechnology Center，1710 University Ave.，Madison，Wis.53705)进行测量。这个软件通过将同源度指定 为各种置换、删除和其他修饰来匹配相似序列。
IL-1结合性融合蛋白捕获拮抗剂
白细胞介素-1(IL-1)捕获剂是包含IL-1受体组分和多聚化组分 的融合蛋白的多聚体，所述多聚化组分能够与存在于另一融合蛋白中 的多聚化组分相互作用形成高级结构，例如二聚体。本发明方法中有 用的IL-1结合性融合蛋白包括结合单个细胞因子的两种不同的受体 组分，导致产生的拮抗剂具有显著增加的超过由单组分反应试剂所提 供的亲和力。IL-1结合性融合蛋白捕获剂包括人I型(IL-1RI)或II 型(IL-1RII)IL-1R的胞外域，随后为人IL-1辅助蛋白(IL-1AcP) 的胞外域，随后为多聚化组分。在一个优选实施方案中，该多聚化组 分为免疫球蛋白衍生结构域，例如，人IgG的Fc区，包括部分铰链区， CH2和CH3结构域。免疫球蛋白衍生结构域可以选自任何主要种类的 免疫球蛋白，包括IgA、IgD、IdE、IgG和IgM，以及任何亚类或亚型， 例如，IgG1、IgG2、IgG3和IgG4；IgA-1和IgA-2。可替代地，本发 明方法中有用的IL-1结合性融合蛋白包括人IL-1AcP的胞外域，随后 为人IL-1RI或IL-1RII的胞外域，随后为多聚化组分。关于IL-1结 合性融合蛋白捕获剂的更详细描述参见WO 00/18932。优选的IL-1拮 抗剂具有SEQ ID NO：2、4、6、8、10、12、14、16、18、20、22、 24和26中显示的氨基酸序列，或与SEQ ID NO：4、6、8、10、12、 14、16、18、20、22、24或26的序列具有至少95％的序列同一性并 且能够结合和抑制IL-1的基本上相同的蛋白。
治疗群体
本发明的治疗方法可用于治疗受CIAS-1突变病症(NOMID、MWS、 FCAS)、FMF、TRAPS或斯蒂尔病侵袭的个体。关于CIAS-1突变相关 疾病(NOMID、MWS、FCAS)、家族性地中海热(FMF)或斯蒂尔病(成 人或幼年发病)的通常所接受的诊断标准是本领域技术人员已知的。 在诊断有FMF的患者的情况下，本发明的治疗方法对于患有用秋水仙 碱难以治疗的疾病的那些可以特别有用。
给药方法
本发明提供了包括对受试者施用有效量的本发明试剂的治疗方 法。在一个优选方面，该试剂是基本上纯化的(例如，基本上不含限 制其效果或产生所不希望的副作用的物质)。
各种递药系统是已知的并且可以用于施用本发明试剂，例如封装 在脂质体中、微粒、微囊、能够表达该化合物的重组细胞、受体介导 的细胞内吞作用(参见，例如Wu和Wu，1987，J.Biol.Chem.262： 4429-4432)、构建核酸作为逆转录病毒或其他载体的一部分，等等。 导入方法可以是经肠的或肠胃外的，包括但不限于皮内、肌内、腹膜 内、静脉内、皮下、鼻内、硬膜外以及口服。所述化合物可以通过任 何方便的途径施用，例如通过输注或推注，通过经上皮的或粘膜与皮 肤的衬层(例如口腔粘膜，直肠和肠粘膜等)的吸收，并且可以与其 他生物学活性试剂一起施用。施用可以是全身的或局部的。此外，可 以希望通过任何适合的途径将本发明的药物组合物导入中枢神经系 统，所述途径包括心室内和鞘内注射；通过例如与贮器例如奥马耶贮 器(Ommaya reservoir)相连的心室内导管可以促进心室内注射。也 可以采用肺给药，例如，通过使用吸入器或雾化器，以及含烟雾剂的 制剂。
在一个具体实施方案中，可以希望在需要治疗的区域局部施用本 发明的药物组合物；这可以通过下列方法达到，所述方法例如且不限 于，通过在手术期间局部输注，局部应用，例如，通过注射，通过导 管，或通过植入物，所述植入物是多孔的、非多孔的或凝胶状的材料， 包括膜例如sialastic膜、纤维、商品化的皮肤替代品或血管成形术 的球囊或支架。
在另一实施方案中，可以在囊泡特别是脂质体中输送活性剂(参 见Langer(1990)Science 249：1527-1533)。在另一实施方案中， 以控释系统输送活性剂。在一个实施方案中，可以利用泵(参见Langer (1990)，同上)。在另一实施方案中，可以使用聚合物材料(参见Howard 等人，(1989)J.Neurosurg.71：105)。在其中本发明的活性剂是编 码蛋白质的核酸的另一实施方案中，通过将其构建为合适的核酸表达 载体的一部分并施用之从而使得它变成细胞内的，该核酸可施用于体 内以促进其编码的蛋白质的表达，例如通过利用逆转录病毒载体(参 见，例如美国专利号4,980,286)，或通过直接注射，或通过利用微 粒轰击(例如，基因枪；Biolistic，Dupont)，或用脂质或细胞表面 受体或转染剂包裹，或通过将其与已知进入核的同源异型框样肽连接 施用(参见例如Joliot等人，，1991，Proc.Natl.Acad.Sci.USA 88：1864-1868)等。可替代地，通过同源重组，核酸可以被导入细胞 内并整合到宿主细胞DNA内以便表达。
组合治疗
在众多实施方案中，在本发明方法中有用的IL-1拮抗剂可以与一 种或多种另外的化合物或疗法组合施用。组合治疗可以是同时的或顺 次的。本发明的IL-1结合性融合蛋白可以与下列物质组合，例如，TNF- 抑制剂例如依那西普(Enbrel，Amgen)、英夫利昔单抗(Remicade， Centocor)、Humira(Abbott)、沙立度胺、类固醇、阿那白滞素 (Kinaret，Amgen)、或秋水仙碱。秋水仙碱是治疗FMF受试者的 主要依靠；在本研究中，受试者将不离开用这种药剂的治疗。对于斯 蒂尔病(以及经典的自身炎症性疾病)，化合物例如甲氨蝶呤、环胞 菌素、苯丁酸氮芥、环磷酰胺(DMARDs)已被用作单一疗法或与非一 致性应答(no consistent responce)组合。某些受试者对高剂量的 类固醇有反应。DMARDs以及更近来的抗TNF试剂已被使用，并有着可 变的成功。本发明的IL-1结合性融合蛋白也可与抗IL-18药物组合， 所述抗IL-18药物例如为IL-18BP或衍生物、IL-18结合性融合蛋白、 抗IL-18、抗IL-18R1或抗IL-18Racp。其他协同疗法包括对于FMF 的低剂量的秋水仙碱，阿司匹林或其他NSAIDs，类固醇例如泼尼松龙， 甲氨蝶呤，低剂量的环胞菌素A，TNF抑制剂例如Enbre1或Humira， 其他炎症抑制剂例如胱天蛋白酶-1的抑制剂、p38、IKK1/2、CTLA-4Ig、 抗IL-6或抗-IL6Ra等。
药物组合物
本发明还提供了药物组合物。此类组合物包括治疗上有效剂量的 活性剂以及药物学上可接受的载体。术语“药物学上可接受的”指经 联邦或州政府管理机构批准的或在美国药典或其他普遍公认的药典中 列出的用于动物并且更具体而言用于人的。术语“载体(carrier)” 是指稀释剂、佐剂、赋形剂或通过其施用治疗剂的媒介物。此类药物 载体可以是无菌的液体，例如水和油，包括石油、动物、植物或合成 来源的那些，例如花生油、大豆油、矿物油、芝麻油等。适当的药物 赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、米、面粉、白 垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、脱脂奶粉、 甘油、丙稀、甘醇、水、乙醇等。需要时，该组合物还可包含少量湿 润剂或乳化剂或pH缓冲剂。这些组合物可采取的形式有溶液、悬浮液、 乳状液、片剂、丸剂、胶囊、粉剂、持续释放制剂等。该组合物可以 被配制为含常规粘合剂和载体例如甘油三酯的栓剂。口服制剂可以包 括标准载体例如药物级别的甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、 纤维素、碳酸镁等。适当的药物载体的实例由E.W.Martin描述于 ″Remington′s Pharmaceutical Sciences″中。
在一个优选实施方案中，该组合物依照常规操作配制为适合于人 类静脉内给药的药物组合物。必要时，该组合物也可包括增溶剂和局 部麻醉剂例如利多卡因以减轻注射位置处的疼痛。该组合物通过输注 施用时，它可以在包含药物级别的无菌水或盐水的输注瓶中分散。该 组合物通过注射施用时，可以提供一安瓿的无菌注射用水或盐水，从 而使得成分可以在给药前被混合。
本发明的活性剂可以被配制为中性或盐形式。药物学上可接受的 盐包括由游离的氨基基团形成的盐，例如从盐酸、磷酸、乙酸、草酸、 酒石酸等衍生的盐，以及由游离的羧基基团形成的盐，例如从钠、钾、 铵、钙、氢氧化铁、异丙胺、三乙胺、2-乙氨基乙醇、组氨酸、普鲁 卡因等衍生的盐。
将在迟发型超敏反应的治疗中有效的本发明活性剂的量可以通过 基于本说明书的标准临床技术确定。此外，体外测定法可任选用于帮 助鉴定最佳剂量范围。用于制剂中的精确剂量还将取决于给药途径以 及病状的严重度，并且应该根据从业医生的判断以及每个受试者的情 况来决定。然而，静脉内给药的合适剂量范围一般高达约2克的活性 化合物。从由体外或动物模型测试系统得到的剂量-响应曲线可以外推 出有效剂量。
对于全身给药，最初可以由体外测定法估计治疗上有效的剂量。 例如，可以在动物模型中配制剂量以达到循环浓度范围，所述循环浓 度范围包括在细胞培养中所测定的IC50。此类信息可用于更精确地测 定在人中的有用剂量。也可利用本领域众所周知的技术由体内数据例 如动物模型估计最初剂量。本领域普通的技术人员基于动物数据可以 很容易地优化对人的给药。
可以单独调整剂量和间隔以提供足够维持疗效的化合物的血浆水 平。在局部给药或选择性摄取的情况下，所述化合物的有效局部浓度 可以与血浆浓度无关。无需过度实验，本领域技术人员将能够优化治 疗上有效的局部剂量。
当然，所施用的化合物的量将取决于被治疗的受试者，取决于该 受试者的体重、痛苦的严重度、给药方式、给药频率以及开处方的医 师的判断。当症状可检测时或甚至当它们不可检测时，可以间歇地重 复该疗法。该疗法可以被单独提供或与其他药物组合提供。
试剂盒
本发明还提供了一种包括包装材料和包含在包装材料内的药物试 剂的制品，其中该药物试剂包括至少一种本发明的IL-1特异性融合蛋 白，并且其中该包装材料包括标签或药品说明书，所述标签或药品说 明书指出该IL-1特异性融合蛋白可以用于治疗自身炎症性疾病或病 状。
本发明的其他特征在下列示例性实施例的描述过程中将是显而易 见的，所述实施例是为了举例说明本发明而给出的而并不是希望限制 本发明。
实施例
提出下列实施例是为了给本领域普通技术人员提供如何制造并使 用本发明方法和组合物的完整公开内容和描述，而不是希望限制本发 明人视为其发明的范围。已付出努力确保关于所使用的数字(例如量、 温度等)的精确性，但某些试验误差和偏差应当被说明。除非另有说 明，份是重量份，分子量是平均分子量，温度是摄氏度数，和压力为 大气压或接近大气压。
实施例1.IL-1捕获剂对人自身炎症性疾病的影响
最初的研究在15名患有已知对IL-1的阻断作出反应的疾病 (NOMID/MWS/FCAS)的成人受试者以及有成人斯蒂尔病和秋水仙碱抗 性FMF的受试者中进行。筛选出合格、临床症状确定、活动性疾病确 认的受试者，并且以一周的间隔大约3次抽取基准血样以确定炎症基 准水平。进行仔细且完全的标准化病史和体格检查(适合于研究中的 疾病)以保证每个受试者的统一的数据收集。在每次就诊时获取生命 体征和体重。临床数据基于包括所有被报告的临床表现的详细调查表。 下列评价程序特别属于CIAS-1突变相关病症并且如临床说明执行：皮 肤病学评估；眼科学评估；耳/鼻/喉科学评估；神经学评估；腰椎穿 刺；头部MRI；X光照片；关节MRI；以及药物代谢动力学作图。
所有研究受试者接受IL-1结合性融合蛋白(SEQ ID NO：10)， 给药方案为连续3天每天1次100mg，这是期望提供2-4周的显著的 IL-1抑制活性的方案。在用IL-1捕获剂治疗开始后第10天，初步结 果在这个期间被测量，包括药物安全性、临床有效性分析以及所选择 的炎症生物标记物(例如急性期反应物，例如CRP、血清淀粉样A和 ESR)的变化。如果在第10天观察到良好反应，在预定的时间点(没 有进一步治疗)监视受试者直到体征和症状回复(发红(flare))。 发红后，受试者适合进入延长期，所述延长期需要用负荷方案(连续 3天100mg/天的IL-1捕获剂)再治疗，随后为每周1次100mg IL-1 捕获剂的定量给药直至一年。
基于研究者的临床判断，如果在延长期以100mg/周定量给药4周 后，受试者第1月的急性期反应物水平没有正常化(CRP＞0.5mg/dL 和/或SAA＞10mg/L)，或基于疾病的持续体征和/或症状而证明增加 剂量具有充分的理由，可以执行IL-1捕获剂剂量增加方案。第一个剂 量增加水平可以是每周1次皮下160。受试者将被观察4周，如果仍 然适合剂量增加的标准，随后剂量可以上升到每周1次皮下320mg。
初步结果。最初参加的是4名有CAPS的受试者。结果表明用IL-1 捕获剂(SEQ ID NO：10)治疗后，所有受试者经历了炎症体征和症状 的快速而广泛的改善，包括患者和医师报告的疾病表现的改善。还观 察到炎症生物标记物例如CRP和SAA的大大下降。体征和症状在初始 给药的21天这一中值(范围9-26)内回复，并随后对再治疗反应迅 速。表1提供了每日日志评分、急性期反应物和临床评估的总结( 对3名受试者执行；*与以前时间点有统计学上显著的差异，p＜0.1水 平；**与以前时间点有统计学上显著的差异，p＜0.05水平)。医师 和受试者总体评价VAS评分反映出在基线处、在发红时以及在指定为 反映最大有效性的时间点上的急性期反应物(SAA、CRP和ESR)的变 化。
表1
基线 中值(范围) 最大有效性 中值(范围) 发红 中值(范围) 每日日志评分 6.06(2.2-7.56) 1.67(0-3.3)* 4.5(2-7.33) 急性期反应物 SAA(mg/L) 96(16.1-468) 8.25(2-19) 84(50-236) CRP(mg/dL) 7.28(2.32-8.65) 0.72(0.07-1.15)** 2.93(0.076-6.21) ESR(mm/hr) 56.67(22-92) 24(7-45)** 34(11-70)* 血细胞计数 WBC 15.28(9.33-19.4) 7.58(7.21-9.9)** 8.48(6.34-11.47) Hgb 12.95(8.1-14.7) 13.3(8.2-15.6)* 13.1(7.9-14.57) Plt 356.5(291-445.5) 303.25(240-377)** 291(257-359.3) 调查表 医师总体VAS(cm) 6.85(4.1-6.95) 0.2(0.2-2.6) 3.3(3.1-3.5) 患者总体VAS(cm) 5.2(3.95-6.9) 1.1(0.95-3.05)** 3.6(3.1-6.45)** 疲劳VAS(cm) 5.55(3.25-8) 1.15(0.5-3.9) 6.6(3.15-6.9) 疼痛VAS(cm) 7.55(3.6-7.7) 0.95(0.2-1.05)* 4.1(0.5-6.55) SF-36身体健康状况 44.38(42.5-47.5) 50.63(33.75-92.5) 41.56(35-69.4) SF-36精神健康状况 41.625(28.5-57.8) 75.88(55-96) 39.6(37-57)
序列表
<110>Regeneron Pharmaceuticals，Inc.
<120>利用IL-1拮抗剂治疗自身炎症性疾病的方法
<130>REG 2090A-WO
<140>to be assigned
<141>2005-06-03
<150>60/577,023
<151>2004-06-04
<160>26
<170>FastSEQ for Windows Version 3.0
<210>1
<211>2733
<212>DNA
<213>智人
<400>1
atg gtg ctt ctg tgg tgt gta gtg agt ctc tac ttt tat gga atc ctg 48
caa agt gat gcc tca gaa cgc tgc gat gac tgg gga cta gac acc atg 96
agg caa atc caa gtg ttt gaa gat gag cca gct cgc atc aag tgc cca 144
ctc ttt gaa cac ttc ttg aaa ttc aac tac agc aca gcc cat tca gct 192
ggc ctt act ctg atc tgg tat tgg act agg cag gac cgg gac ctt gag 240
gag cca att aac ttc cgc ctc ccc gag aac cgc att agt aag gag aaa 288
gat gtg ctg tgg ttc cgg ccc act ctc ctc aat gac act ggc aac tat 336
acc tgc atg tta agg aac act aca tat tgc agc aaa gtt gca ttt ccc 384
ttg gaa gtt gtt caa aaa gac agc tgt ttc aat tcc ccc atg aaa ctc 432
cca gtg cat aaa ctg tat ata gaa tat ggc att cag agg atc act tgt 480
cca aat gta gat gga tat ttt cct tcc agt gtc aaa ccg act atc act 528
tgg tat atg ggc tgt tat aaa ata cag aat ttt aat aat gta ata ccc 576
gaa ggt atg aac ttg agt ttc ctc att gcc tta att tca aat aat gga 624
aat tac aca tgt gtt gtt aca tat cca gaa aat gga cgt acg ttt cat 672
ctc acc agg act ctg act gta aag gta gta ggc tct cca aaa aat gca 720
gtg ccc cct gtg atc cat tca cct aat gat cat gtg gtc tat gag aaa 768
gaa cca gga gag gag cta ctc att ccc tgt acg gtc tat ttt agt ttt 816
ctg atg gat tct cgc aat gag gtt tgg tgg acc att gat gga aaa aaa 864
cct gat gac atc act att gat gtc acc att aac gaa agt ata agt cat 912
agt aga aca gaa gat gaa aca aga act cag att ttg agc atc aag aaa 960
gtt acc tct gag gat ctc aag cgc agc tat gtc tgt cat gct aga agt 1008
gcc aaa ggc gaa gtt gcc aaa gca gcc aag gtg aag cag aaa gtg cca 1056
gct cca aga tac aca gtg tcc ggt ggc gcg cct atg ctg agc gag gct 1104
gat aaa tgc aag gaa cgt gaa gaa aaa ata att tta gtg tca tct gca 1152
aat gaa att gat gtt cgt ccc tgt cct ctt aac cca aat gaa cac aaa 1200
ggc act ata act tgg tat aag gat gac agc aag aca cct gta tct aca 1248
gaa caa gcc tcc agg att cat caa cac aaa gag aaa ctt tgg ttt gtt 1296
cct gct aag gtg gag gat tca gga cat tac tat tgc gtg gta aga aat 1344
tca tct tac tgc ctc aga att aaa ata agt gca aaa ttt gtg gag aat 1392
gag cct aac tta tgt tat aat gca caa gcc ata ttt aag cag aaa cta 1440
ccc gtt gca gga gac gga gga ctt gtg tgc cct tat atg gag ttt ttt 1488
aaa aat gaa aat aat gag tta cct aaa tta cag tgg tat aag gat tgc 1536
aaa cct cta ctt ctt gac aat ata cac ttt agt gga gtc aaa gat agg 1584
ctc atc gtg atg aat gtg gct gaa aag cat aga ggg aac tat act tgt 1632
cat gca tcc tac aca tac ttg ggc aag caa tat cct att acc cgg gta 1680
ata gaa ttt att act cta gag gaa aac aaa ccc aca agg cct gtg att 1728
gtg agc cca gct aat gag aca atg gaa gta gac ttg gga tcc cag ata 1776
caa ttg atc tgt aat gtc acc ggc cag ttg agt gac att gct tac tgg 1824
aag tgg aat ggg tca gta att gat gaa gat gac cca gtg cta ggg gaa 1872
gac tat tac agt gtg gaa aat cct gca aac aaa aga agg agt acc ctc 1920
atc aca gtg ctt aat ata tcg gaa att gag agt aga ttt tat aaa cat 1968
cca ttt acc tgt ttt gcc aag aat aca cat ggt ata gat gca gca tat 2016
atc cag tta ata tat cca gtc act aat tcc gga gac aaa act cac aca 2064
tgc cca ccg tgc cca gca cct gaa ctc ctg ggg gga ccg tca gtc ttc 2112
ctc ttc ccc cca aaa ccc aag gac acc ctc atg atc tcc cgg acc cct 2160
gag gtc aca tgc gtg gtg gtg gac gtg agc cac gaa gac cct gag gtc 2208
aag ttc aac tgg tac gtg gac ggc gtg gag gtg cat aat gcc aag aca 2256
aag ccg cgg gag gag cag tac aac agc acg tac cgt gtg gtc agc gtc 2304
ctc acc gtc ctg cac cag gac tgg ctg aat ggc aag gag tac aag tgc 2352
aag gtc tcc aac aaa gcc ctc cca gcc ccc atc gag aaa acc atc tcc 2400
aaa gcc aaa ggg cag ccc cga gaa cca cag gtg tac acc ctg ccc cca 2448
tcc cgg gag gag atg acc aag aac cag gtc agc ctg acc tgc ctg gtc 2496
aaa ggc ttc tat ccc agc gac atc gcc gtg gag tgg gag agc aat ggg 2544
cag ccg gag aac aac tac aag acc acg cct ccc gtg ctg gac tcc gac 2592
ggc tcc ttc ttc ctc tat agc aag ctc acc gtg gac aag agc agg tgg 2640
cag cag ggg aac gtc ttc tca tgc tcc gtg atg cat gag gct ctg cac 2688
aac cac tac acg cag aag agc ctc tcc ctg tct ccg ggt aaa 2730
tga 2733
<210>2
<211>910
<212>PRT
<213>智人
<400>2
Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu
1 5 10 15
Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met
20 25 30
Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro
35 40 45
Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala
50 55 60
Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu
65 70 75 80
Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys
85 90 95
Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr
100 105 110
Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro
115 120 125
Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu
130 135 140
Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys
145 150 155 160
Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr
165 170 175
Trp Tyr Met Gly Cys Tyr Lys Ile Gln Ash Phe Asn Asn Val Ile Pro
180 185 190
Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Ash Asn Gly
195 200 205
Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His
210 215 220
Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala
225 230 235 240
Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys
245 250 255
Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe
260 265 270
Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys
275 280 285
Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His
290 295 300
Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys
305 310 315 320
Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser
325 330 335
Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro
340 345 350
Ala Pro Arg Tyr Thr Val Ser Gly Gly Ala Pro Met Leu Ser Glu Ala
355 360 365
Asp Lys Cys Lys Glu Arg Glu Glu Lys Ile Ile Leu Val Ser Ser Ala
370 375 380
Asn Glu Ile Asp Val Arg Pro Cys Pro Leu Asn Pro Asn Glu His Lys
385 390 395 400
Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser Lys Thr Pro Val Ser Thr
405 410 415
Glu Gln Ala Ser Arg Ile His Gln His Lys Glu Lys Leu Trp Phe Val
420 425 430
Pro Ala Lys Val Glu Asp Ser Gly His Tyr Tyr Cys Val Val Arg Asn
435 440 445
Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser Ala Lys Phe Val Glu Asn
450 455 460
Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala Ile Phe Lys Gln Lys Leu
465 470 475 480
Pro Val Ala Gly Asp Gly Gly Leu Val Cys Pro Tyr Met Glu Phe Phe
485 490 495
Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu Gln Trp Tyr Lys Asp Cys
500 505 510
Lys Pro Leu Leu Leu Asp Asn Ile His Phe Ser Gly Val Lys Asp Arg
515 520 525
Leu Ile Val Met Asn Val Ala Glu Lys His Arg Gly Asn Tyr Thr Cys
530 535 540
His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln Tyr Pro Ile Thr Arg Val
545 550 555 560
Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys Pro Thr Arg Pro Val Ile
565 570 575
Val Ser Pro Ala Asn Glu Thr Met Glu Val Asp Leu Gly Ser Gln Ile
580 585 590
Gln Leu Ile Cys Asn Val Thr Gly Gln Leu Ser Asp Ile Ala Tyr Trp
595 600 605
Lys Trp Asn Gly Ser Val Ile Asp Glu Asp Asp Pro Val Leu Gly Glu
610 615 620
Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn Lys Arg Arg Ser Thr Leu
625 630 635 640
Ile Thr Val Leu Asn Ile Ser Glu Ile Glu Ser Arg Phe Tyr Lys His
645 650 655
Pro Phe Thr Cys Phe Ala Lys Asn Thr His Gly Ile Asp Ala Ala Tyr
660 665 670
Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser Gly Asp Lys Thr His Thr
675 680 685
Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe
690 695 700
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
705 710 715 720
Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
725 730 735
Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
740 745 750
Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
755 760 765
Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
770 775 780
Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
785 790 795 800
Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
805 810 815
Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val
820 825 830
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
835 840 845
Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp
850 855 860
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
865 870 875 880
Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
885 890 895
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
900 905 910
<210>3
<211>2703
<212>DNA
<213>智人
<400>3
atggtgttac tcagacttat ttgtttcata gctctactga tttcttctct ggaggctgat 60
aaatgcaagg aacgtgaaga aaaaataatt ttagtgtcat ctgcaaatga aattgatgtt 120
cgtccctgtc ctcttaaccc aaatgaacac aaaggcacta taacttggta taaggatgac 180
agcaagacac ctgtatctac agaacaagcc tccaggattc atcaacacaa agagaaactt 240
tggtttgttc ctgctaaggt ggaggattca ggacattact attgcgtggt aagaaattca 300
tcttactgcc tcagaattaa aataagtgca aaatttgtgg agaatgagcc taacttatgt 360
tataatgcac aagccatatt taagcagaaa ctacccgttg caggagacgg aggacttgtg 420
tgcccttata tggagttttt taaaaatgaa aataatgagt tacctaaatt acagtggtat 480
aaggattgca aacctctact tcttgacaat atacacttta gtggagtcaa agataggctc 540
atcgtgatga atgtggctga aaagcataga gggaactata cttgtcatgc atcctacaca 600
tacttgggca agcaatatcc tattacccgg gtaatagaat ttattactct agaggaaaac 660
aaacccacaa ggcctgtgat tgtgagccca gctaatgaga caatggaagt agacttggga 720
tcccagatac aattgatctg taatgtcacc ggccagttga gtgacattgc ttactggaag 780
tggaatgggt cagtaattga tgaagatgac ccagtgctag gggaagacta ttacagtgtg 840
gaaaatcctg caaacaaaag aaggagtacc ctcatcacag tgcttaatat atcggaaatt 900
gagagtagat tttataaaca tccatttacc tgttttgcca agaatacaca tggtatagat 960
gcagcatata tccagttaat atatccagtc actaattcag aacgctgcga tgactgggga 1020
ctagacacca tgaggcaaat ccaagtgttt gaagatgagc cagctcgcat caagtgccca 1080
ctctttgaac acttcttgaa attcaactac agcacagccc attcagctgg ccttactctg 1140
atctggtatt ggactaggca ggaccgggac cttgaggagc caattaactt ccgcctcccc 1200
gagaaccgca ttagtaagga gaaagatgtg ctgtggttcc ggcccactct cctcaatgac 1260
actggcaact atacctgcat gttaaggaac actacatatt gcagcaaagt tgcatttccc 1320
ttggaagttg ttcaaaaaga cagctgtttc aattccccca tgaaactccc agtgcataaa 1380
ctgtatatag aatatggcat tcagaggatc acttgtccaa atgtagatgg atattttcct 1440
tccagtgtca aaccgactat cacttggtat atgggctgtt ataaaataca gaattttaat 1500
aatgtaatac ccgaaggtat gaacttgagt ttcctcattg ccttaatttc aaataatgga 1560
aattacacat gtgttgttac atatccagaa aatggacgta cgtttcatct caccaggact 1620
ctgactgtaa aggtagtagg ctctccaaaa aatgcagtgc cccctgtgat ccattcacct 1680
aatgatcatg tggtctatga gaaagaacca ggagaggagc tactcattcc ctgtacggtc 1740
tattttagtt ttctgatgga ttctcgcaat gaggtttggt ggaccattga tggaaaaaaa 1800
cctgatgaca tcactattga tgtcaccatt aacgaaagta taagtcatag tagaacagaa 1860
gatgaaacaa gaactcagat tttgagcatc aagaaagtta cctctgagga tctcaagcgc 1920
agctatgtct gtcatgctag aagtgccaaa ggcgaagttg ccaaagcagc caaggtgaag 1980
cagaaagtgc cagctccaag atacacagtg gaatccggag acaaaactca cacatgccca 2040
ccgtgcccag cacctgaact cctgggggga ccgtcagtct tcctcttccc cccaaaaccc 2100
aaggacaccc tcatgatctc ccggacccct gaggtcacat gcgtggtggt ggacgtgagc 2160
cacgaagacc ctgaggtcaa gttcaactgg tacgtggacg gcgtggaggt gcataatgcc 2220
aagacaaagc cgcgggagga gcagtacaac agcacgtacc gtgtggtcag cgtcctcacc 2280
gtcctgcacc aggactggct gaatggcaag gagtacaagt gcaaggtctc caacaaagcc 2340
ctcccagccc ccatcgagaa aaccatctcc aaagccaaag ggcagccccg agaaccacag 2400
gtgtacaccc tgcccccatc ccgggaggag atgaccaaga accaggtcag cctgacctgc 2460
ctggtcaaag gcttctatcc cagcgacatc gccgtggagt gggagagcaa tgggcagccg 2520
gagaacaact acaagaccac gcctcccgtg ctggactccg acggctcctt cttcctctat 2580
agcaagctca ccgtggacaa gagcaggtgg cagcagggga acgtcttctc atgctccgtg 2640
atgcatgagg ctctgcacaa ccactacacg cagaagagcc tctccctgtc tccgggtaaa 2700
tga 2703
<210>4
<211>900
<212>PRT
<213>智人
<400>4
Met Val Leu Leu Arg Leu Ile Cys Phe Ile Ala Leu Leu Ile Ser Ser
1 5 10 15
Leu Glu Ala Asp Lys Cys Lys Glu Arg Glu Glu Lys Ile Ile Leu Val
20 25 30
Ser Ser Ala Asn Glu Ile Asp Val Arg Pro Cys Pro Leu Asn Pro Asn
35 40 45
Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser Lys Thr Pro
50 55 60
Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys Glu Lys Leu
65 70 75 80
Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr Tyr Cys Val
85 90 95
Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser Ala Lys Phe
100 105 110
Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala Ile Phe Lys
115 120 125
Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys Pro Tyr Met
130 135 140
Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu Gln Trp Tyr
145 150 155 160
Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe Ser Gly Val
165 170 175
Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His Arg Gly Asn
180 185 190
Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln Tyr Pro Ile
195 200 205
Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys Pro Thr Arg
210 215 220
Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val Asp Leu Gly
225 230 235 240
Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu Ser Asp Ile
245 250 255
Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp Asp Pro Val
260 265 270
Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn Lys Arg Arg
275 280 285
Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu Ser Arg Phe
290 295 300
Tyr Lys His Pro Phe Thr Cys Phe Ala Lys Asn Thr His Gly Ile Asp
305 310 315 320
Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser Glu Arg Cys
325 330 335
Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp
340 345 350
Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe
355 360 365
Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp
370 375 380
Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro
385 390 395 400
Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr
405 410 415
Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr
420 425 430
Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val Gln Lys Asp Ser
435 440 445
Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu
450 455 460
Tyr Gly Ile Gln Arg Ile Thr Cys Pr0 Asn Val Asp Gly Tyr Phe Pro
465 470 475 480
Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile
485 490 495
Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu
500 505 510
Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr
515 520 525
Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys
530 535 540
Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro
545 550 555 560
Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile
565 570 575
Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val
580 585 590
Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val
595 600 605
Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg
610 615 620
Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg
625 630 635 640
Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala
645 650 655
Ala Lys Val Lys Gln Lys Val Pro Ala Pro Arg Tyr Thr Val Glu Ser
660 665 670
Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
675 680 685
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
690 695 700
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
705 710 715 720
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
725 730 735
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
740 745 750
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
755 760 765
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
770 775 780
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
785 790 795 800
Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val
805 810 815
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
820 825 830
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
835 840 845
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
850 855 860
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
865 870 875 880
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
885 890 895
Ser Pro Gly Lys
900
<210>5
<211>2709
<212>DNA
<213>智人
<400>5
atggtgttac tcagacttat ttgtttcata gctctactga tttcttctct ggaggctgat 60
aaatgcaagg aacgtgaaga aaaaataatt ttagtgtcat ctgcaaatga aattgatgtt 120
cgtccctgtc ctcttaaccc aaatgaacac aaaggcacta taacttggta taaggatgac 180
agcaagacac ctgtatctac agaacaagcc tccaggattc atcaacacaa agagaaactt 240
tggtttgttc ctgctaaggt ggaggattca ggacattact attgcgtggt aagaaattca 300
tcttactgcc tcagaattaa aataagtgca aaatttgtgg agaatgagcc taacttatgt 360
tataatgcac aagccatatt taagcagaaa ctacccgttg caggagacgg aggacttgtg 420
tgcccttata tggagttttt taaaaatgaa aataatgagt tacctaaatt acagtggtat 480
aaggattgca aacctctact tcttgacaat atacacttta gtggagtcaa agataggctc 540
atcgtgatga atgtggctga aaagcataga gggaactata cttgtcatgc atcctacaca 600
tacttgggca agcaatatcc tattacccgg gtaatagaat ttattactct agaggaaaac 660
aaacccacaa ggcctgtgat tgtgagccca gctaatgaga caatggaagt agacttggga 720
tcccagatac aattgatctg taatgtcacc ggccagttga gtgacattgc ttactggaag 780
tggaatgggt cagtaattga tgaagatgac ccagtgctag gggaagacta ttacagtgtg 840
gaaaatcctg caaacaaaag aaggagtacc ctcatcacag tgcttaatat atcggaaatt 900
gagagtagat tttataaaca tccatttacc tgttttgcca agaatacaca tggtatagat 960
gcagcatata tccagttaat atatccagtc actaattcag aacgctgcga tgactgggga 1020
ctagacacca tgaggcaaat ccaagtgttt gaagatgagc cagctcgcat caagtgccca 1080
ctctttgaac acttcttgaa attcaactac agcacagccc attcagctgg ccttactctg 1140
atctggtatt ggactaggca ggaccgggac cttgaggagc caattaactt ccgcctcccc 1200
gagaaccgca ttagtaagga gaaagatgtg ctgtggttcc ggcccactct cctcaatgac 1260
actggcaact atacctgcat gttaaggaac actacatatt gcagcaaagt tgcatttccc 1320
ttggaagttg ttcaaaaaga cagctgtttc aattccccca tgaaactccc agtgcataaa 1380
ctgtatatag aatatggcat tcagaggatc acttgtccaa atgtagatgg atattttcct 1440
tccagtgtca aaccgactat cacttggtat atgggctgtt ataaaataca gaattttaat 1500
aatgtaatac ccgaaggtat gaacttgagt ttcctcattg ccttaatttc aaataatgga 1560
aattacacat gtgttgttac atatccagaa aatggacgta cgtttcatct caccaggact 1620
ctgactgtaa aggtagtagg ctctccaaaa aatgcagtgc cccctgtgat ccattcacct 1680
aatgatcatg tggtctatga gaaagaacca ggagaggagc tactcattcc ctgtacggtc 1740
tattttagtt ttctgatgga ttctcgcaat gaggtttggt ggaccattga tggaaaaaaa 1800
cctgatgaca tcactattga tgtcaccatt aacgaaagta taagtcatag tagaacagaa 1860
gatgaaacaa gaactcagat tttgagcatc aagaaagtta cctctgagga tctcaagcgc 1920
agctatgtct gtcatgctag aagtgccaaa ggcgaagttg ccaaagcagc caaggtgaag 1980
cagaaagtgc cagctccaag atacacagtg gaatccggag agtccaaata cggtccgcca 2040
tgcccatcat gcccagcacc tgagttcctg gggggaccat cagtcttcct gttcccccca 2100
aaacccaagg acactctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac 2160
gtgagccagg aagaccccga ggtccagttc aactggtacg tggatggcgt ggaggtgcat 2220
aatgccaaga caaagccgcg ggaggagcag ttcaacagca cgtaccgtgt ggtcagcgtc 2280
ctcaccgtcc tgcaccagga ctggctgaac ggcaaggagt acaagtgcaa ggtctccaac 2340
aaaggcctcc cgtcctccat cgagaaaacc atctccaaag ccaaagggca gccccgagag 2400
ccacaggtgt acaccctgcc cccatcccag gaggagatga ccaagaacca ggtcagcctg 2460
acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga gagcaatggg 2520
cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 2580
ctctacagca ggctaaccgt ggacaagagc aggtggcagg aggggaatgt cttctcatgc 2640
tccgtgatgc atgaggctct gcacaaccac tacacacaga agagcctctc cctgtctctg 2700
ggtaaatga 2709
<210>6
<211>902
<21 2>PRI
<213>智人
<400>6
Met Val Leu Leu Arg Leu Ile Cys Phe Ile Ala Leu Leu Ile Ser Ser
1 5 10 15
Leu Glu Ala Asp Lys Cys Lys Glu Arg Glu Glu Lys Ile Ile Leu Val
20 25 30
Ser Ser Ala Asn Glu Ile Asp Val Arg Pro Cys Pro Leu Asn Pro Asn
35 40 45
Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser Lys Thr Pro
50 55 60
Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys Glu Lys Leu
65 70 75 80
Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr Tyr Cys Val
85 90 95
Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser Ala Lys Phe
100 105 110
Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala Ile Phe Lys
115 120 125
Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys Pro Tyr Met
130 135 140
Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu Gln Trp Tyr
145 150 155 160
Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe Ser Gly Val
165 170 175
Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His Arg Gly Asn
180 185 190
Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln Tyr Pro Ile
195 200 205
Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys Pro Thr Arg
210 215 220
Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val Asp Leu Gly
225 230 235 240
Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu Ser Asp Ile
245 250 255
Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp Asp Pro Val
260 265 270
Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn Lys Arg Arg
275 280 285
Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu Ser Arg Phe
290 295 300
Tyr Lys His Pro Phe Thr Cys Phe Ala Lys Asn Thr His Gly Ile Asp
305 310 315 320
Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser Glu Arg Cys
325 330 335
Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp
340 345 350
Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe
355 360 365
Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp
370 375 380
Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro
385 390 395 400
Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr
405 410 415
Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr
420 425 430
Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val Gln Lys Asp Ser
435 440 445
Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu
450 455 460
Tyr Gly Ile Gln Arg Ile Thr Cys Pro Asn Val Asp Gly Tyr Phe Pro
465 470 475 480
Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile
485 490 495
Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu
500 505 510
Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr
515 520 525
Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys
530 535 540
Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro
545 550 555 560
Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile
565 570 575
Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val
580 585 590
Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val
595 600 605
Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg
610 615 620
Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg
625 630 635 640
Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala
645 650 655
Ala Lys Val Lys Gln Lys Val Pro Ala Pro Arg Tyr Thr Val Glu Ser
660 665 670
Gly Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu
675 680 685
Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
690 695 700
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
705 710 715 720
Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
725 730 735
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
740 745 750
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
755 760 765
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
770 775 780
Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
785 790 795 800
Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn
805 810 815
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
820 825 830
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
835 840 845
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg
850 855 860
Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys
865 870 875 880
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
885 890 895
Ser Leu Ser Leu Gly Lys
900
<210>7
<211>2709
<212>DNA
<213>智人
<400>7
atggtgttac tcagacttat ttgtttcata gctctactga tttcttctct ggaggctgat 60
aaatgcaagg aacgtgaaga aaaaataatt ttagtgtcat ctgcaaatga aattgatgtt 120
cgtccctgtc ctcttaaccc aaatgaacac aaaggcacta taacttggta taaggatgac 180
agcaagacac ctgtatctac agaacaagcc tccaggattc atcaacacaa agagaaactt 240
tggtttgttc ctgctaaggt ggaggattca ggacattact attgcgtggt aagaaattca 300
tcttactgcc tcagaattaa aataagtgca aaatttgtgg agaatgagcc taacttatgt 360
tataatgcac aagccatatt taagcagaaa ctacccgttg caggagacgg aggacttgtg 420
tgcccttata tggagttttt taaaaatgaa aataatgagt tacctaaatt acagtggtat 480
aaggattgca aacctctact tcttgacaat atacacttta gtggagtcaa agataggctc 540
atcgtgatga atgtggctga aaagcataga gggaactata cttgtcatgc atcctacaca 600
tacttgggca agcaatatcc tattacccgg gtaatagaat ttattactct agaggaaaac 660
aaacccacaa ggcctgtgat tgtgagccca gctaatgaga caatggaagt agacttggga 720
tcccagatac aattgatctg taatgtcacc ggccagttga gtgacattgc ttactggaag 780
tggaatgggt cagtaattga tgaagatgac ccagtgctag gggaagacta ttacagtgtg 840
gaaaatcctg caaacaaaag aaggagtacc ctcatcacag tgcttaatat atcggaaatt 900
gagagtagat tttataaaca tccatttacc tgttttgcca agaatacaca tggtatagat 960
gcagcatata tccagttaat atatccagtc actaattcag aacgctgcga tgactgggga 1020
ctagacacca tgaggcaaat ccaagtgttt gaagatgagc cagctcgcat caagtgccca 1080
ctctttgaac acttcttgaa attcaactac agcacagccc attcagctgg ccttactctg 1140
atctggtatt ggactaggca ggaccgggac cttgaggagc caattaactt ccgcctcccc 1200
gagaaccgca ttagtaagga gaaagatgtg ctgtggttcc ggcccactct cctcaatgac 1260
actggcaact atacctgcat gttaaggaac actacatatt gcagcaaagt tgcatttccc 1320
ttggaagttg ttcaaaaaga cagctgtttc aattccccca tgaaactccc agtgcataaa 1380
ctgtatatag aatatggcat tcagaggatc acttgtccaa atgtagatgg atattttcct 1440
tccagtgtca aaccgactat cacttggtat atgggctgtt ataaaataca gaattttaat 1500
aatgtaatac ccgaaggtat gaacttgagt ttcctcattg ccttaatttc aaataatgga 1560
aattacacat gtgttgttac atatccagaa aatggacgta cgtttcatct caccaggact 1620
ctgactgtaa aggtagtagg ctctccaaaa aatgcagtgc cccctgtgat ccattcacct 1680
aatgatcatg tggtctatga gaaagaacca ggagaggagc tactcattcc ctgtacggtc 1740
tattttagtt ttctgatgga ttctcgcaat gaggtttggt ggaccattga tggaaaaaaa 1800
cctgatgaca tcactattga tgtcaccatt aacgaaagta taagtcatag tagaacagaa 1860
gatgaaacaa gaactcagat tttgagcatc aagaaagtta cctctgagga tctcaagcgc 1920
agctatgtct gtcatgctag aagtgccaaa ggcgaagttg ccaaagcagc caaggtgaag 1980
cagaaagtgc cagctccaag atacacagtg gaatccggag agtccaaata cggtccgcca 2040
tgcccaccat gcccagcacc tgagttcctg gggggaccat cagtcttcct gttcccccca 2100
aaacccaagg acactctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac 2160
gtgagccagg aagaccccga ggtccagttc aactggtacg tggatggcgt ggaggtgcat 2220
aatgccaaga caaagccgcg ggaggagcag ttcaacagca cgtaccgtgt ggtcagcgtc 2280
ctcaccgtcc tgcaccagga ctggctgaac ggcaaggagt acaagtgcaa ggtctccaac 2340
aaaggcctcc cgtcctccat cgagaaaacc atctccaaag ccaaagggca gccccgagag 2400
ccacaggtgt acaccctgcc cccatcccag gaggagatga ccaagaacca ggtcagcctg 2460
acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga gagcaatggg 2520
cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 2580
ctctacagca ggctaaccgt ggacaagagc aggtggcagg aggggaatgt cttctcatgc 2640
tccgtgatgc atgaggctct gcacaaccac tacacacaga agagcctctc cctgtctctg 2700
ggtaaatga 2709
<210>8
<211>902
<212>PRT
<213>智人
<400>8
Met Val Leu Leu Arg Leu Ile Cys Phe Ile Ala Leu Leu Ile Ser Ser
1 5 10 15
Leu Glu Ala Asp Lys Cys Lys Glu Arg Glu Glu Lys Ile Ile Leu Val
20 25 30
Ser Ser Ala Asn Glu Ile Asp Val Arg Pro Cys Pro Leu Asn Pro Asn
35 40 45
Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser Lys Thr Pro
50 55 60
Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys Glu Lys Leu
65 70 75 80
Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr Tyr Cys Val
85 90 95
Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser Ala Lys Phe
100 105 110
Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala Ile Phe Lys
115 120 125
Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys Pro Tyr Met
130 135 140
Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu Gln Trp Tyr
145 150 155 160
Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe Ser Gly Val
165 170 175
Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His Arg Gly Asn
180 185 190
Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln Tyr Pro Ile
195 200 205
Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys Pro Thr Arg
210 215 220
Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val Asp Leu Gly
225 230 235 240
Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu Ser Asp Ile
245 250 255
Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp Asp Pro Val
260 265 270
Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn Lys Arg Arg
275 280 285
Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu Ser Arg Phe
290 295 300
Tyr Lys His Pro Phe Thr Cys Phe Ala Lys Asn Thr His Gly Ile Asp
305 310 315 320
Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser Glu Arg Cys
325 330 335
Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp
340 345 350
Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe
355 360 365
Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp
370 375 380
Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro
385 390 395 400
Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr
405 410 415
Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr
420 425 430
Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val Gln Lys Asp Ser
435 440 445
Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu
450 455 460
Tyr Gly Ile Gln Arg Ile Thr Cys Pro Asn Val Asp Gly Tyr Phe Pro
465 470 475 480
Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile
485 490 495
Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu
500 505 510
Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr
515 520 525
Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys
530 535 540
Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro
545 550 555 560
Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile
565 570 575
Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val
580 585 590
Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val
595 600 605
Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg
6l0 615 620
Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg
625 630 635 640
Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala
645 650 655
Ala Lys Val Lys Gln Lys Val Pro Ala Pro Arg Tyr Thr Val Glu Ser
660 665 670
Gly Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu
675 680 685
Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
690 695 700
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
705 710 715 720
Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
725 730 735
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
740 745 750
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
755 760 765
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
770 775 780
Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
785 790 795 800
Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn
805 810 815
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
820 825 830
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
835 840 845
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg
850 855 860
Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys
865 870 875 880
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
885 890 895
Ser Leu Ser Leu Gly Lys
900
<210>9
<211>2703
<212>DNA
<213>智人
<400>9
atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc 60
tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat 120
gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca 180
gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag 240
gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg 300
ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca 360
tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc 420
cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt 480
ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc 540
tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc 600
attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga 660
cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca 720
gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag 780
gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt 840
tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa 900
agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa 960
gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa 1020
gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtggaaaaa 1080
tgcaaggaac gtgaagaaaa aataatttta gtgagctcag caaatgaaat cgatgttcgt 1140
ccctgtcctc ttaacccaaa tgaacacaaa ggcactataa cttggtataa ggatgacagc 1200
aagacacctg tatctacaga acaagcctcc aggattcatc aacacaaaga gaaactttgg 1260
tttgttcctg ctaaggtgga ggattcagga cattactatt gcgtggtaag aaattcatct 1320
tactgcctca gaattaaaat aagtgcaaaa tttgtggaga atgagcctaa cttatgttat 1380
aatgcacaag ccatatttaa gcagaaacta cccgttgcag gagacggagg acttgtgtgc 1440
ccttatatgg agttttttaa aaatgaaaat aatgagttac ctaaattaca gtggtataag 1500
gattgcaaac ctctacttct tgacaatata cactttagtg gagtcaaaga taggctcatc 1560
gtgatgaatg tggctgaaaa gcatagaggg aactatactt gtcatgcatc ctacacatac 1620
ttgggcaagc aatatcctat tacccgggta atagaattta ttactctaga ggaaaacaaa 1680
cccacaaggc ctgtgattgt gagcccagct aatgagacaa tggaagtaga cttgggatcc 1740
cagatacaat tgatctgtaa tgtcaccggc cagttgagtg acattgctta ctggaagtgg 1800
aatgggtcag taattgatga agatgaccca gtgctagggg aagactatta cagtgtggaa 1860
aatcctgcaa acaaaagaag gagtaccctc atcacagtgc ttaatatatc ggaaattgag 1920
agtagatttt ataaacatcc atttacctgt tttgccaaga atacacatgg tatagatgca 1980
gcatatatcc agttaatata tccagtcact aattccggag acaaaactca cacatgccca 2040
ccgtgcccag cacctgaact cctgggggga ccgtcagtct tcctcttccc cccaaaaccc 2100
aaggacaccc tcatgatctc ccggacccct gaggtcacat gcgtggtggt ggacgtgagc 2160
cacgaagacc ctgaggtcaa gttcaactgg tacgtggacg gcgtggaggt gcataatgcc 2220
aagacaaagc cgcgggagga gcagtacaac agcacgtacc gtgtggtcag cgtcctcacc 2280
gtcctgcacc aggactggct gaatggcaag gagtacaagt gcaaggtctc caacaaagcc 2340
ctcccagccc ccatcgagaa aaccatctcc aaagccaaag ggcagccccg agaaccacag 2400
gtgtacaccc tgcccccatc ccgggatgag ctgaccaaga accaggtcag cctgacctgc 2460
ctggtcaaag gcttctatcc cagcgacatc gccgtggagt gggagagcaa tgggcagccg 2520
gagaacaact acaagaccac gcctcccgtg ctggactccg acggctcctt cttcctctac 2580
agcaagctca ccgtggacaa gagcaggtgg cagcagggga acgtcttctc atgctccgtg 2640
atgcatgagg ctctgcacaa ccactacacg cagaagagcc tctccctgtc tccgggtaaa 2700
tga 2703
<210>10
<211>900
<212>PRT
<213>智人
<400>10
Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu
1 5 10 15
Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met
20 25 30
Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro
35 40 45
Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala
50 55 60
Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu
65 70 75 80
Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys
85 90 95
Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr
100 105 110
Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro
115 120 125
Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu
130 135 140
Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys
145 150 155 160
Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr
165 170 175
Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro
180 185 190
Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly
195 200 205
Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His
210 215 220
Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala
225 230 235 240
Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys
245 250 255
Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe
260 265 270
Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys
275 280 285
Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His
290 295 300
Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys
305 310 315 320
Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser
325 330 335
Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro
340 345 350
Ala Pro Arg Tyr Thr Val Glu Lys Cys Lys Glu Arg Glu Glu Lys Ile
355 360 365
Ile Leu Val Ser Ser Ala Asn Glu Ile Asp Val Arg Pro Cys Pro Leu
370 375 380
Asn Pro Asn Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser
385 390 395 400
Lys Thr Pro Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys
405 410 415
Glu Lys Leu Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr
420 425 430
Tyr Cys Val Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser
435 440 445
Ala Lys Phe Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala
450 455 460
Ile Phe Lys Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys
465 470 475 480
Pro Tyr Met Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu
485 490 495
Gln Trp Tyr Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe
500 505 510
Ser Gly Val Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His
515 520 525
Arg Gly Asn Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln
530 535 540
Tyr Pro Ile Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys
545 550 555 560
Pro Thr Arg Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val
565 570 575
Asp Leu Gly Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu
580 585 590
Ser Asp Ile Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp
595 600 605
Asp Pro Val Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn
610 615 620
Lys Arg Arg Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu
625 630 635 640
Ser Arg Phe Tyr Lys His Pro Phe Thr Cys Phe Ala Lys Asn Thr His
645 650 655
Gly Ile Asp Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser
660 665 670
Gly Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
675 680 685
Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu
690 695 700
Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser
705 710 715 720
His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu
725 730 735
Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
740 745 750
Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
755 760 765
Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro
770 775 780
Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
785 790 795 800
Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val
805 810 815
Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
820 825 830
Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro
835 840 845
Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr
850 855 860
Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
865 870 875 880
Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
885 890 895
Ser Pro Gly Lys
900
<210>11
<211>2709
<212>DNA
<213>智人
<400>11
atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc 60
tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat 120
gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca 180
gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag 240
gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg 300
ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca 360
tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc 420
cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt 480
ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc 540
tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc 600
attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga 660
cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca 720
gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag 780
gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt 840
tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa 900
agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa 960
gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa 1020
gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtggaaaaa 1080
tgcaaggaac gtgaagaaaa aataatttta gtgagctcag caaatgaaat cgatgttcgt 1140
ccctgtcctc ttaacccaaa tgaacacaaa ggcactataa cttggtataa ggatgacagc 1200
aagacacctg tatctacaga acaagcctcc aggattcatc aacacaaaga gaaactttgg 1260
tttgttcctg ctaaggtgga ggattcagga cattactatt gcgtggtaag aaattcatct 1320
tactgcctca gaattaaaat aagtgcaaaa tttgtggaga atgagcctaa cttatgttat 1380
aatgcacaag ccatatttaa gcagaaacta cccgttgcag gagacggagg acttgtgtgc 1440
ccttatatgg agttttttaa aaatgaaaat aatgagttac ctaaattaca gtggtataag 1500
gattgcaaac ctctacttct tgacaatata cactttagtg gagtcaaaga taggctcatc 1560
gtgatgaatg tggctgaaaa gcatagaggg aactatactt gtcatgcatc ctacacatac 1620
ttgggcaagc aatatcctat tacccgggta atagaattta ttactctaga ggaaaacaaa 1680
cccacaaggc ctgtgattgt gagcccagct aatgagacaa tggaagtaga cttgggatcc 1740
cagatacaat tgatctgtaa tgtcaccggc cagttgagtg acattgctta ctggaagtgg 1800
aatgggtcag taattgatga agatgaccca gtgctagggg aagactatta cagtgtggaa 1860
aatcctgcaa acaaaagaag gagtaccctc atcacagtgc ttaatatatc ggaaattgag 1920
agtagatttt ataaacatcc atttacctgt tttgccaaga atacacatgg tatagatgca 1980
gcatatatcc agttaatata tccagtcact aattccggag agtccaaata cggtccgcca 2040
tgcccatcat gcccagcacc tgagttcctg gggggaccat cagtcttcct gttcccccca 2100
aaacccaagg acactctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac 2160
gtgagccagg aagaccccga ggtccagttc aactggtacg tggatggcgt ggaggtgcat 2220
aatgccaaga caaagccgcg ggaggagcag ttcaacagca cgtaccgtgt ggtcagcgtc 2280
ctcaccgtcc tgcaccagga ctggctgaac ggcaaggagt acaagtgcaa ggtctccaac 2340
aaaggcctcc cgtcctccat cgagaaaacc atctccaaag ccaaagggca gccccgagag 2400
ccacaggtgt acaccctgcc cccatcccag gaggagatga ccaagaacca ggtcagcctg 2460
acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga gagcaatggg 2520
cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 2580
ctctacagca ggctaaccgt ggacaagagc aggtggcagg aggggaatgt cttctcatgc 2640
tccgtgatgc atgaggctct gcacaaccac tacacacaga agagcctctc cctgtctctg 2700
ggtaaatga 2709
<210>12
<211>902
<212>PRT
<213>智人
<400>l2
Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu
1 5 10 15
Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met
20 25 30
Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro
35 40 45
Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala
50 55 60
Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu
65 70 75 80
Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys
85 90 95
Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr
100 105 110
Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro
115 120 125
Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu
130 135 140
Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys
145 150 155 160
Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr
165 170 175
Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro
180 185 190
Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly
195 200 205
Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His
210 215 220
Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala
225 230 235 240
Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys
245 250 255
Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe
260 265 270
Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys
275 280 285
Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His
290 295 300
Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys
305 310 315 320
Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser
325 330 335
Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro
340 345 350
Ala Pro Arg Tyr Thr Val Glu Lys Cys Lys Glu Arg Glu Glu Lys Ile
355 360 365
Ile Leu Val Ser Ser Ala Asn Glu Ile Asp Val Arg Pro Cys Pro Leu
370 375 380
Asn Pro Asn Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser
385 390 395 400
Lys Thr Pro Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys
405 410 415
Glu Lys Leu Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr
420 425 430
Tyr Cys Val Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser
435 440 445
Ala Lys Phe Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala
450 455 460
Ile Phe Lys Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys
465 470 475 480
Pro Tyr Met Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu
485 490 495
Gln Trp Tyr Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe
500 505 510
Ser Gly Val Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His
515 520 525
Arg Gly Asn Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln
530 535 540
Tyr Pro Ile Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys
545 550 555 560
Pro Thr Arg Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val
565 570 575
Asp Leu Gly Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu
580 585 590
Ser Asp Ile Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp
595 600 605
Asp Pro Val Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn
610 615 620
Lys Arg Arg Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu
625 630 635 640
Ser Arg Phe Tyr Lys His Pro Phe Thr Cys Phe Ala Lys Asn Thr His
645 650 655
Gly Ile Asp Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser
660 665 670
Gly Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu
675 680 685
Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
690 695 700
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
705 710 715 720
Val Set Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
725 730 735
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
740 745 750
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
755 760 765
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
770 775 780
Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
785 790 795 800
Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn
805 810 815
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
820 825 830
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
835 840 845
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg
850 855 860
Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys
865 870 875 880
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
885 890 895
Ser Leu Ser Leu Gly Lys
900
<210>13
<211>2709
<212>DNA
<213>智人
<400>13
atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc 60
tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat 120
gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca 180
gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag 240
gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg 300
ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca 360
tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc 420
cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt 480
ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc 540
tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc 600
attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga 660
cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca 720
gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag 780
gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt 840
tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa 900
agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa 960
gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa 1020
gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtggaaaaa 1080
tgcaaggaac gtgaagaaaa aataatttta gtgagctcag caaatgaaat cgatgttcgt 1140
ccctgtcctc ttaacccaaa tgaacacaaa ggcactataa cttggtataa ggatgacagc 1200
aagacacctg tatctacaga acaagcctcc aggattcatc aacacaaaga gaaactttgg 1260
tttgttcctg ctaaggtgga ggattcagga cattactatt gcgtggtaag aaattcatct 1320
tactgcctca gaattaaaat aagtgcaaaa tttgtggaga atgagcctaa cttatgttat 1380
aatgcacaag ccatatttaa gcagaaacta cccgttgcag gagacggagg acttgtgtgc 1440
ccttatatgg agttttttaa aaatgaaaat aatgagttac ctaaattaca gtggtataag 1500
gattgcaaac ctctacttct tgacaatata cactttagtg gagtcaaaga taggctcatc 1560
gtgatgaatg tggctgaaaa gcatagaggg aactatactt gtcatgcatc ctacacatac 1620
ttgggcaagc aatatcctat tacccgggta atagaattta ttactctaga ggaaaacaaa 1680
cccacaaggc ctgtgattgt gagcccagct aatgagacaa tggaagtaga cttgggatcc 1740
cagatacaat tgatctgtaa tgtcaccggc cagttgagtg acattgctta ctggaagtgg 1800
aatgggtcag taattgatga agatgaccca gtgctagggg aagactatta cagtgtggaa 1860
aatcctgcaa acaaaagaag gagtaccctc atcacagtgc ttaatatatc ggaaattgag 1920
agtagatttt ataaacatcc atttacctgt tttgccaaga atacacatgg tatagatgca 1980
gcatatatcc agttaatata tccagtcact aattccggag agtccaaata cggtccgcca 2040
tgcccaccat gcccagcacc tgagttcctg gggggaccat cagtcttcct gttcccccca 2100
aaacccaagg acactctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac 2160
gtgagccagg aagaccccga ggtccagttc aactggtacg tggatggcgt ggaggtgcat 2220
aatgccaaga caaagccgcg ggaggagcag ttcaacagca cgtaccgtgt ggtcagcgtc 2280
ctcaccgtcc tgcaccagga ctggctgaac ggcaaggagt acaagtgcaa ggtctccaac 2340
aaaggcctcc cgtcctccat cgagaaaacc atctccaaag ccaaagggca gccccgagag 2400
ccacaggtgt acaccctgcc cccatcccag gaggagatga ccaagaacca ggtcagcctg 2460
acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga gagcaatggg 2520
cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg ctccttcttc 2580
ctctacagca ggctaaccgt ggacaagagc aggtggcagg aggggaatgt cttctcatgc 2640
tccgtgatgc atgaggctct gcacaaccac tacacacaga agagcctctc cctgtctctg 2700
ggtaaatga 2709
<210>14
<211>902
<212>PRT
<213>智人
<400>14
Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu
1 5 10 15
Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met
20 25 30
Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro
35 40 45
Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala
50 55 60
Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu
65 70 75 80
Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys
85 90 95
Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr
100 105 110
Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro
115 120 125
Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu
130 135 140
Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys
145 150 155 160
Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr
165 170 175
Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro
180 185 190
Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly
195 200 205
Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His
210 215 220
Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala
225 230 235 240
Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys
245 250 255
Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe
260 265 270
Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys
275 280 285
Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His
290 295 300
Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys
305 310 315 320
Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser
325 330 335
Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro
340 345 350
Ala Pro Arg Tyr Thr Val Glu Lys Cys Lys Glu Arg Glu Glu Lys Ile
355 360 365
Ile Leu Val Ser Ser Ala Asn Glu Ile Asp Val Arg Pro Cys Pro Leu
370 375 380
Asn Pro Asn Glu His Lys Gly Thr Ile Thr Trp Tyr Lys Asp Asp Ser
385 390 395 400
Lys Thr Pro Val Ser Thr Glu Gln Ala Ser Arg Ile His Gln His Lys
405 410 415
Glu Lys Leu Trp Phe Val Pro Ala Lys Val Glu Asp Ser Gly His Tyr
420 425 430
Tyr Cys Val Val Arg Asn Ser Ser Tyr Cys Leu Arg Ile Lys Ile Ser
435 440 445
Ala Lys Phe Val Glu Asn Glu Pro Asn Leu Cys Tyr Asn Ala Gln Ala
450 455 460
Ile Phe Lys Gln Lys Leu Pro Val Ala Gly Asp Gly Gly Leu Val Cys
465 470 475 480
Pro Tyr Met Glu Phe Phe Lys Asn Glu Asn Asn Glu Leu Pro Lys Leu
485 490 495
Gln Trp Tyr Lys Asp Cys Lys Pro Leu Leu Leu Asp Asn Ile His Phe
500 505 510
Ser Gly Val Lys Asp Arg Leu Ile Val Met Asn Val Ala Glu Lys His
515 520 525
Arg Gly Asn Tyr Thr Cys His Ala Ser Tyr Thr Tyr Leu Gly Lys Gln
530 535 540
Tyr Pro Ile Thr Arg Val Ile Glu Phe Ile Thr Leu Glu Glu Asn Lys
545 550 555 560
Pro Thr Arg Pro Val Ile Val Ser Pro Ala Asn Glu Thr Met Glu Val
565 570 575
Asp Leu Gly Ser Gln Ile Gln Leu Ile Cys Asn Val Thr Gly Gln Leu
580 585 590
Ser Asp Ile Ala Tyr Trp Lys Trp Asn Gly Ser Val Ile Asp Glu Asp
595 600 605
Asp Pro Val Leu Gly Glu Asp Tyr Tyr Ser Val Glu Asn Pro Ala Asn
610 615 620
Lys Arg Arg Ser Thr Leu Ile Thr Val Leu Asn Ile Ser Glu Ile Glu
625 630 635 640
Ser Arg Phe Tyr Lys His Pro Phe Thr Cys Phe Ala Lys Asn Thr His
645 650 655
Gly Ile Asp Ala Ala Tyr Ile Gln Leu Ile Tyr Pro Val Thr Asn Ser
660 665 670
Gly Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu
675 680 685
Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp
690 695 700
Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp
705 710 715 720
Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly
725 730 735
Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
740 745 750
Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
755 760 765
Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
770 775 780
Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu
785 790 795 800
Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn
805 810 815
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile
820 825 830
Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
835 840 845
Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg
850 855 860
Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys
865 870 875 880
Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
885 890 895
Ser Leu Ser Leu Gly Lys
900
<210>15
<211>2748
<212>DNA
<213>智人
<400>15
atggtgcgct tgtacgtgtt ggtaatggga gtttctgcct tcacccttca gcctgcggca 60
cacacagggg ctgccagaag ctgccggttt cgtgggaggc attacaagcg ggagttcagg 120
ctggaagggg agcctgtagc cctgaggtgc ccccaggtgc cctactggtt gtgggcctct 180
gtcagccccc gcatcaacct gacatggcat aaaaatgact ctgctaggac ggtcccagga 240
gaagaagaga cacggatgtg ggcccaggac ggtgctctgt ggcttctgcc agccttgcag 300
gaggactctg gcacctacgt ctgcactact agaaatgctt cttactgtga caaaatgtcc 360
attgagctca gagtttttga gaatacagat gctttcctgc cgttcatctc atacccgcaa 420
attttaacct tgtcaacctc tggggtatta gtatgccctg acctgagtga attcacccgt 480
gacaaaactg acgtgaagat tcaatggtac aaggattctc ttcttttgga taaagacaat 540
gagaaatttc taagtgtgag ggggaccact cacttactcg tacacgatgt ggccctggaa 600
gatgctggct attaccgctg tgtcctgaca tttgcccatg aaggccagca atacaacatc 660
actaggagta ttgagctacg catcaagaaa aaaaaagaag agaccattcc tgtgatcatt 720
tcccccctca agaccatatc agcttctctg gggtcaagac tgacaatccc atgtaaggtg 780
tttctgggaa ccggcacacc cttaaccacc atgctgtggt ggacggccaa tgacacccac 840
atagagagcg cctacccggg aggccgcgtg accgaggggc cacgccagga atattcagaa 900
aataatgaga actacattga agtgccattg atttttgatc ctgtcacaag agaggatttg 960
cacatggatt ttaaatgtgt tgtccataat accctgagtt ttcagacact acgcaccaca 1020
gtcaaggaag cctcctccac gttctcagaa cgctgcgatg actggggact agacaccatg 1080
aggcaaatcc aagtgtttga agatgagcca gctcgcatca agtgcccact ctttgaacac 1140
ttcttgaaat tcaactacag cacagcccat tcagctggcc ttactctgat ctggtattgg 1200
actaggcagg accgggacct tgaggagcca attaacttcc gcctccccga gaaccgcatt 1260
agtaaggaga aagatgtgct gtggttccgg cccactctcc tcaatgacac tggcaactat 1320
acctgcatgt taaggaacac tacatattgc agcaaagttg catttccctt ggaagttgtt 1380
caaaaagaca gctgtttcaa ttcccccatg aaactcccag tgcataaact gtatatagaa 1440
tatggcattc agaggatcac ttgtccaaat gtagatggat attttccttc cagtgtcaaa 1500
ccgactatca cttggtatat gggctgttat aaaatacaga attttaataa tgtaataccc 1560
gaaggtatga acttgagttt cctcattgcc ttaatttcaa ataatggaaa ttacacatgt 1620
gttgttacat atccagaaaa tggacgtacg tttcatctca ccaggactct gactgtaaag 1680
gtagtaggct ctccaaaaaa tgcagtgccc cctgtgatcc attcacctaa tgatcatgtg 1740
gtctatgaga aagaaccagg agaggagcta ctcattccct gtacggtcta ttttagtttt 1800
ctgatggatt ctcgcaatga ggtttggtgg accattgatg gaaaaaaacc tgatgacatc 1860
actattgatg tcaccattaa cgaaagtata agtcatagta gaacagaaga tgaaacaaga 1920
actcagattt tgagcatcaa gaaagttacc tctgaggatc tcaagcgcag ctatgtctgt 1980
catgctagaa gtgccaaagg cgaagttgcc aaagcagcca aggtgaagca gaaagtgcca 2040
gctccaagat acacagtgtc cggagacaaa actcacacat gcccaccgtg cccagcacct 2100
gaactcctgg ggggaccgtc agtcttcctc ttccccccaa aacccaagga caccctcatg 2160
atctcccgga cccctgaggt cacatgcgtg gtggtggacg tgagccacga agaccctgag 2220
gtcaagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagcegcgg 2280
gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac 2340
tggctgaatg gcaaggagta caagtgcaag gtctccaaca aagccctccc agcccccatc 2400
gagaaaacca tctccaaagc caaagggcag ccccgagaac cacaggtgta caccctgccc 2460
ccatcccggg atgagctgac caagaaccag gtcagcctga cctgcctggt caaaggcttc 2520
tatcccagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag 2580
accacgcctc ccgtgctgga ctccgacggc tccttcttcc tctatagcaa gctcaccgtg 2640
gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg 2700
cacaaccact acacgcagaa gagcctctcc ctgtctccgg gtaaatga 2748
<210>16
<211>915
<212>PRT
<213>智人
<400>16
Met Val Arg Leu Tyr Val Leu Val Met Gly Val Ser Ala Phe Thr Leu
1 5 10 15
Gln Pro Ala Ala His Thr Gly Ala Ala Arg Ser Cys Arg Phe Arg Gly
20 25 30
Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val Ala Leu
35 40 45
Arg Cys Pro Gln Val Pro Tyr Trp Leu Trp Ala Ser Val Ser Pro Arg
50 55 60
Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val Pro Gly
65 70 75 80
Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp Leu Leu
85 90 95
Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr Arg Asn
100 105 110
Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe Glu Asn
115 120 125
Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu Thr Leu
130 135 140
Ser Thr Ser Gly Val Leu Val Cys Pro Asp Leu Ser Glu Phe Thr Arg
145 150 155 160
Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu Leu Leu
165 170 175
Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr His Leu
180 185 190
Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg Cys Val
195 200 205
Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg Ser Ile
210 215 220
Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val Ile Ile
225 230 235 240
Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu Thr Ile
245 250 255
Pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr Met Leu
260 265 270
Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro Gly Gly
275 280 285
Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn Glu Asn
290 295 300
Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu Asp Leu
305 310 315 320
His Met Asp Phe Lys Cys Val Val His Asn Thr Leu Ser Phe Gln Thr
325 330 335
Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Glu Arg Cys
340 345 350
Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp
355 360 365
Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe
370 375 380
Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp
385 390 395 400
Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro
405 410 415
Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr
420 425 430
Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr
435 440 445
Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val Gln Lys Asp Ser
450 455 460
Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu
465 470 475 480
Tyr Gly Ile Gln Arg Ile Thr Cys Pro Asn Val Asp Gly Tyr Phe Pro
485 490 495
Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile
500 505 510
Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu
515 520 525
Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr
530 535 540
Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys
545 550 555 560
Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro
565 570 575
Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile
580 585 590
Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val
595 600 605
Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val
610 615 620
Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg
625 630 635 640
Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg
645 650 655
Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala
660 665 670
Ala Lys Val Lys Gln Lys Val Pro Ala Pro Arg Tyr Thr Val Ser Gly
675 680 685
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
690 695 700
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
705 710 715 720
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
725 730 735
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
740 745 750
His Ash Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
755 760 765
Arg VaI Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
770 775 780
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
785 790 795 800
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
805 810 815
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
820 825 830
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
835 840 845
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
850 855 860
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
865 870 875 880
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
885 890 895
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
900 905 910
Pro Gly Lys
915
<210>17
<211>2754
<212>DNA
<213>智人
<400>17
atggtgcgct tgtacgtgtt ggtaatggga gtttctgcct tcacccttca gcctgcggca 60
cacacagggg ctgccagaag ctgccggttt cgtgggaggc attacaagcg ggagttcagg 120
ctggaagggg agcctgtagc cctgaggtgc ccccaggtgc cctactggtt gtgggcctct 180
gtcagccccc gcatcaacct gacatggcat aaaaatgact ctgctaggac ggtcccagga 240
gaagaagaga cacggatgtg ggcccaggac ggtgctctgt ggcttctgcc agccttgcag 300
gaggactctg gcacctacgt ctgcactact agaaatgctt cttactgtga caaaatgtcc 360
attgagctca gagtttttga gaatacagat gctttcctgc cgttcatctc atacccgcaa 420
attttaacct tgtcaacetc tggggtatta gtatgccctg acctgagtga attcaccegt 480
gacaaaactg acgtgaagat tcaatggtac aaggattctc ttcttttgga taaagacaat 540
gagaaatttc taagtgtgag ggggaccact cacttactcg tacacgatgt ggccctggaa 600
gatgctggct attaccgctg tgtcctgaca tttgcccatg aaggccagca atacaacatc 660
actaggagta ttgagctacg catcaagaaa aaaaaagaag agaccattcc tgtgatcatt 720
tcccccctca agaccatatc agcttctctg gggtcaagac tgacaatccc atgtaaggtg 780
tttctgggaa ccggcacacc cttaaccacc atgctgtggt ggacggccaa tgacacccac 840
atagagagcg cctacccggg aggccgcgtg accgaggggc cacgccagga atattcagaa 900
aataatgaga actacattga agtgccattg atttttgatc ctgtcacaag agaggatttg 960
cacatggatt ttaaatgtgt tgtccataat accctgagtt ttcagacact acgcaccaca 1020
gtcaaggaag cctcctccac gttctcagaa cgctgcgatg actggggact agacaccatg 1080
aggcaaatcc aagtgtttga agatgagcca gctcgcatca agtgcccact ctttgaacac 1140
ttcttgaaat tcaactacag cacagcccat tcagctggcc ttactctgat ctggtattgg 1200
actaggcagg accgggacct tgaggagcca attaacttcc gcctccccga gaaccgcatt 1260
agtaaggaga aagatgtgct gtggttccgg cccactctcc tcaatgacac tggcaactat 1320
acctgcatgt taaggaacac tacatattgc agcaaagttg catttccctt ggaagttgtt 1380
caaaaagaca gctgtttcaa ttcccccatg aaactcccag tgcataaact gtatatagaa 1440
tatggcattc agaggatcac ttgtccaaat gtagatggat attttccttc cagtgtcaaa 1500
ccgactatca cttggtatat gggctgttat aaaatacaga attttaataa tgtaataccc 1560
gaaggtatga acttgagttt cctcattgcc ttaatttcaa ataatggaaa ttacacatgt 1620
gttgttacat atccagaaaa tggacgtacg tttcatctca ccaggactct gactgtaaag 1680
gtagtaggct ctccaaaaaa tgcagtgccc cctgtgatcc attcacctaa tgatcatgtg 1740
gtctatgaga aagaaccagg agaggagcta ctcattccct gtacggtcta ttttagtttt 1800
ctgatggatt ctcgcaatga ggtttggtgg accattgatg gaaaaaaacc tgatgacatc 1860
actattgatg tcaccattaa cgaaagtata agtcatagta gaacagaaga tgaaacaaga 1920
actcagattt tgagcatcaa gaaagttacc tctgaggatc tcaagcgcag ctatgtctgt 1980
catgctagaa gtgccaaagg cgaagttgcc aaagcagcca aggtgaagca gaaagtgcca 2040
gctccaagat acacagtgtc cggagagtcc aaatacggtc cgccatgccc atcatgccca 2100
gcacctgagt tcctgggggg accatcagtc ttcctgttcc ccccaaaacc caaggacact 2160
ctcatgatct cccggacccc tgaggtcacg tgcgtggtgg tggacgtgag ccaggaagac 2220
cccgaggtcc agttcaactg gtacgtggat ggcgtggagg tgcataatgc caagacaaag 2280
ccgcgggagg agcagttcaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 2340
caggactggc tgaacggcaa ggagtacaag tgcaaggtct ccaacaaagg cctcccgtcc 2400
tccatcgaga aaaccatctc caaagccaaa gggcagcccc gagagccaca ggtgtacacc 2460
ctgcccccat cccaggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 2520
ggcttctacc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 2580
tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaggcta 2640
accgtggaca agagcaggtg gcaggagggg aatgtcttct catgctccgt gatgcatgag 2700
gctctgcaca accactacac acagaagagc ctctccctgt ctctgggtaa atga 2754
<210>18
<211>917
<212>PRT
<213>智人
<400>18
Met Val Arg Leu Tyr Val Leu Val Met Gly Val Ser Ala Phe Thr Leu
1 5 10 15
Gln Pro Ala Ala His Thr Gly Ala Ala Arg Ser Cys Arg Phe Arg Gly
20 25 30
Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val Ala Leu
35 40 45
Arg Cys Pro Gln Val Pro Tyr Trp Leu Trp Ala Ser Val Ser Pro Arg
50 55 60
Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val Pro Gly
65 70 75 80
Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp Leu Leu
85 90 95
Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr Arg Asn
100 105 110
Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe Glu Asn
115 120 125
Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu Thr Leu
130 135 140
Ser Thr Ser Gly Val Leu Val Cys Pro Asp Leu Ser Glu Phe Thr Arg
145 150 155 160
Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu Leu Leu
165 170 175
Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr His Leu
180 185 190
Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg Cys Val
195 200 205
Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg Ser Ile
210 215 220
Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val Ile Ile
225 230 235 240
Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu Thr Ile
245 250 255
Pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr Met Leu
260 265 270
Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro Gly Gly
275 280 285
Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn Glu Asn
290 295 300
Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu Asp Leu
305 310 315 320
His Met Asp Phe Lys Cys Val Val His Asn Thr Leu Ser Phe Gln Thr
325 330 335
Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Glu Arg Cys
340 345 350
Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp
355 360 365
Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe
370 375 380
Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp
385 390 395 400
Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro
405 410 415
Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr
420 425 430
Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr
435 440 445
Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val Gln Lys Asp Ser
450 455 460
Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu
465 470 475 480
Tyr Gly Ile Gln Arg Ile Thr Cys Pro Asn Val Asp Gly Tyr Phe Pro
485 490 495
Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile
500 505 510
Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu
515 520 525
Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr
530 535 540
Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys
545 550 555 560
Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro
565 570 575
Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile
580 585 590
Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val
595 600 605
Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val
610 615 620
Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg
625 630 635 640
Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg
645 650 655
Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala
660 665 670
Ala Lys Val Lys Gln Lys Val Pro Ala Pro Arg Tyr Thr Val Ser Gly
675 680 685
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu Phe
690 695 700
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
705 710 715 720
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
725 730 735
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
740 745 750
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
755 760 765
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
770 775 780
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
785 790 795 800
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
805 810 815
Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
820 825 830
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
835 840 845
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
850 855 860
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
865 870 875 880
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
885 890 895
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
900 905 910
Leu Ser Leu Gly Lys
915
<210>19
<211>2754
<212>DNA
<213>智人
<400>19
atggtgcgct tgtacgtgtt ggtaatggga gtttctgcct tcacccttca gcctgcggca 60
cacacagggg ctgccagaag ctgccggttt cgtgggaggc attacaagcg ggagttcagg 120
ctggaagggg agcctgtagc cctgaggtgc ccccaggtgc cctactggtt gtgggcctct 180
gtcagccccc gcatcaacct gacatggcat aaaaatgact ctgctaggac ggtcccagga 240
gaagaagaga cacggatgtg ggcccaggac ggtgctctgt ggcttctgcc agccttgcag 300
gaggactctg gcacctacgt ctgcactact agaaatgctt cttactgtga caaaatgtcc 360
attgagctca gagtttttga gaatacagat gctttcctgc cgttcatctc atacccgcaa 420
attttaacct tgtcaacctc tggggtatta gtatgccctg acctgagtga attcacccgt 480
gacaaaactg acgtgaagat tcaatggtac aaggattctc ttcttttgga taaagacaat 540
gagaaatttc taagtgtgag ggggaccact cacttactcg tacacgatgt ggccctggaa 600
atgctggct attaccgctg tgtcctgaca tttgcccatg aaggccagca atacaacatc 660
actaggagta ttgagctacg catcaagaaa aaaaaagaag agaccattcc tgtgatcatt 720
tcccccctca agaccatatc agcttctctg gggtcaagac tgacaatccc atgtaaggtg 780
tttctgggaa ccggcacacc cttaaccacc atgctgtggt ggacggccaa tgacacccac 840
atagagagcg cctacccggg aggccgcgtg accgaggggc cacgccagga atattcagaa 900
aataatgaga actacattga agtgccattg atttttgatc ctgtcacaag agaggatttg 960
cacatggatt ttaaatgtgt tgtccataat accctgagtt ttcagacact acgcaccaca 1020
gtcaaggaag cctcctccac gttctcagaa cgctgcgatg actggggact agacaccatg 1080
aggcaaatcc aagtgtttga agatgagcca gctcgcatca agtgcccact ctttgaacac 1140
ttcttgaaat tcaactacag cacagcccat tcagctggcc ttactctgat ctggtattgg 1200
actaggcagg accgggacct tgaggagcca attaacttcc gcctccccga gaaccgcatt 1260
agtaaggaga aagatgtgct gtggttccgg cccactctcc tcaatgacac tggcaactat 1320
acctgcatgt taaggaacac tacatattgc agcaaagttg catttccctt ggaagttgtt 1380
caaaaagaca gctgtttcaa ttcccccatg aaactcccag tgcataaact gtatatagaa 1440
tatggcattc agaggatcac ttgtccaaat gtagatggat attttccttc cagtgtcaaa 1500
ccgactatca cttggtatat gggctgttat aaaatacaga attttaataa tgtaataccc 1560
gaaggtatga acttgagttt cctcattgcc ttaatttcaa ataatggaaa ttacacatgt 1620
gttgttacat atccagaaaa tggacgtacg tttcatctca ccaggactct gactgtaaag 1680
gtagtaggct ctccaaaaaa tgcagtgccc cctgtgatcc attcacctaa tgatcatgtg 1740
gtctatgaga aagaaccagg agaggagcta ctcattccct gtacggtcta ttttagtttt 1800
ctgatggatt ctcgcaatga ggtttggtgg accattgatg gaaaaaaacc tgatgacatc 1860
actattgatg tcaccattaa cgaaagtata agtcatagta gaacagaaga tgaaacaaga 1920
actcagattt tgagcatcaa gaaagttacc tctgaggatc tcaagcgcag ctatgtctgt 1980
catgctagaa gtgccaaagg cgaagttgcc aaagcagcca aggtgaagca gaaagtgcca 2040
gctccaagat acacagtgtc cggagagtcc aaatacggtc cgccatgccc accatgccca 2100
gcacctgagt tcctgggggg accatcagtc ttcctgttcc ccccaaaacc caaggacact 2160
ctcatgatct cccggacccc tgaggtcacg tgcgtggtgg tggacgtgag ccaggaagac 2220
cccgaggtcc agttcaactg gtacgtggat ggcgtggagg tgcataatgc caagacaaag 2280
ccgcgggagg agcagttcaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 2340
caggactggc tgaacggcaa ggagtacaag tgcaaggtct ccaacaaagg cctcccgtcc 2400
tccatcgaga aaaccatctc caaagccaaa gggcagcccc gagagccaca ggtgtacacc 2460
ctgcccccat cccaggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 2520
ggcttctacc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 2580
tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaggcta 2640
accgtggaca agagcaggtg gcaggagggg aatgtcttct catgctccgt gatgcatgag 2700
gctctgcaca accactacac acagaagagc ctctccctgt ctctgggtaa atga 2754
<210>20
<211>917
<212>PRT
<213>智人
<400>20
Met Val Arg Leu Tyr Val Leu Val Met Gly Val Ser Ala Phc Thr Leu
1 5 10 15
Gln Pro Ala Ala His Thr Gly Ala Ala Arg Ser Cys Arg Phe Arg Gly
20 25 30
Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val Ala Leu
35 40 45
Arg Cys Pro Gln Val Pro Tyr Trp Leu Trp Ala Ser Val Ser Pro Arg
50 55 60
Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val Pro Gly
65 70 75 80
Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp Leu Leu
85 90 95
Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr Arg Asn
100 105 110
Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe Glu Asn
115 120 125
Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu Thr Leu
130 135 140
Ser Thr Ser Gly Val Leu Val Cys Pro Asp Leu Ser Glu Phe Thr Arg
145 150 155 160
Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu Leu Leu
165 170 175
Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr His Leu
180 185 190
Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg Cys Val
195 200 205
Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg Ser Ile
210 215 220
Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val Ile Ile
225 230 235 240
Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu Thr Ile
245 250 255
Pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr Met Leu
260 265 270
Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro Gly Gly
275 280 285
Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn Glu Asn
290 295 300
Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu Asp Leu
305 310 315 320
His Met Asp Phe Lys Cys Val Val His Asn Thr Leu Ser Phe Gln Thr
325 330 335
Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Glu Arg Cys
340 345 350
Asp Asp Trp Gly Leu Asp Thr Met Arg Gln Ile Gln Val Phe Glu Asp
355 360 365
Glu Pro Ala Arg Ile Lys Cys Pro Leu Phe Glu His Phe Leu Lys Phe
370 375 380
Asn Tyr Ser Thr Ala His Ser Ala Gly Leu Thr Leu Ile Trp Tyr Trp
385 390 395 400
Thr Arg Gln Asp Arg Asp Leu Glu Glu Pro Ile Asn Phe Arg Leu Pro
405 410 415
Glu Asn Arg Ile Ser Lys Glu Lys Asp Val Leu Trp Phe Arg Pro Thr
420 425 430
Leu Leu Asn Asp Thr Gly Asn Tyr Thr Cys Met Leu Arg Asn Thr Thr
435 440 445
Tyr Cys Ser Lys Val Ala Phe Pro Leu Glu Val Val Gln Lys Asp Ser
450 455 460
Cys Phe Asn Ser Pro Met Lys Leu Pro Val His Lys Leu Tyr Ile Glu
465 470 475 480
Tyr Gly Ile Gln Arg Ile Thr Cys Pro Asn Val Asp Gly Tyr Phe Pro
485 490 495
Ser Ser Val Lys Pro Thr Ile Thr Trp Tyr Met Gly Cys Tyr Lys Ile
500 505 510
Gln Asn Phe Asn Asn Val Ile Pro Glu Gly Met Asn Leu Ser Phe Leu
515 520 525
Ile Ala Leu Ile Ser Asn Asn Gly Asn Tyr Thr Cys Val Val Thr Tyr
530 535 540
Pro Glu Asn Gly Arg Thr Phe His Leu Thr Arg Thr Leu Thr Val Lys
545 550 555 560
Val Val Gly Ser Pro Lys Asn Ala Val Pro Pro Val Ile His Ser Pro
565 570 575
Asn Asp His Val Val Tyr Glu Lys Glu Pro Gly Glu Glu Leu Leu Ile
580 585 590
Pro Cys Thr Val Tyr Phe Ser Phe Leu Met Asp Ser Arg Asn Glu Val
595 600 605
Trp Trp Thr Ile Asp Gly Lys Lys Pro Asp Asp Ile Thr Ile Asp Val
610 615 620
Thr Ile Asn Glu Ser Ile Ser His Ser Arg Thr Glu Asp Glu Thr Arg
625 630 635 640
Thr Gln Ile Leu Ser Ile Lys Lys Val Thr Ser Glu Asp Leu Lys Arg
645 650 655
Ser Tyr Val Cys His Ala Arg Ser Ala Lys Gly Glu Val Ala Lys Ala
660 665 670
Ala Lys Val Lys Gln Lys Val Pro Ala Pro Arg Tyr Thr Val Ser Gly
675 680 685
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe
690 695 700
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
705 710 715 720
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
725 730 735
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
740 745 750
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
755 760 765
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
770 775 780
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
785 790 795 800
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
805 810 815
Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
820 825 830
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
835 840 845
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
850 855 860
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
865 870 875 880
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
885 890 895
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
900 905 910
Leu Ser Leu Gly Lys
915
<210>21
<211>2748
<212>DNA
<213>智人
<400>21
atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc 60
tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat 120
gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca 180
gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag 240
gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg 300
ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca 360
tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc 420
cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt 480
ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc 540
tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc 600
attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga 660
cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca 720
gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag 780
gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt 840
tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa 900
agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa 960
gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa 1020
gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtgcacaca 1080
ggggctgcca gaagctgccg gtttcgtggg aggcattaca agcgggagtt caggctggaa 1140
ggggagcctg tagccctgag gtgcccccag gtgccctact ggttgtgggc ctctgtcagc 1200
ccccgcatca acctgacatg gcataaaaat gactctgcta ggacggtccc aggagaagaa 1260
gagacacgga tgtgggccca ggacggtgct ctgtggcttc tgccagcctt gcaggaggac 1320
tctggcacct acgtctgcac tactagaaat gcttcttact gtgacaaaat gtccattgag 1380
ctcagagttt ttgagaatac agatgctttc ctgccgttca tctcataccc gcaaatttta 1440
accttgtcaa cctctggggt attagtatgc cctgacctga gtgaattcac ccgtgacaaa 1500
actgacgtga agattcaatg gtacaaggat tctcttcttt tggataaaga caatgagaaa 1560
tttctaagtg tgagggggac cactcactta ctcgtacacg atgtggccct ggaagatgct 1620
ggctattacc gctgtgtcct gacatttgcc catgaaggcc agcaatacaa catcactagg 1680
agtattgagc tacgcatcaa gaaaaaaaaa gaagagacca ttcctgtgat catttccccc 1740
ctcaagacca tatcagcttc tctggggtca agactgacaa tcccatgtaa ggtgtttctg 1800
ggaaccggca cacccttaac caccatgctg tggtggacgg ccaatgacac ccacatagag 1860
agcgcctacc cgggaggccg cgtgaccgag gggccacgcc aggaatattc agaaaataat 1920
gagaactaca ttgaagtgcc attgattttt gatcctgtca caagagagga tttgcacatg 1980
gattttaaat gtgttgtcca taataccctg agttttcaga cactacgcac cacagtcaag 2040
gaagcctcct ccacgttctc cggagacaaa actcacacat gcccaccgtg cccagcacct 2100
gaactcctgg ggggaccgtc agtcttcctc ttccccccaa aacccaagga caccctcatg 2160
atctcccgga cccctgaggt cacatgcgtg gtggtggacg tgagccacga agaccctgag 2220
gtcaagttca actggtacgt ggacggcgtg gaggtgcata atgccaagac aaagccgcgg 2280
gaggagcagt acaacagcac gtaccgtgtg gtcagcgtcc tcaccgtcct gcaccaggac 2340
tggctgaatg gcaaggagta caagtgcaag gtctccaaca aagccctccc agcccccatc 2400
gagaaaacca tctccaaagc caaagggcag ccccgagaac cacaggtgta caccctgccc 2460
ccatcccggg atgagctgac caagaaccag gtcagcctga cctgcctggt caaaggcttc 2520
tatcccagcg acatcgccgt ggagtgggag agcaatgggc agccggagaa caactacaag 2580
accacgcctc ccgtgctgga ctccgacggc tccttcttcc tctatagcaa gctcaccgtg 2640
gacaagagca ggtggcagca ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg 2700
cacaaccact acacgcagaa gagcctctcc ctgtctccgg gtaaatga 2748
<210>22
<211>915
<212>PRT
<213>智人
<400>22
Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu
1 5 10 15
Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met
20 25 30
Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro
35 40 45
Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala
50 55 60
Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu
65 70 75 80
Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys
85 90 95
Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr
100 105 110
Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro
115 120 125
Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu
130 135 140
Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys
145 150 155 160
Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr
165 170 175
Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro
180 185 190
Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly
195 200 205
Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His
210 215 220
Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala
225 230 235 240
Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys
245 250 255
Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe
260 265 270
Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys
275 280 285
Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His
290 295 300
Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys
305 310 315 320
Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser
325 330 335
Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro
340 345 350
Ala Pro Arg Tyr Thr Val His Thr Gly Ala Ala Arg Ser Cys Arg Phe
355 360 365
Arg Gly Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val
370 375 380
Ala Leu Arg Cys Pro Gln Val Pro Tyr Trp Leu Trp Ala Ser Val Ser
385 390 395 400
Pro Arg Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val
405 410 415
Pro Gly Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp
420 425 430
Leu Leu Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr
435 440 445
Arg Asn Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe
450 455 460
Glu Asn Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu
465 470 475 480
Thr Leu Ser Thr Ser Gly Val Leu Val Cys Pro Asp Leu Ser Glu Phe
485 490 495
Thr Arg Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu
500 505 510
Leu Leu Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr
515 520 525
His Leu Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg
530 535 540
Cys Val Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg
545 550 555 560
Ser Ile Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val
565 570 575
Ile Ile Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu
580 585 590
Thr Ile Pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr
595 600 605
Met Leu Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro
610 615 620
Gly Gly Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn
625 630 635 640
Glu Asn Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu
645 650 655
Asp Leu His Met Asp Phe Lys Cys Val Val His Asn Thr Leu Ser Phe
660 665 670
Gln Thr Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Gly
675 680 685
Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly
690 695 700
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
705 710 715 720
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
725 730 735
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
740 745 750
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
755 760 765
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
770 775 780
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
785 790 795 800
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
805 810 815
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
820 825 830
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
835 840 845
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
850 855 860
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
865 870 875 880
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
885 890 895
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
900 905 910
Pro Gly Lys
915
<210>23
<211>2754
<212>DNA
<213>智人
<400>23
atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc 60
tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat 120
gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca 180
gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag 240
gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg 300
ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca 360
tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc 420
cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt 480
ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc 540
tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc 600
attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga 660
cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca 720
gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag 780
gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt 840
tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa 900
agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa 960
gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa 1020
gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtgcacaca 1080
ggggctgcca gaagctgccg gtttcgtggg aggcattaca agcgggagtt caggctggaa 1140
ggggagcctg tagccctgag gtgcccccag gtgccctact ggttgtgggc ctctgtcagc 1200
ccccgcatca acctgacatg gcataaaaat gactctgcta ggacggtccc aggagaagaa 1260
gagacacgga tgtgggccca ggacggtgct ctgtggcttc tgccagcctt gcaggaggac 1320
tctggcacct acgtctgcac tactagaaat gcttcttact gtgacaaaat gtccattgag 1380
ctcagagttt ttgagaatac agatgctttc ctgccgttca tctcataccc gcaaatttta 1440
accttgtcaa cctctggggt attagtatgc cctgacctga gtgaattcac ccgtgacaaa 1500
actgacgtga agattcaatg gtacaaggat tctcttcttt tggataaaga caatgagaaa 1560
tttctaagtg tgagggggac cactcactta ctcgtacacg atgtggccct ggaagatgct 1620
ggctattacc gctgtgtcct gacatttgcc catgaaggcc agcaatacaa catcactagg 1680
agtattgagc tacgcatcaa gaaaaaaaaa gaagagacca ttcctgtgat catttccccc 1740
ctcaagacca tatcagcttc tctggggtca agactgacaa tcccatgtaa ggtgtttctg 1800
ggaaccggca cacccttaac caccatgctg tggtggacgg ccaatgacac ccacatagag 1860
agcgcctacc cgggaggccg cgtgaccgag gggccacgcc aggaatattc agaaaataat 1920
gagaactaca ttgaagtgcc attgattttt gatcctgtca caagagagga tttgcacatg 1980
gattttaaat gtgttgtcca taataccctg agttttcaga cactacgcac cacagtcaag 2040
gaagcctcct ccacgttctc cggagagtcc aaatacggtc cgccatgccc atcatgccca 2100
gcacctgagt tcctgggggg accatcagtc ttcctgttcc ccccaaaacc caaggacact 2160
ctcatgatct cccggacccc tgaggtcacg tgcgtggtgg tggacgtgag ccaggaagac 2220
cccgaggtcc agttcaactg gtacgtggat ggcgtggagg tgcataatgc caagacaaag 2280
ccgcgggagg agcagttcaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 2340
caggactggc tgaacggcaa ggagtacaag tgcaaggtct ccaacaaagg cctcccgtcc 2400
tccatcgaga aaaccatctc caaagccaaa gggcagcccc gagagccaca ggtgtacacc 2460
ctgcccccat cccaggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 2520
ggcttctacc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 2580
tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaggcta 2640
accgtggaca agagcaggtg gcaggagggg aatgtcttct catgctccgt gatgcatgag 2700
gctctgcaca accactacac acagaagagc ctctccctgt ctctgggtaa atga 2754
<210>24
<211>917
<212>PRT
<213>智人
<400>24
Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu
1 5 10 15
Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met
20 25 30
Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro
35 40 45
Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala
50 55 60
Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu
65 70 75 80
Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys
85 90 95
Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr
100 105 110
Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro
115 120 125
Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu
130 135 140
Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys
145 150 155 160
Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr
165 170 175
Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro
180 185 190
Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly
195 200 205
Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His
210 215 220
Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala
225 230 235 240
Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys
245 250 255
Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe
260 265 270
Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys
275 280 285
Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His
290 295 300
Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys
305 310 315 320
Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser
325 330 335
Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro
340 345 350
Ala Pro Arg Tyr Thr Val His Thr Gly Ala Ala Arg Ser Cys Arg Phe
355 360 365
Arg Gly Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val
370 375 380
Ala Leu Arg Cys Pro Gln Val Pro Tyr Trp Leu Trp Ala Ser Val Ser
385 390 395 400
Pro Arg Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val
405 410 415
Pro Gly Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp
420 425 430
Leu Leu Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr
435 440 445
Arg Asn Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe
450 455 460
Glu Asn Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu
465 470 475 480
Thr Leu Ser Thr Ser Gly Val Leu Val Cys Pro Asp Leu Ser Glu Phe
485 490 495
Thr Arg Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu
500 505 510
Leu Leu Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr
515 520 525
His Leu Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg
530 535 540
Cys Val Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg
545 550 555 560
Ser Ile Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val
565 570 575
Ile Ile Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu
580 585 590
Thr Ile Pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr
595 600 605
Met Leu Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro
610 615 620
Gly Gly Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn
625 630 635 640
Glu Asn Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu
645 650 655
Asp Leu His Met Asp Phe Lys Cys Val Val His Asn Thr Leu Ser Phe
660 665 670
Gln Thr Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Gly
675 680 685
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu Phe
690 695 700
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
705 710 715 720
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
725 730 735
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
740 745 750
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
755 760 765
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
770 775 780
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
785 790 795 800
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
805 810 815
Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
820 825 830
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
835 840 845
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
850 855 860
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
865 870 875 880
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
885 890 895
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
900 905 910
Leu Ser Leu Gly Lys
915
<210>25
<211>2754
<212>DNA
<213>智人
<400>25
atggtgcttc tgtggtgtgt agtgagtctc tacttttatg gaatcctgca aagtgatgcc 60
tcagaacgct gcgatgactg gggactagac accatgaggc aaatccaagt gtttgaagat 120
gagccagctc gcatcaagtg cccactcttt gaacacttct tgaaattcaa ctacagcaca 180
gcccattcag ctggccttac tctgatctgg tattggacta ggcaggaccg ggaccttgag 240
gagccaatta acttccgcct ccccgagaac cgcattagta aggagaaaga tgtgctgtgg 300
ttccggccca ctctcctcaa tgacactggc aactatacct gcatgttaag gaacactaca 360
tattgcagca aagttgcatt tcccttggaa gttgttcaaa aagacagctg tttcaattcc 420
cccatgaaac tcccagtgca taaactgtat atagaatatg gcattcagag gatcacttgt 480
ccaaatgtag atggatattt tccttccagt gtcaaaccga ctatcacttg gtatatgggc 540
tgttataaaa tacagaattt taataatgta atacccgaag gtatgaactt gagtttcctc 600
attgccttaa tttcaaataa tggaaattac acatgtgttg ttacatatcc agaaaatgga 660
cgtacgtttc atctcaccag gactctgact gtaaaggtag taggctctcc aaaaaatgca 720
gtgccccctg tgatccattc acctaatgat catgtggtct atgagaaaga accaggagag 780
gagctactca ttccctgtac ggtctatttt agttttctga tggattctcg caatgaggtt 840
tggtggacca ttgatggaaa aaaacctgat gacatcacta ttgatgtcac cattaacgaa 900
agtataagtc atagtagaac agaagatgaa acaagaactc agattttgag catcaagaaa 960
gttacctctg aggatctcaa gcgcagctat gtctgtcatg ctagaagtgc caaaggcgaa 1020
gttgccaaag cagccaaggt gaagcagaaa gtgccagctc caagatacac agtgcacaca 1080
ggggctgcca gaagctgccg gtttcgtggg aggcattaca agcgggagtt caggctggaa 1140
ggggagcctg tagccctgag gtgcccccag gtgccctact ggttgtgggc ctctgtcagc 1200
ccccgcatca acctgacatg gcataaaaat gactctgcta ggacggtccc aggagaagaa 1260
gagacacgga tgtgggccca ggacggtgct ctgtggcttc tgccagcctt gcaggaggac 1320
tctggcacct acgtctgcac tactagaaat gcttcttact gtgacaaaat gtccattgag 1380
ctcagagttt ttgagaatac agatgctttc ctgccgttca tctcataccc gcaaatttta 1440
accttgtcaa cctctggggt attagtatgc cctgacctga gtgaattcac ccgtgacaaa 1500
actgacgtga agattcaatg gtacaaggat tctcttcttt tggataaaga caatgagaaa 1560
tttctaagtg tgagggggac cactcactta ctcgtacacg atgtggccct ggaagatgct 1620
ggctattacc gctgtgtcct gacatttgcc catgaaggcc agcaatacaa catcactagg 1680
agtattgagc tacgcatcaa gaaaaaaaaa gaagagacca ttcctgtgat catttccccc 1740
ctcaagacca tatcagcttc tctggggtca agactgacaa tcccatgtaa ggtgtttctg 1800
ggaaccggca cacccttaac caccatgctg tggtggacgg ccaatgacac ccacatagag 1860
agcgcctacc cgggaggccg cgtgaccgag gggccacgcc aggaatattc agaaaataat 1920
gagaactaca ttgaagtgcc attgattttt gatcctgtca caagagagga tttgcacatg 1980
gattttaaat gtgttgtcca taataccctg agttttcaga cactacgcac cacagtcaag 2040
gaagcctcct ccacgttctc cggagagtcc aaatacggtc cgccatgccc accatgccca 2100
gcacctgagt tcctgggggg accatcagtc ttcctgttcc ccccaaaacc caaggacact 2160
ctcatgatct cccggacccc tgaggtcacg tgcgtggtgg tggacgtgag ccaggaagac 2220
cccgaggtcc agttcaactg gtacgtggat ggcgtggagg tgcataatgc caagacaaag 2280
ccgcgggagg agcagttcaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 2340
caggactggc tgaacggcaa ggagtacaag tgcaaggtct ccaacaaagg cctcccgtcc 2400
tccatcgaga aaaccatctc caaagccaaa gggcagcccc gagagccaca ggtgtacacc 2460
ctgcccccat cccaggagga gatgaccaag aaccaggtca gcctgacctg cctggtcaaa 2520
ggcttctacc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 2580
tacaagacca cgcctcccgt gctggactcc gacggctcct tcttcctcta cagcaggcta 2640
accgtggaca agagcaggtg gcaggagggg aatgtcttct catgctccgt gatgcatgag 2700
gctctgcaca accactacac acagaagagc ctctccctgt ctctgggtaa atga 2754
<210>26
<211>917
<212>PRT
<213>智人
<400>26
Met Val Leu Leu Trp Cys Val Val Ser Leu Tyr Phe Tyr Gly Ile Leu
1 5 10 15
Gln Ser Asp Ala Ser Glu Arg Cys Asp Asp Trp Gly Leu Asp Thr Met
20 25 30
Arg Gln Ile Gln Val Phe Glu Asp Glu Pro Ala Arg Ile Lys Cys Pro
35 40 45
Leu Phe Glu His Phe Leu Lys Phe Asn Tyr Ser Thr Ala His Ser Ala
50 55 60
Gly Leu Thr Leu Ile Trp Tyr Trp Thr Arg Gln Asp Arg Asp Leu Glu
65 70 75 80
Glu Pro Ile Asn Phe Arg Leu Pro Glu Asn Arg Ile Ser Lys Glu Lys
85 90 95
Asp Val Leu Trp Phe Arg Pro Thr Leu Leu Asn Asp Thr Gly Asn Tyr
100 105 110
Thr Cys Met Leu Arg Asn Thr Thr Tyr Cys Ser Lys Val Ala Phe Pro
115 120 125
Leu Glu Val Val Gln Lys Asp Ser Cys Phe Asn Ser Pro Met Lys Leu
130 135 140
Pro Val His Lys Leu Tyr Ile Glu Tyr Gly Ile Gln Arg Ile Thr Cys
145 150 155 160
Pro Asn Val Asp Gly Tyr Phe Pro Ser Ser Val Lys Pro Thr Ile Thr
165 170 175
Trp Tyr Met Gly Cys Tyr Lys Ile Gln Asn Phe Asn Asn Val Ile Pro
180 185 190
Glu Gly Met Asn Leu Ser Phe Leu Ile Ala Leu Ile Ser Asn Asn Gly
195 200 205
Asn Tyr Thr Cys Val Val Thr Tyr Pro Glu Asn Gly Arg Thr Phe His
210 215 220
Leu Thr Arg Thr Leu Thr Val Lys Val Val Gly Ser Pro Lys Asn Ala
225 230 235 240
Val Pro Pro Val Ile His Ser Pro Asn Asp His Val Val Tyr Glu Lys
245 250 255
Glu Pro Gly Glu Glu Leu Leu Ile Pro Cys Thr Val Tyr Phe Ser Phe
260 265 270
Leu Met Asp Ser Arg Asn Glu Val Trp Trp Thr Ile Asp Gly Lys Lys
275 280 285
Pro Asp Asp Ile Thr Ile Asp Val Thr Ile Asn Glu Ser Ile Ser His
290 295 300
Ser Arg Thr Glu Asp Glu Thr Arg Thr Gln Ile Leu Ser Ile Lys Lys
305 310 315 320
Val Thr Ser Glu Asp Leu Lys Arg Ser Tyr Val Cys His Ala Arg Ser
325 330 335
Ala Lys Gly Glu Val Ala Lys Ala Ala Lys Val Lys Gln Lys Val Pro
340 345 350
Ala Pro Arg Tyr Thr Val His Thr Gly Ala Ala Arg Ser Cys Arg Phe
355 360 365
Arg Gly Arg His Tyr Lys Arg Glu Phe Arg Leu Glu Gly Glu Pro Val
370 375 380
Ala Leu Arg Cys Pro Gln Val Pro Tyr Trp Leu Trp Ala Ser Val Ser
385 390 395 400
Pro Arg Ile Asn Leu Thr Trp His Lys Asn Asp Ser Ala Arg Thr Val
405 410 415
Pro Gly Glu Glu Glu Thr Arg Met Trp Ala Gln Asp Gly Ala Leu Trp
420 425 430
Leu Leu Pro Ala Leu Gln Glu Asp Ser Gly Thr Tyr Val Cys Thr Thr
435 440 445
Arg Asn Ala Ser Tyr Cys Asp Lys Met Ser Ile Glu Leu Arg Val Phe
450 455 460
Glu Asn Thr Asp Ala Phe Leu Pro Phe Ile Ser Tyr Pro Gln Ile Leu
465 470 475 480
Thr Leu Ser Thr Ser Gly Val Leu Val Cys Pro Asp Leu Ser Glu Phe
485 490 495
Thr Arg Asp Lys Thr Asp Val Lys Ile Gln Trp Tyr Lys Asp Ser Leu
500 505 510
Leu Leu Asp Lys Asp Asn Glu Lys Phe Leu Ser Val Arg Gly Thr Thr
515 520 525
His Leu Leu Val His Asp Val Ala Leu Glu Asp Ala Gly Tyr Tyr Arg
530 535 540
Cys Val Leu Thr Phe Ala His Glu Gly Gln Gln Tyr Asn Ile Thr Arg
545 550 555 560
Ser Ile Glu Leu Arg Ile Lys Lys Lys Lys Glu Glu Thr Ile Pro Val
565 570 575
Ile Ile Ser Pro Leu Lys Thr Ile Ser Ala Ser Leu Gly Ser Arg Leu
580 585 590
Thr Ile Pro Cys Lys Val Phe Leu Gly Thr Gly Thr Pro Leu Thr Thr
595 600 605
Met Leu Trp Trp Thr Ala Asn Asp Thr His Ile Glu Ser Ala Tyr Pro
610 615 620
Gly Gly Arg Val Thr Glu Gly Pro Arg Gln Glu Tyr Ser Glu Asn Asn
625 630 635 640
Glu Asn Tyr Ile Glu Val Pro Leu Ile Phe Asp Pro Val Thr Arg Glu
645 650 655
Asp Leu His Met Asp Phe Lys Cys Val Val His Asn Thr Leu Ser Phe
660 665 670
Gln Thr Leu Arg Thr Thr Val Lys Glu Ala Ser Ser Thr Phe Ser Gly
675 680 685
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe
690 695 700
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr
705 710 715 720
Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
725 730 735
Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val
740 745 750
Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser
755 760 765
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu
770 775 780
Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser
785 790 795 800
Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
805 810 815
Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln
820 825 830
Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala
835 840 845
Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr
850 855 860
Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu
865 870 875 880
Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser
885 890 895
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
900 905 910
Leu Ser Leu Gly Lys
915