CN115427559A - 末端脱氧核苷酸转移酶变体及其用途 - Google Patents
末端脱氧核苷酸转移酶变体及其用途 Download PDFInfo
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Abstract
本发明涉及来自多种物种的末端脱氧核苷酸转移酶(TdT)变体，其在将可逆性封闭的三磷酸核苷掺入多核苷酸中展示出增强的效率，并且涉及此类TdT在合成任何预定序列的多核苷酸中的用途。
Description
背景
合成预定序列的多核苷酸是许多技术的核心，所述技术包括分子诊断学、基因组和诊断测序、核酸扩增、治疗性抗体开发、合成生物学、基于核酸的治疗、DNA折纸术、基于DNA的数据存储等。最近，由于无模板聚合酶(例如末端脱氧核苷酸转移酶(TdT))已证实的效率和温和的无毒反应条件的益处，通过使用此类酶的基于酶促的方法，产生了对补充或替代基于化学的合成方法的兴趣，例如Ybert等人的国际专利公开WO2015/159023；Hiatt等人的美国专利5763594；Jensen等人，Biochemistry,57:1821-1832(2018)等等。大多数基于酶的合成方法需要使用可逆封闭的三磷酸核苷，以便在多核苷酸产物中获得所期望的序列。然而，不幸的是，与未修饰的三磷酸核苷相比，天然TdT以极大降低的效率掺入这此类修饰的三磷酸核苷。
鉴于上述情况，如果可以获得可以以更高的效率掺入可逆性封闭的三磷酸核苷的新的无模板聚合酶(如变体TDT)，则将促进无模板的基于酶促的多核苷酸合成的领域。
发明概述
本发明涉及来自多种物种的末端脱氧核苷酸转移酶(TdT)变体，其在将可逆性封闭的三磷酸核苷掺入多核苷酸中展示出增强的效率，并且涉及它们在合成任何预定序列的多核苷酸中的用途。
在一些实施方案中，本发明涉及末端脱氧核苷酸转移酶(TdT)变体，其包含与选自SEQ ID NO:2、5、8、11、14、17、20、23、26、29、32、35、38、41、44或47的氨基酸序列至少60％相同的氨基酸序列，其中：
对于SEQ ID NO:2，第61位的亮氨酸被取代，第170位的半胱氨酸被取代，第204位的精氨酸被取代，第326位的精氨酸被取代，和第329位的甘氨酸被取代；
对于SEQ ID NO:5，第48位的亮氨酸被取代，第158位的半胱氨酸被取代，第192位的精氨酸被取代，第314位的精氨酸被取代，和第317位的甘氨酸被取代；
对于SEQ ID NO:8，第61位的亮氨酸被取代，第171位的酪氨酸被取代，第205位的精氨酸被取代，第327位的精氨酸被取代，和第329位的谷氨酸被取代；
对于SEQ ID NO:11，第61位的亮氨酸被取代，第171位的酪氨酸被取代，第205位的精氨酸被取代，第324位的精氨酸被取代，和第327位的谷氨酸被取代；
对于SEQ ID NO:14，第61位的甘氨酸被取代，第205位的精氨酸被取代，第327位的精氨酸被取代，和第330位的谷氨酸被取代；
对于SEQ ID NO:17，第61位的精氨酸可以被取代或可以不被取代，第158位的丙氨酸被取代，第192位的精氨酸被取代，第311位的精氨酸被取代，和第314位的谷氨酸被取代；
对于SEQ ID NO:20，第61位的精氨酸可以被取代或可以不被取代，第171位的脯氨酸可以被取代或可以不被取代，第205位的精氨酸被取代，第321位的苏氨酸被取代，和第324位的谷氨酸被取代；
对于SEQ ID NO:23，第61位的精氨酸可以被取代或可以不被取代，第171位的丙氨酸可以被取代或可以不被取代，第205位的精氨酸被取代，第322位的丙氨酸可以被取代或可以不被取代，和第325位的谷氨酸被取代；
对于SEQ ID NO:26，第61位的精氨酸可以被取代或可以不被取代，第171位的丙氨酸可以被取代或可以不被取代，第205位的精氨酸被取代，第322位的精氨酸被取代，和第325位的谷氨酸被取代；
对于SEQ ID NO:29，第48位的甲硫氨酸被取代，第158位的半胱氨酸被取代，第192位的精氨酸被取代，第310位的精氨酸被取代，和第313位的谷氨酸被取代；
对于SEQ ID NO:32，第61位的甲硫氨酸被取代，第171位的半胱氨酸被取代，第205位的精氨酸被取代，第323位的精氨酸被取代，和第326位的谷氨酸被取代；
对于SEQ ID NO:35，第61位的甲硫氨酸被取代，第171位的半胱氨酸被取代，第205位的精氨酸被取代，第323位的精氨酸被取代，和第326位的谷氨酸被取代；
对于SEQ ID NO:38，第61位的甲硫氨酸被取代，第171位的半胱氨酸被取代，第205位的精氨酸被取代，第323位的精氨酸被取代，和第326位的谷氨酸被取代；
对于SEQ ID NO:41，第61位的甲硫氨酸被取代，第171位的半胱氨酸被取代，第205位的精氨酸被取代，第323位的精氨酸被取代，和第326位的谷氨酸被取代；
对于SEQ ID NO:44，第48位的甲硫氨酸被取代，第158位的半胱氨酸被取代，第192位的精氨酸被取代，第309位的精氨酸被取代，和第312位的谷氨酸被取代；以及
对于SEQ ID NO:47，第61位的甲硫氨酸被取代，第171位的半胱氨酸被取代，第205位的精氨酸被取代，第323位的精氨酸被取代，和第326位的谷氨酸被取代；以及
其中所述TdT变体(i)无需模板就能够合成核酸片段，和(ii)能够将3’-O-修饰的核苷酸掺入到核酸片段的游离3’-羟基上。
在一些实施方案中，对在以下位置处的亮氨酸的上述取代选自R或Q：SEQ ID NO:2、8或11中的第61位，或者SEQ ID NO:5中的第48位。在一些实施方案中，对在以下位置处的半胱氨酸的上述取代选自G、R、P、A、V、S、N、Q或D：SEQ ID NO:2中的第170位，或SEQ ID NO:5、29或44中的第158位，或SEQ ID NO:32、35、38、41或47中的第171位；并且在其它实施方案中，对在前述位置处的半胱氨酸的所述取代选自G或R。在一些实施方案中，对SEQ ID NO:8或11的第171位的酪氨酸的上述取代选自G、R、P、A、V、S、N、Q或D；并且在其它实施方案中，对在前述位置处的酪氨酸的所述取代选自G或R。在一些实施方案中，对在以下位置处的丙氨酸的上述取代选自G、R、P、V、S、N、Q或D：SEQ ID NO:17的第158位，或SEQ ID NO:23或26的第171位；并且在其它实施方案中，对在前述位置处的丙氨酸的所述取代选自G或R。在一些实施方案中，对SEQ ID NO:20的第171位的脯氨酸的上述取代选自G、R、A、V、S、N、Q或D；并且在其它实施方案中，对在前述位置处的酪氨酸的所述取代选自G或R。在一些实施方案中，对在以下位置处的精氨酸的上述取代选自L或N：SEQ ID NO：2的第204位，或SEQ ID NO：5、17、29或44的第192位，或SEQ ID NO：8、11、14、20、23、26、32、35、38、41或47的第205位。在一些实施方案中，对在以下位置处的精氨酸的上述取代选自P、N或A：SEQ ID NO:2的第326位，或SEQ ID NO:5的第314位，或SEQ ID NO:8或14的第327位，或SEQ ID NO:11的第324位，或SEQID NO:17的第311位，或SEQ ID NO:20的第321位，或SEQ ID NO:23或26的第322位，或SEQID NO:29的第310位，或SEQ ID NO:32、35、38、41或47的第323位，或SEQ ID NO:44的第309位。在一些实施方案中，对SEQ ID NO:20的第321位的苏氨酸的上述取代选自P、N或A。在一些实施方案中，对SEQ ID NO:2或5的第329位的甘氨酸的上述取代选自N、L、T或S。在一些实施方案中，对在以下位置处的谷氨酸的上述取代选自N、L、T或S：SEQ ID NO:8或14的第330位，或SEQ ID NO:11的第327位，或SEQ ID NO:17的第311位，或SEQ ID NO:20的第324位，或SEQ ID NO:23或26的第325位，或SEQ ID NO:29的第313位，SEQ ID NO:32、35、38、41或47的第326位，或SEQ ID NO:44的第312位。
在其它实施方案中，本发明涉及末端脱氧核苷酸转移酶(TdT)变体，其包含如上所述被取代并且进一步如下被取代的与选自SEQ IDNO：2、5、8、11、14、17、20、23、26、29、32、35、38、41、44或47的氨基酸序列至少60％相同的氨基酸序列：
对于SEQ ID NO:2，第327位的谷氨酰胺被取代；
对于SEQ ID NO:5，第315位的谷氨酸被取代；
对于SEQ ID NO:8，第328位的谷氨酰胺被取代；
对于SEQ ID NO:11，第325位的谷氨酰胺被取代；
对于SEQ ID NO:14，第328位的谷氨酰胺被取代；
对于SEQ ID NO:17，第312位的谷氨酰胺被取代；
对于SEQ ID NO:20，第322位的谷氨酰胺被取代；
对于SEQ ID NO:23，第323位的谷氨酰胺被取代；
对于SEQ ID NO:26，第323位的甲硫氨酸被取代；
对于SEQ ID NO:29，第311位的谷氨酰胺被取代；
对于SEQ ID NO:32，第324位的谷氨酰胺被取代；
对于SEQ ID NO:35，第324位的谷氨酰胺被取代；
对于SEQ ID NO:38，第324位的谷氨酰胺被取代；
对于SEQ ID NO:41，第324位的谷氨酰胺被取代；
对于SEQ ID NO:44，第310位的谷氨酰胺被取代；和
对于SEQ ID NO:47，第324位的谷氨酰胺被取代；
并且其中所述TdT变体(i)无需模板能够合成核酸片段，和(ii)能够将3’-O-修饰的核苷酸掺入到核酸片段的游离3’-羟基上。在一些实施方案中，谷氨酰胺和谷氨酸的前述取代是T、F、L或M。
在一些实施方案中，本发明涉及末端脱氧核苷酸转移酶(TdT)变体，其包含与选自SEQ ID NO：3、6、9、12、15、18、21、24、27、30、33、36、39、42、45或48的氨基酸序列至少90％相同的氨基酸序列，其中：
对于SEQ ID NO:3，第61位的氨基酸是R，第171位的氨基酸是R，第205位的氨基酸是L，第327位的氨基酸是A，和第330位的氨基酸是N；
对于SEQ ID NO:6，第48位的氨基酸是R，第158位的氨基酸是R，第192位的氨基酸是L，第314位的氨基酸是P，和第317位的氨基酸是N；
对于SEQ ID NO:9，第61位的氨基酸是R，第171位的氨基酸是R，第205位的氨基酸是L，第327位的氨基酸是A，和第330位的氨基酸是N；
对于SEQ ID NO:12，第61位的氨基酸是R，第171位的氨基酸是A，第205位的氨基酸是L，第324位的氨基酸是P，和第327位的氨基酸是N；
对于SEQ ID NO:15，第61位的氨基酸是R，第171位的氨基酸是R，第205位的氨基酸是L，第328位的氨基酸是P，和第331位的氨基酸是N；
对于SEQ ID NO:18，第48位的氨基酸是R，第158位的氨基酸是R，第192位的氨基酸是L，第311位的氨基酸是P，和第314位的氨基酸是N；
对于SEQ ID NO:21，第61位的氨基酸是R，第171位的氨基酸是P，第205位的氨基酸是L，第321位的氨基酸是A，和第324位的氨基酸是N；
对于SEQ ID NO:24，第61位的氨基酸是R，第171位的氨基酸是A，第205位的氨基酸是L，第322位的氨基酸是A，和第325位的氨基酸是N；
对于SEQ ID NO:27，第61位的氨基酸是R，第171位的氨基酸是R，第205位的氨基酸是L，第327位的氨基酸是A，和第330位的氨基酸是N；
对于SEQ ID NO:30，第48位的氨基酸是R，第158位的氨基酸是R，第192位的氨基酸是L，第310位的氨基酸是P，和第313位的氨基酸是N；
对于SEQ ID NO:33，第61位的氨基酸是R，第171位的氨基酸是R，第205位的氨基酸是L，第323位的氨基酸是P，和第326位的氨基酸是N；
对于SEQ ID NO:36，第61位的氨基酸是R，第171位的氨基酸是R，第205位的氨基酸是L，第323位的氨基酸是A，和第326位的氨基酸是N；
对于SEQ ID NO:39，第61位的氨基酸是R，第171位的氨基酸是R，第205位的氨基酸是L，第323位的氨基酸是P，和第326位的氨基酸是N；
对于SEQ ID NO:42，第61位的氨基酸是R，第171位的氨基酸是R，第205位的氨基酸是L，第323位的氨基酸是A，和第326位的氨基酸是N；
对于SEQ ID NO:45，第48位的氨基酸是R，第158位的氨基酸是R，第192位的氨基酸是L，第310位的氨基酸是A，和第313位的氨基酸是N；
对于SEQ ID NO:48，第61位的氨基酸是R，第171位的氨基酸是R，第205位的氨基酸是L，第323位的氨基酸是P，和第326位的氨基酸是N；以及
其中所述TdT变体(i)无需模板就能够合成核酸片段，和(ii)能够将3’-O-修饰的核苷酸掺入到核酸片段的游离3’-羟基上。
在一些实施方案中，在前述TdT变体中，对于SEQ ID NO:3，第328位的氨基酸是Q或选自T、F、L或M；
对于SEQ ID NO:6，第315位的氨基酸是Q或选自T、F、L或M；
对于SEQ ID NO:9，第328位的氨基酸是Q或选自T、F、L或M；
对于SEQ ID NO:12，第325位的氨基酸是Q或选自T、F、L或M；
对于SEQ ID NO:15，第329位的氨基酸是Q或选自T、F、L或M；
对于SEQ ID NO:18，第312位的氨基酸是Q或选自T、F、L或M；
对于SEQ ID NO:21，第322位的氨基酸是Q或选自T、F、L或M；
对于SEQ ID NO:24，第323位的氨基酸是Q或选自T、F、L或M；
对于SEQ ID NO:27，第328位的氨基酸是Q或选自T、F、L或M；
对于SEQ ID NO:30，第311位的氨基酸是Q或选自T、F、L或M；
对于SEQ ID NO:33，第324位的氨基酸是Q或选自T、F、L或M；
对于SEQ ID NO:36，第324位的氨基酸是Q或选自T、F、L或M；
对于SEQ ID NO:39，第324位的氨基酸是Q或选自T、F、L或M；
对于SEQ ID NO:42，第324位的氨基酸是Q或选自T、F、L或M；
对于SEQ ID NO:45，第311位的氨基酸是Q或选自T、F、L或M；以及
对于SEQ ID NO：48，第324位的氨基酸是Q或选自T、F、L或M。
在一些实施方案中，本发明涉及末端脱氧核苷酸转移酶(TdT)变体，其包含选自SEQ ID NO:3、6、9、12、15、18、21、24、27、30、33、36、39、42、45或48的氨基酸序列。
在一些实施方案中，关于前述TdT变体中的每一个的同一性百分比值与所示的SEQID NO具有至少80％的同一性；在一些实施方案中，上述同一性值百分比与所示的SEQ IDNO具有至少90％的同一性；在一些实施方案中，上述百分比同一性值与所示的SEQ ID NO具有至少95％的同一性；在一些实施方案中，上述同一性百分比值为至少97％的同一性；在一些实施方案中，上述同一性百分比值为至少98％的同一性；在一些实施方案中，上述同一性百分比值是至少99％的同一性。如本文所用的，用于比较参考序列与变体序列的同一性百分比值不包括明确指定的包含变体序列的取代的氨基酸位置；也就是说，同一性百分比关系是在参考蛋白的序列和包含变体中取代的明确指定位置之外的变体蛋白的序列之间。因此，例如，如果参考序列和变体序列各自包含100个氨基酸，并且变体序列在第25和81位具有突变，那么同源性百分比将是关于序列1-24、26-80和82-100的。关于上述(ii)，在一些实施方案中，此类3’-O-修饰的核苷酸可以包含3’-O-NH2-三磷酸核苷酯、3’-O-叠氮基甲基-三磷酸核苷酯、3’-O-烯丙基-三磷酸核苷酯、3’-O-(2-硝基苄基)-三磷酸核苷酯、3’-O-硝基-三磷酸核苷酯或3’-O-炔丙基-三磷酸核苷酯。在其它实施方案中，此类3’-O-修饰的核苷酸可以包含3’-O-NH2-三磷酸核苷或3’-O-叠氮基甲基-三磷酸核苷。
本发明还涉及本发明的TdT变体通过向核酸片段连续添加一个或多个3’-O-修饰的核苷酸来无模板合成核酸分子的用途。在一些实施方案中，此类方法包括以下步骤：(a)提供包含具有游离3’-羟基的寡核苷酸的起始子；(b)在酶促延伸条件下，在3’-O-可逆封闭的三磷酸核苷的存在下的情况下，使本发明的TdT变体与所述起始子或延伸的起始子反应。在一些实施方案中，此类方法还包括以下步骤：(c)使所述延伸的起始子去封闭以形成具有游离3’-羟基的延伸的起始子，和(d)重复步骤(b)和(c)直到合成预定序列的核酸分子。
在其它实施方案中，本发明包括编码上述变体TDT的核酸分子，包含此类核酸分子的表达载体，和包含上述核酸分子或上述表达载体的宿主细胞。在其它实施方案中，本发明包括生产本发明的变体TdT的方法，其中在允许编码所述变体TdT的核酸表达的培养条件下培养宿主细胞，并且其中任选地回收所述变体TdT。本发明还包括用于进行任何预定序列的无模板多核苷酸延长的试剂盒，其中所述试剂盒包括本发明的TdT变体。此类试剂盒还可以包含用于DNA延长的A、C、G和T的3’-O-封闭的三磷酸脱氧核苷(dNTP)，或用于RNA延长的rA、rC、rG和U的3’-O-封闭的三磷酸核糖核苷(rNTP)。
本发明通过提供新的TdT变体，有利地克服了与3’-O-修饰的三磷酸核苷的有效掺入相关的无模板酶促核酸合成领域中的问题，所述新的TdT变体具有掺入3’-O-修饰的核苷酸的能力，其具有比野生型TDT或先前可用的TdT变体更高的效率或更高的速率。在一些实施方案中，本发明还有利地通过提供与野生型TDT相比具有增加的稳定性的新TdT变体来克服上述领域中的问题。
附图简述
图1图解说明了使用本发明的TdT变体的无模板酶促核酸合成方法的步骤。
发明详述
虽然本发明可以进行各种修改和可替代的形式，但是其细节已经通过附图中的实例示出并将被详细描述。应当理解，本发明不限于所描述的具体实施方案。它旨在覆盖落入本发明的精神和范围内的所有修改、等同物和可替代物。本发明的方面的指导可在本领域普通技术人员熟知的许多可用参考文献和论文中找到，包括例如Sambrook等人(1989)，Molecular cloning:A Laboratory Manual,Cold Spring Harbor Laboratory等。
本发明提供了TdT聚合酶的变体，其可以被用于合成预定序列的多核苷酸(如DNA或RNA)而不使用模板链。本发明的TdT变体允许修饰的核苷酸，并且更具体地3’O-可逆性封闭的三磷酸核苷被用于基于酶的多核苷酸合成方法中。本发明的变体是根据它们在特定残基处的突变或取代来描述的，它们的位置是针对特定的SEQ ID NO来指定的。
本发明的TDT变体来源于没有它们的BRCT样N-末端氨基酸序列的天然TDT。此类截短的序列在本文中有时被称为“截短的野生型”TDT。更具体地，本发明的TdT变体衍生自以下天然TdT：
表1
在一些实施方案中，TdT变体可以被可操作地连接到包括共价键或非共价键的连接子部分；氨基酸标签(例如，聚氨基酸标签、聚His标签、6His-标签)；化合物(例如，聚乙二醇)；蛋白-蛋白结合对(例如，生物素-亲和素)；亲和偶联；捕获探针；或这些的任意组合。连接子部分可以与TdT变体分开或者是TdT变体的一部分(例如，重组His标记的聚合酶，如以下对所例证的：SEQ ID NO:(3,4)、(6,7)、(9,10)、(12,13)、(15,16)、(18,19)、(21,22)、(24,25)、(27,28)、(30,31)、(33,34)、(36,37)、(39,40)、(42,43)、(45,46)和(48,49))。通常，连接子部分不干扰核苷酸结合活性或TdT变体的催化活性。
在上述的一些实施方案中，变体TdT在掺入3’O-修饰的三磷酸核苷中的效率是先前可用的TdT野生型或变体的至少105％；在其它实施方案中，变体TdT在掺入3’O-修饰的三磷酸核苷中的效率是先前可用的TdT野生型或变体的至少110％；在其它实施方案中，变体TdT掺入3’O-修饰的三磷酸核苷的效率是以前可用的TdT野生型或变体的至少150％。
如上所述的本发明的TDT变体各自包含与指定的SEQ ID NO具有百分比序列同一性的氨基酸序列，其条件是存在指定的取代。在一些实施方案中，以这种方式描述的本发明的TdT变体与指定的SEQ ID NO之间的序列差异的数目和类型可以是由于取代、缺失和/或插入，并且被取代、缺失和/或插入的氨基酸可以包含任何氨基酸。在一些实施方案中，此类缺失、取代和/或插入仅包含天然存在的氨基酸。在一些实施方案中，取代仅包括保守性或同义的氨基酸改变，如描述于Grantham,Science,185:862-864(1974)。也就是说，氨基酸的取代只能在其同义氨基酸集的成员中发生。在一些实施方案中，可以使用的同义氨基酸集列于表2A中。
表2A：氨基酸的同义集I
在一些实施方案中，可以使用的同义氨基酸集列于表2B中。
表2B：氨基酸的同义集II
核苷酸掺入活性的测量
本发明变体的核苷酸掺入效率可通过延伸或延长测定来测量，例如，描述于Boule等人(下文引用)；Bentolila等人(下文引用)；和Hiatt等人的美国专利5808045，后者通过引用并入到本文中。简而言之，在此类测定的一种形式中，在TdT延伸条件下，在可逆封闭的三磷酸核苷存在下，具有游离3’-羟基的荧光标记的寡核苷酸与待测试的变体TdT反应预定的持续时间，之后终止延伸反应，并且在通过凝胶电泳分离后对延伸产物和未延伸的起始寡核苷酸的量进行定量。通过此类测定，变体TdT的掺入效率可以容易地与其它变体或野生型或参考TdT或其它聚合酶的效率比较。在一些实施方案中，变体TdT效率的量度可以是在等同测定中使用变体TdT的延伸产物的量与使用野生型TdT的延伸产物的量的比率(以百分比给出)。
在一些实施方案中，以下特定延伸测定可以被用于测量TdT的掺入效率：所用引物如下：
5’-AAAAAAAAAAAAAAGGGG-3’(SEQ ID NO:50)
所述引物在5’末端还具有ATTO荧光染料。使用的代表性修饰核苷酸(在表3中被记为dNTP)包括3’-O-氨基-2’,3’-二脱氧核苷酸-5’-三磷酸(ONH2,Firebird Biosciences)，如3’-O-氨基-2’,3’-二脱氧腺苷-5’-三磷酸。对于每个测试的不同变体，使用一个管进行反应。将试剂加入管中，从水开始，然后按表3的顺序加入。在37℃下30min后，通过添加甲酰胺(Sigma)终止反应。
表3：延伸活性测定试剂
活性缓冲液包含例如补充有CoCl2的TdT反应缓冲液(可获自New EnglandBiolabs)。
通过常规聚丙烯酰胺凝胶电泳分析测定的产物。例如，上述测定的产物可以在16％聚丙烯酰胺变性凝胶(Bio-Rad)中分析。刚好在分析之前通过将聚丙烯酰胺倾倒在玻璃板内并使其聚合来制备凝胶。将玻璃板内的凝胶安装在装有用于电泳步骤的TBE缓冲液(Sigma)的适合的缸中。将待分析的样品加载在凝胶的顶部。在室温下，在凝胶的顶部和底部之间施加500至2,000V的电压进行3至6h。分离后，使用例如Typhoon扫描仪(GE LifeSciences)扫描凝胶的荧光。使用ImageJ软件(imagej.nih.gov/ij/)或其等同物分析凝胶图像，以计算修饰核苷酸的掺入百分比。
发夹完成测定。在一方面，本发明包括测量聚合酶(如TdT变体)将dNTP掺入多核苷酸(即“测试多核苷酸”)的3’末端的能力的方法。一种此类方法包括在反应条件下提供具有游离3’羟基的测试多核苷酸，其中所述测试多核苷酸基本上仅是单链的，但在用聚合酶(如TdT变体)延伸时形成包含单链环和双链茎的稳定发夹结构，从而允许通过双链多核苷酸的存在检测3’端的延伸。双链结构可以以多种方式检测，包括但不限于，插入双链结构时优先发荧光的荧光染料，延伸多核苷酸上的受体(或供体)和寡核苷酸上的供体(或受体)之间的荧光共振能量转移(FRET)，所述寡核苷酸与新形成的发夹茎、FRET受体和供体形成三链体，在形成发夹等时，所述FRET受体和供体都连接到测试多核苷酸并且被带入FRET附近。在一些实施方案中，在由单核苷酸延伸后的测试多核苷酸的茎部分的长度在4至6个碱基对的范围内；在其它实施方案中，此类茎部分的长度为4至5个碱基对；在其它实施方案中，此类茎部分的长度为4个碱基对。在一些实施方案中，测试多核苷酸的长度在10至20个核苷酸的范围内；在其它实施方案中，测试多核苷酸的长度在12至15个核苷酸的范围内。在一些实施方案中，有利的是或方便的是用核苷酸延伸测试多核苷酸，所述核苷酸使没有延伸的茎和有延伸的茎的解链温度之间的差异最大化；因此，在一些实施方案中，用dC或dG延伸测试多核苷酸(并因此选择具有用于茎形成的适当互补核苷酸的测试多核苷酸)。
用于发夹完成测定的示例性测试多核苷酸包括p875(5’-CAGTTAAAAACT)(SEQ IDNO:51)，其通过用dGTP延伸而完成；p876(5’-GAGTTAAAACT)(SEQ ID NO:52)，其通过用dCTP延伸而完成；和p877(5’-CAGCAAGGCT)(SEQ ID NO:53)，其通过用dGTP延伸而完成。用于此类测试多核苷酸的示例性反应条件可以包括：2.5-5M的测试多核苷酸、1:4000稀释的
(来自Biotium,Inc.,Fremont,CA的嵌入染料)、200mM卡可基酸盐KOH(pH6.8)、1mM CoCl2、0-20％的DMSO和期望浓度的3’-ONH2 dGTP和TdT。发夹的完成可以通过使用常规荧光计(如TECAN读取器)在28-38℃的反应温度下，使用设置为360nm的激发滤光片和设置为635nm的发射滤光片来增加
染料的荧光来监测。在本发明该方面的一些实施方案中，可以通过以下步骤测试TdT变体对无模板掺入三磷酸核苷的能力：(a)在其中测试多核苷酸是单链的但掺入三磷酸核苷后形成具有双链茎区域的发夹的条件下，组合具有游离3’-羟基的测试多核苷酸、TdT变体和三磷酸核苷，和(b)检测形成的双链茎区域的量，作为TdT变体掺入三磷酸核苷的能力的量度。在一些实施方案中，三磷酸核苷是3’-O-封闭的三磷酸核苷。
寡核苷酸的无模板酶促合成
通常，无模板(或等效地“模板非依赖性”)酶促DNA合成的方法包括重复的步骤循环(如图1所示的)，其中在每个循环中将预定的核苷酸偶联到起始子或生长链上。在以下参考文献中描述了无模板的酶促合成的一般要素：Ybert等人，国际专利公开WO/2015/159023；Ybert等人，国际专利公开WO/2017/216472；Hyman，美国专利5436143；Hiatt等人，美国专利5763594；Jensen等人，Biochemistry，57:1821-1832(2018)；Mathews等人，Organic&Biomolecular Chemistry,DOI:0.1039/c60ob01371f(2016)；Schmitz等人，Organic Lett.,1(11):1729-1731(1999)。
提供了起始多核苷酸(100)，例如连接于具有游离3’-羟基(103)的固体支持物(102)的起始多核苷酸(100)。在有效将3’-O-经保护的-dNTP酶促掺入起始多核苷酸(100)(或延长的起始多核苷酸)的3’端的条件下，向起始多核苷酸(100)(或后续循环中的延长的起始多核苷酸)中加入(104)3’-O-经保护的dNTP和无模板聚合酶(如TdT或其变体)(例如Ybert等人，WO/2017/216472；Champion等人，WO2019/135007)。该反应产生其3’-羟基被保护的伸长的起始多核苷酸(106)。如果延长的序列没有完成，则执行另一个添加循环(108)。如果延长的起始多核苷酸含有竞争的序列，则3’-O-保护基团可以被去除或去保护，并且所期望的序列可以从原始起始多核苷酸中被切割(110)。此类切割可以使用多种单链切割技术中的任一种进行，例如，通过在原始起始多核苷酸内的预定位置处插入可切割的核苷酸。示例性的可切割核苷酸可以是被尿嘧啶DNA糖基化酶切割的尿嘧啶核苷酸。如果延长的起始多核苷酸不包含完整的序列，则去除3’-O-保护基团以暴露游离的3’-羟基(103)，并且延长的起始多核苷酸经历核苷酸添加和去保护的另一个循环。
如本文所用的，关于特定基团(例如核苷酸或核苷的3’-羟基)的术语“经保护的”和“封闭的”可互换使用，并且旨在表示部分共价连接至特定基团，其防止在化学或酶促过程期间基团的化学变化。每当指定基团是三磷酸核苷的3’-羟基，或其中已掺入3’-经保护的(或封闭的)-三磷酸核苷的延伸片段(或“延伸中间体”)时，阻止的化学变化是延伸片段(或“延伸中间体”)通过酶偶联反应的进一步或随后的延伸。
如本文所用的，“起始子”(或等同术语，如“起始片段”、“起始核酸”、“起始子寡核苷酸”等)通常是指在其末端具有游离3’-羟基的短寡核苷酸序列，其可进一步通过无模板聚合酶(如TdT)延长。在一个实施方案中，起始片段是DNA起始片段。在可替代的实施方案中，起始片段是RNA起始片段。在一些实施方案中，起始片段具有3至100个核苷酸，特别是3至20个核苷酸。在一些实施方案中，起始片段是单链的。在可替代的实施方案中，起始片段可以是双链的。在一些实施方案中，起始寡核苷酸可以通过其5’端连接到合成支持物；并且在其它实施方案中，可以通过与直接连接到合成支持物(例如通过共价键)上的互补寡核苷酸形成双链体，将起始寡核苷酸间接连接到合成支持物上。在一些实施方案中，合成支持物是固体支持物，其可以是固体平面固体的离散区域，或可以是珠。
在一些实施方案中，起始子可以包含具有游离羟基的非核酸化合物，TdT可以将3’-O-经保护的dNTP偶联到该游离羟基，例如Baiga，美国专利公开US2019/0078065和US2019/0078126。
在合成完成后，具有所期望核苷酸序列的多核苷酸可以通过切割从起始子和固体支持物中被释放出来。为此目的，可以使用多种可切割的连接或可切割的核苷酸。在一些实施方案中，切割所期望的多核苷酸在切割的链上留下天然的游离5’-羟基；然而，在可替代的实施方案中，切割步骤可以留下可以在随后的步骤中去除(例如通过磷酸酶处理)的部分(例如5’-磷酸)。切割步骤可以化学地、用热的方法、酶促地或通过光化学方法进行。在一些实施方案中，可切割的核苷酸可以是核苷酸类似物，如脱氧尿苷或8-氧代-脱氧鸟苷，其被特异性糖基化酶(例如尿嘧啶脱氧糖基化酶，随后分别是核酸内切酶VIII和8-氧代鸟嘌呤DNA糖基化酶)识别。在一些实施方案中，切割可以通过提供具有脱氧肌苷作为倒数第二个3’核苷酸的起始子来完成，其可以在起始子的3’端处被核酸内切酶V切割，在释放的多核苷酸上留下5’-磷酸。用于切割单链多核苷酸的其它方法公开于以下参考文献中，其通过引用并入：美国专利第5,739,386号、第5,700,642号和第5,830,655号；以及美国专利公开第2003/0186226号和第2004/0106728号；以及在Urdea和horn的美国专利5367066中。
在一些实施方案中，糖基化酶和/或核酸内切酶的切割可能需要双链DNA底物。
回到图1，在一些实施方案中，在每个合成步骤中，在3’-O-经保护的dNTP存在的情况下，使用无模板聚合酶(如TdT)，将核苷酸的有序序列与起始核酸偶联。在一些实施方案中，合成寡核苷酸的方法包括以下步骤：(a)提供具有游离3’-羟基(103)的起始子(例如(100))；(b)在延伸条件下，在3’-O-经保护的三磷酸核苷存在的情况下，使所述起始子或具有游离3’-羟基的延伸中间体与无模板聚合酶反应(104)，以产生3’-O-经保护的延伸中间体(106)；(c)使所述延伸中间体去保护以产生具有游离3’-羟基的延伸中间体；和(d)重复步骤(b)和(c)(108)，直至合成多核苷酸(110)。(有时术语“延伸中间物”和“延伸片段”可互换使用)。在一些实施方案中，起始子作为连接到固体支持物(例如通过其5’端)上的寡核苷酸提供。上述方法还可以包括在反应或延伸步骤之后以及在去保护步骤之后的洗涤步骤。例如，反应步骤可以包括在预定的孵育期或反应时间之后去除未掺入的三磷酸核苷的子步骤(例如通过洗涤)。此类预定的孵育时间或反应时间可以是几秒(例如30sec)至几分钟(例如30min)。
当合成支撑物上的多核苷酸序列包括反向互补子序列时，可以通过在反向互补区之间形成氢键来产生二级分子内或交叉分子结构。在一些实施方案中，选择用于环外胺的碱基保护部分，使得经保护的氮的氢不能参与氢键合，从而防止此类二级结构的形成。也就是说，可以使用碱基保护部分来防止氢键的形成，如在正常碱基配对中形成，例如在核苷A和T之间以及在G和C之间。在合成结束时，可以去除碱基保护部分，并且可以将多核苷酸产物从固体支持物上切割下来，例如通过将其从其起始子上切割下来。
除了提供具有碱基保护基团的3’-O-封闭的dNTP单体之外，可以使用热稳定的无模板聚合酶在更高温度下进行延长反应。例如，可以使用具有高于40℃的活性的热稳定的无模板聚合酶；或者，在一些实施方案中，可以使用具有40-85℃范围内活性的热稳定的无模板聚合酶；或者，在一些实施方案中，可以使用具有40-65℃范围内活性的热稳定的无模板聚合酶。
在一些实施方案中，延长条件可以包括向延长反应混合物中添加抑制氢键合或碱堆积的溶剂。此类溶剂包括具有低介电常数的水混溶性溶剂(如二甲基亚砜(DMSO)、甲醇等)。同样，在一些实施方案中，延长条件可以包括提供离液剂，其包括但不限于正丁醇、乙醇、氯化胍、高氯酸锂、乙酸锂、氯化镁、苯酚、2-丙醇、十二烷基硫酸钠、硫脲、脲等。在一些实施方案中，延长条件包括存在二级结构抑制量的DMSO。在一些实施方案中，延长条件可以包括提供抑制二级结构形成的DNA结合蛋白，其中此类蛋白包括但不限于单链结合蛋白、解旋酶、DNA乙二醇酯酶(DNA glycolases)等。
无碱基保护的3’-O-封闭的dNTP可以从商业供应商购买或使用公开的技术合成，例如美国专利7057026；Guo等人，Proc.Natl.Acad.Sci.,105(27):9145-9150(2008)；Benner，美国专利7544794and 8212020；国际专利公开WO2004/005667、WO91/06678；Canard等人，Gene(本文引用的)；Metzker等人，Nucleic Acids Research,22:4259-4267(1994)；Meng等人，J.Org.Chem.，14:3248-3252(3006)；美国专利公开2005/037991。具有碱基保护的3’-O-封闭的dNTP可以如下所述合成。
当使用碱基保护的dNTP时，图1的上述方法还可以包括步骤(e)去除碱基保护部分的，其在酰基或脒保护基团的情况下可以(例如)包括用浓氨处理。
上述方法还可以包括加帽步骤以及在反应或延伸步骤之后以及在去保护步骤之后的洗涤步骤。如上所述，在一些实施方案中，可以包括加帽步骤，其中未延伸的游离3’-羟基与防止加帽链的任何进一步延伸的化合物反应。在一些实施方案中，此类化合物可以是三磷酸二脱氧核苷。在其它实施方案中，具有游离3’-羟基的非延伸链可以通过用3’-核酸外切酶活性(例如Exo I)处理而降解。例如，参见Hyman，美国专利5436143。同样，在一些实施方案中，未被去封闭的链可以被处理以去除链或使其对进一步的延伸是惰性的。
在一些实施方案中，用于延长步骤(有时也被称为延伸步骤或偶联步骤)的反应条件可以包括以下：2.0μM纯化的TdT；125-600μM的3’-O-封闭的dNTP(例如3’-O-NH2-封闭的dNTP)；约10至约500mM的卡可基酸钾缓冲液(pH为6.5至7.5)和约0.01至约10mM的二价阳离子(例如CoCl2或MnCl2)，其中延长反应可以在RT至45℃范围内的温度下，在50μL反应体积中进行3分钟。在其中3’-O-封闭的dNTP是3’-O-NH2-封闭的dNTP的实施方案中，用于去封闭步骤的反应条件可以包括以下：700mM NaNO2；1M乙酸钠(用乙酸调节至pH在4.8-6.5的范围内)，其中去封闭反应可以在RT至45℃的范围内的温度下在50μL体积中进行30秒至几分钟。可以用卡可基酸盐缓冲液进行洗涤，而不需要偶联反应的组分(例如酶、单体、二价阳离子)。
根据具体应用，去封闭和/或切割的步骤可以包括各种化学或物理条件，例如光、热、pH、能够切割特定化学键的特定试剂(如酶)的存在。在选择3’-O-封闭基团和相应的去封闭条件方面的指导可以在以下参考文献中找到，其通过引用并入本文：Benner，美国专利7544794和8212020；美国专利5808045；美国专利8808988；国际专利公开WO91/06678；以及以下引用的参考文献。在一些实施方案中，切割剂(有时也被称为去封闭试剂或去封闭剂)是化学切割剂(如例如二硫苏糖醇(DTT))。在可替代的实施方案中，切割剂可以是酶切割剂，如例如磷酸酶，其可以切割3’-磷酸封闭基团。本领域技术人员将理解，去封闭剂的选择取决于所用的3’-核苷酸封闭基团的类型，是否使用一个或多个封闭基团，起始子是否连接到活细胞或生物体或固体支持物等，这需要温和的处理。例如，膦(如三(2-羧乙基)膦(TCEP))可以被用于切割3’O-叠氮基甲基，钯络合物可以被用于切割3’O-烯丙基，或亚硝酸钠可以被用于切割3’O-氨基。在具体的实施方案中，切割反应涉及TCEP、钯络合物或亚硝酸钠。
如上所述，在一些实施方案中，期望采用两个或更多个封闭基团，这些封闭基团可以使用正交去封闭条件来去除。以下示例性的封闭基团对(表4)可以被用于平行合成实施方案中。应当理解，其他封闭基团对或包含多于两个的基团可能可用于本发明的这些实施方案中。
表4：示例性的封闭基团对
| 3’-O-NH2 | 3’-O-叠氮基甲基 |
| 3’-O-NH2 | 3’-O-烯丙基 |
| 3’-O-NH2 | 3’-O-磷酸酯 |
| 3’-O-叠氮基甲基 | 3’-O-烯丙基 |
| 3’-O-叠氮基甲基 | 3’-O-磷酸酯 |
| 3’-O-烯丙基 | 3’-O-磷酸酯 |
在活细胞上合成寡核苷酸需要温和的去封闭或去保护的条件，即不破坏细胞膜、不使蛋白质变性、不干扰关键细胞功能等的条件。在一些实施方案中，去保护的条件在与细胞存活相容的生理条件范围内。在此类实施方案中，酶促去保护是可期望的，因为它可以在生理条件下进行。在一些实施方案中，特定的酶促可去除的封闭基团与特定的酶缔合以去除它们。例如，基于酯-或酰基-的封闭基团可以用酯酶(如乙酰酯酶)或类似酶去除，并且磷酸酯封闭基团可以用3’磷酸酶(如T4多核苷酸激酶)去除。例如，可以通过用溶液(100mM的Tris-HCl(pH 6.5)、10mM的MgCl2、5mM的2-巯基乙醇和一种Unit T4多核苷酸激酶)处理来去除3’-O-磷酸酯。反应在37℃的温度下进行一分钟。
“3’-磷酸酯封闭的”或“3’-磷酸酯保护的”核苷酸是指其中3’-位置处的羟基通过存在的含磷酸酯部分封闭的核苷酸。根据本发明的3’-磷酸酯封闭的核苷酸的实例是核苷酸基(nucleotidyl)-3’-磷酸单酯/核苷酸基-2’,3’-环磷酸酯、核苷酸基-2’-磷酸单酯和核苷酸基-2’或3’-烷基磷酸二酯，以及核苷酸基-2’或3’-焦磷酸酯。也可以使用硫代磷酸酯或此类化合物的其他类似物，只要该取代不会阻止磷酸酶去磷酸化产生游离的3’-OH。
3’-O-酯保护的dNTP或3’-O-磷酸酯保护的dNTP的合成和酶促去保护的其他实例在以下参考文献中有描述：Canard等人，Proc.Natl.Acad.Sci.,92:10859-10863(1995)；Canard等人，Gene,148:1-6(1994)；Cameron等人，Biochemistry,16(23):5120-5126(1977)；Rasolonjatovo等人，Nucleosides&Nucleotides,18(4&5):1021-1022(1999)；Ferrero等人，Monatshefte fur Chemie,131:585-616(2000)；Taunton-Rigby等人，J.Org.Chem.,38(5):977-985(1973)；Uemura等人，Tetrahedron Lett.,30(29):3819-3820(1989)；Becker等人，J.Biol.Chem.,242(5):936-950(1967)；Tsien,国际专利公开WO1991/006678。
在一些实施方案中，经修饰的核苷酸包含经修饰的核苷酸或核苷分子，其包含嘌呤或嘧啶碱基和核糖或脱氧核糖糖部分，所述糖部分具有与其共价连接的可去除的3’-OH封闭基团，使得3’碳原子连接一组结构：
-O-Z
其中–Z是以下中的任一个：–C(R’)2-O-R”、-C(R’)2-N(R”)2、-C(R’)2-N(H)R”、-C(R’)2-S-R”和–C(R’)2-F，其中每个R”是可去除的保护基团或其一部分；每个R’独立地是氢原子、烷基、取代烷基、芳烷基、烯基、炔基、芳基、杂芳基、杂环基、酰基、氰基、烷氧基、芳氧基、杂芳氧基或氨基，或通过连接基团连接的可检测标记；条件是在一些实施方案中，此类取代基具有至多10个碳原子和/或至多5个氧或氮杂原子；或(R’)2表示式＝C(R”’)2的基团，其中每个R”’可以相同或不同，并且选自氢和卤原子以及烷基，条件是在一些实施方案中，每个R’”的烷基具有1-3个碳原子；并且其中所述分子可以反应产生中间体，其中每个R”被交换为H，或者，其中Z是–(R’)2-F，F被交换为OH、SH或NH2，优选OH，该中间体在水性条件下解离得到具有游离3’-OH的分子；条件是其中Z是–C(R’)2-S-R”，两个R’基团都不是H。在某些实施方案中，经修饰的核苷酸或核苷的R’是烷基或取代的烷基，条件是此类烷基或取代的烷基具有1至10个碳原子和0至4个氧或氮杂原子。在某些实施方案中，经修饰的核苷酸或核苷的-Z具有式–C(R’)2-N3。在某些实施方案中，Z是叠氮基甲基。
在一些实施方案中，Z是具有或不具有分子量为200或更小的杂原子的可切割有机部分。在其他实施方案中，Z是具有或不具有分子量为100或更小的杂原子的可切割有机部分。在其他实施方案中，Z是具有或不具有分子量为50或更小的杂原子的可切割有机部分。在一些实施方案中，Z是具有或不具有分子量为200或更小的杂原子的酶促可切割的有机部分。在其他实施方案中，Z是具有或不具有分子量为100或更小的杂原子的酶促可切割的有机部分。在其他实施方案中，Z是具有或不具有分子量为50或更小的杂原子的酶促可切割的有机部分。在其他实施方案中，Z是分子量为200或更小的酶促可切割的酯基。在其他实施方案中，Z是可被3’-磷酸酶去除的磷酸酯基团。在一些实施方案中，以下3’-磷酸酶中的一种或多种可以与制造商推荐的方案一起使用：T4多核苷酸激酶、小牛肠碱性磷酸酶、重组虾碱性磷酸酶(例如可从New England Biolabs，Beverly，MA获得)。
在其他实施方案中，3’-封闭的三磷酸核苷酸被3’-O-叠氮基甲基、3’-O-NH2或3’-O-烯丙基封闭。在其他实施方案中，本发明的3’-O-封闭基团包括3’-O-甲基、3’-O-(2-硝基苄基)、3’-O-烯丙基、3’-O-胺、3’-O-叠氮基甲基、3’-O-叔丁氧乙氧基、3’-O-(2-氰乙基)、3’-O-硝基和3’-O-炔丙基。在其他实施方案中，3’-封闭的三磷酸核苷酸被3’-O-叠氮基甲基或3’-O-NH2封闭。此类3’封闭的三磷酸核苷的合成和使用在以下参考文献中被公开：美国专利9410197；8808988；6664097；5744595；7544794；8034923；8212020；10472383；Guo等人，Proc.Natl.Acad.Sci.,105(27):9145-9150(2008)；以及类似参考文献。
在一些实施方案中，3’-O-保护基团是电化学不稳定的基团。即，保护基团的去保护或可切割是通过改变导致可切割的保护基团附近的电化学条件来完成的。电化学条件的此类变化可以通过改变或施加物理量(如电压差或光)来引起以激活辅助物质，这反过来会导致保护基团位置处电化学条件的变化(如pH升高或降低)。在一些实施方案中，电化学不稳定基团包括例如pH敏感保护基团，其在pH变化至预定值时被切割。在其他实施方案中，电化学不稳定的基团包括保护基团，当还原或氧化条件改变时，例如通过增加或减少保护基团位置处的电压差，其直接被切割。
变体TDT的产生
本发明的变体可以通过突变已知的参考或野生型TdT编码多核苷酸，然后使用常规分子生物学技术表达它来产生。例如，编码具有所期望序列的多肽的所期望基因或DNA片段可以使用常规分子生物学技术从合成片段组装，例如使用Stemmer等人，Gene,164:49-53(1995)；Kodumal等人，Proc.Natl.Acad.Sci.,101:15573-15578(2004)等描述的方案；或者此类基因或DNA片段可以使用常规方案从选定物种的细胞中直接克隆，例如由Boule等人，Mol.Biotechnology,10:199-208(1998),或Bentolila等人，EMBO J.,14:4221-4229(1995)等描述的。
可将编码所期望TdT变体的分离基因插入表达载体(如pET32(Novagen))中，以产生表达载体，然后可以使用常规方案将其用于制备和表达变体TdT蛋白。具有正确序列的载体可以被转化到大肠杆菌(E.coli)生产菌株中。
使用常规技术将转化的菌株培养成细胞团，从中提取TdT蛋白。例如，将先前制备的细胞团在30-37℃的水浴中解冻。一旦完全解冻后，将细胞团重新悬浮在由50mM tris-HCL(Sigma)pH 7.5、150mM NaCl(Sigma)、0.5mM巯基乙醇(Sigma)、5％甘油(Sigma)、20mM咪唑(Sigma)和1片的100mL蛋白酶混合物抑制剂(Thermofisher)组成的裂解缓冲液中。进行仔细的再悬浮，以避免过早裂解和残留聚集体。将重悬的细胞通过几个循环的弗氏压碎器裂解，直到获得全色均一性。通常使用的压力是14,000psi。然后以10,000rpm的速度将裂解物离心1h-1h30。将离心液通过0.2μm过滤器以在柱纯化前去除任何碎屑。
可以在一步亲和程序中从离心液中纯化TdT蛋白。例如，Ni-NTA亲和柱(GEHealthcare)可以被用于结合TdT聚合酶。最初，用15倍柱体积的50mM tris-HCL(Sigma)pH7.5、150mM NaCl(Sigma)和20mM咪唑(Sigma)洗涤和平衡柱。TdT聚合酶在平衡后与柱结合；然后，例如由50mM tris-HCL(Sigma)pH 7.5、500mM NaCl(Sigma)和20mM咪唑(Sigma)组成的洗涤缓冲液可以以15倍柱体积应用于柱。在此类洗涤之后，用50mM tris-HCL(Sigma)pH7.5、500mM NaCl(Sigma)和0.5M咪唑(Sigma)洗脱TdT聚合酶。收集与最高浓度的目标TdT聚合酶相对应的级分并在单个样品中合并。用透析缓冲液(20mM Tris-HCl,pH 6.8、200mMNaCl、50mM MgOAc、100mM[NH4]2SO4)对合并的级分进行透析。随后在浓缩过滤器(AmiconUltra-30,Merk Millipore)的帮助下浓缩透析液。将浓缩的酶以小等分试样分配，加入50％最终甘油，然后将这些等分试样在-20℃冷冻并长期储存。在SDSPAGE凝胶中分析5μL不同纯化酶级分。
在一些实施方案中，TdT变体可以可操作地连接至包括共价或非共价键的连接子部分；氨基酸标签(例如，聚氨基酸标签、聚His标签、6His标签等)；化合物(例如聚乙二醇)；蛋白质-蛋白质结合对(例如，生物素-亲和素)；亲和偶联；捕获探针；或这些的任何组合。连接子部分可以与TdT变体分开或作为TdT变体的一部分。与本发明的TdT变体一起使用的示例性His标签是MASSHHHHHHSSGSENLYFQTGSSG-(SEQ ID NO:54))。标签-连接子部分不干扰TdT变体的核苷酸结合活性或催化活性。
上述过程或等效过程产生可与多种试剂混合的分离的TdT变体，所述试剂为诸如盐、pH缓冲剂、载体化合物等，它们对于活性和/或保存是必需的或有用的。
用于实施本发明方法的试剂盒
本发明包括用于实施本发明方法的多种试剂盒。在一方面，本发明的试剂盒在适合进行本文所述的无模板酶促多核苷酸合成的制剂中包含本发明的TdT变体。此类试剂盒还可以包括合成缓冲液，其为优化无模板添加或将3’-O-经保护的dNTP掺入生长链提供反应条件。在一些实施方案中，本发明的试剂盒还包括3’-O-可逆保护的dNTP。在此类实施方案中，3’-O-可逆保护的dNTP可以包含3’-O-氨基-dNTP或3’-O-叠氮基甲基-dNTP。在其他实施方案中，试剂盒可以单独或与上述项目一起包括以下项目中的一项或多项：(i)用于进行如本文所述的去保护步骤的去保护试剂，(ii)具有连接其上的起始子的固体支持物，(iii)用于从固体支持物上释放完整多核苷酸的切割试剂，(iv)用于在酶促添加或偶联步骤结束时去除未反应的3’-O-经保护的dNTP的洗涤试剂或缓冲液，和(v)合成后处理试剂，如纯化柱、脱盐试剂、洗脱试剂等。在一些实施方案中，本发明的试剂盒可以包括用于在单次操作中进行多个合成反应的反应孔阵列。在一些实施方案中，此类阵列可以是包含24、48、96、384或1536个孔的常规滤板。
关于上述项目(ii)和(iii)，某些起始子和切割试剂一起使用。例如，包含肌苷可切割核苷酸的起始子可以与核酸内切酶V切割试剂一起提供；包含硝基苄基光可切割连接子的起始子可以与用于切割光可切割连接子的合适光源一起提供；包含尿嘧啶的起始子可以与尿嘧啶DNA糖基化酶切割试剂一起提供等。
实施例1
测试TDT变体的掺入活性
表5中所列出的TDT变体使用常规技术来制备、纯化并在如上所述的两个单独的发夹测定中使用3’-O-氨基-2’-三磷酸脱氧核苷单体进行测试。将它们在测定中的性能与已知具有高掺入率的小鼠-牛嵌合TdT(被命名为M57，SEQ ID NO:55)的性能进行比较。
表5
从数据可以看出，许多TdT变体具有比标准M57大得多的偶联效率。反应在低浓度的3’-封端的dNTP(20μM)存在下进行，因此增加主要归因于对特定dNTP的更好的亲和力。表达水平对应于从Ni-NTA(总共300μL，来自50ml培养物)洗脱后的蛋白质浓度。
定义
氨基酸由根据以下命名法的它们的单字母或三字母代码表示：A：丙氨酸(Ala)；C：半胱氨酸(Cys)；D：天冬氨酸(Asp)；E：谷氨酸(Glu)；F：苯丙氨酸(Phe)；G：甘氨酸(Gly)；H：组氨酸(His)；I：异亮氨酸(Ile)；K：赖氨酸(Lys)；L：亮氨酸(Leu)；M：甲硫氨酸(Met)；N：天冬酰胺(Asn)；P：脯氨酸(Pro)；Q：谷氨酰胺(Gln)；R：精氨酸(Arg)；S：丝氨酸(Ser)；T：苏氨酸(Thr)；V：缬氨酸(Val)；W：色氨酸(Trp)和Y：酪氨酸(Tyr)。
关于取代残基的“功能上等同的”是指变体TdT的取代残基与具有与SEQ ID NO:1同源的序列的另一TdT的序列中的残基具有相同的功能作用。功能上等同的残基可以通过使用序列比对来鉴定，例如，使用Mutalin线比对软件(http://multalin.toulouse.inra.fr/MultAlin/multalin.html；1988年，Nucl.Acids Res.,16(22),25 10881-10890)。在比对后，功能上等同的残基位于所考虑的不同序列上的同源位置。可以在任何TdT和它们的天然变体(包括物种间变体)之间确定序列比对和功能等同残基的鉴定。
关于蛋白质的“分离的”是指此类化合物，其已经从其天然环境的组分或从非均相反应混合物中鉴定和分离和/或回收。天然环境或反应混合物的污染物组分是会干扰蛋白质功能的物质，并且可以包括酶、激素和其它蛋白质或非蛋白质溶质。在一些实施方案中，如通过Lowry方法所确定的，将本发明的蛋白质纯化至(1)大于95重量％的蛋白质，并且最优选大于99重量％，(2)通过使用旋转杯测序仪足以获得N-末端或内部氨基酸序列的至少15个残基的程度，或(3)通过SDS-PAGE在还原或非还原条件下使用考马斯蓝或优选地银染色的同质性。当通过重组方法制备时，本发明的分离的蛋白质可以包括在重组细胞内的原位本发明的蛋白质，因为蛋白质的天然环境的至少一个组分将不存在。通常，通过至少一个纯化步骤制备本发明的分离的蛋白质。
“试剂盒”是指用于递送用于实施本发明方法的材料或试剂的任何递送系统。在反应测定的上下文中，此类递送系统包括允许存储、运输或递送反应试剂(例如，在适当容器中的一种或多种TdT变体、反应缓冲液、3’-O-保护的-dNTP、去保护试剂、连接有起始子的固体支持物等)和/或支持材料(例如，在适当容器中)的系统和/或化合物(例如稀释剂、表面活性剂、载体等)和/或从一个位置到另一个位置的支持材料(例如缓冲液，用于进行测定的书面说明等))。例如，试剂盒包括含有相关反应试剂和/或支持材料的一个或多个外壳(例如，盒子)。此类内容物可以一起或分开递送到预期的接受者。例如，第一容器可以包含用于合成方法的一种或多种TdT变体，而第二或另外的容器可以包含去保护剂，具有起始子的固体支持物、3’-O-经保护的dNTP等。
可互换使用的“突变体”或“变体”是指来源于本文所述的天然或参考TdT多肽的多肽，并且包含在一个或多个位置处的修饰或改变，即取代、插入和/或缺失。变体可以通过本领域熟知的各种技术获得。具体地，用于改变编码野生型蛋白质的DNA序列的技术的实例包括但不限于定点诱变、随机诱变、序列改组和合成寡核苷酸构建。诱变活性在于缺失、插入或取代蛋白质序列中的一个或几个氨基酸，或者在本发明的聚合酶的情况下缺失、插入或取代一个或几个氨基酸。以下术语被用于指定取代：L238A表示参考或野生型序列的第238位氨基酸残基(亮氨酸，L)改变为丙氨酸(A)。A132V/I/M表示亲本序列第132位的氨基酸残基(丙氨酸，A)被下列氨基酸之一取代：缬氨酸(V)、异亮氨酸(I)或甲硫氨酸(M)。取代可以是保守性或非保守性取代。保守性取代的实例属于以下组；碱性氨基酸(精氨酸、赖氨酸和组氨酸)、酸性氨基酸(谷氨酸和天冬氨酸)、极性氨基酸(谷氨酰胺、天冬酰胺和苏氨酸)、疏水性氨基酸(甲硫氨酸、亮氨酸、异亮氨酸、半胱氨酸和缬氨酸)、芳香族氨基酸(苯丙氨酸、色氨酸和酪氨酸)和小氨基酸(甘氨酸、丙氨酸和丝氨酸)。
“序列同一性”是指两个序列(如两个多肽序列或两个多核苷酸序列)之间的匹配(例如，相同的氨基酸残基)的数目(或分数，通常被表示为百分比)。通过比较比对时的序列来确定序列同一性，以便在最小化序列间隙的同时最大化重叠和同一性。具体地，序列同一性可以使用许多数学全局或局部比对算法中的任何一种来确定，这取决于两个序列的长度。相似长度的序列优选使用在整个长度上最优地比对序列的全局比对算法(例如Needleman和Wunsch算法；Needleman和Wunsch，1970)进行比对，而基本上不同长度的序列优选地使用局部比对算法(例如Smith和Waterman算法(Smith和Waterman，1981)或Altschul算法(Altschul等人，1997；Altschul等人，2005))进行比对。用于确定氨基酸序列同一性百分比的比对可以以本领域技术人员所熟知的各种方式实现，例如，使用可在互联网网站上获得的公开可获得的计算机软件，如http://blast.ncbi.nlm.nih.gov/或ttp://www.ebi.ac.uk/tools/emboss/。本领域技术人员可以确定用于测量比对的适当参数，其包括在所比较的序列的整个长度上实现最大比对所需的任何算法。出于本文的目的，氨基酸序列同一性％值是指使用成对序列比对程序EMBOSS Needle产生的值，其使用Needleman-Wunsch算法创建两个序列的最佳全局比对，其中所有搜索参数被设置为默认值，即，评分矩阵＝BLOSUM62，缺口开放(Gap open)＝10，缺口延伸(Gap extend)＝0.5，末端缺口罚分＝假，末端缺口开放＝10和末端缺口延伸＝0.5。
“多核苷酸”或“寡核苷酸”可互换使用，并且每个意指核苷酸单体或其类似物的线性聚合物。组成多核苷酸和寡核苷酸的单体能够通过单体与单体相互作用的规则模式的方式与天然多核苷酸特异性结合，如Watson-Crick类型的碱基配对、碱基堆叠、Hoogsteen或反向Hoogsteen类型的碱基配对等。此类单体及其核苷间连接可以是天然存在的或可以是其类似物(例如天然存在的或非天然存在的类似物)。非天然存在的类似物可以包括PNA、硫代磷酸酯核苷间连接、含有允许连接标记(如荧光团)或半抗原的连接基团的碱基等。每当寡核苷酸或多核苷酸的使用需要酶促加工(诸如通过聚合酶延伸、通过连接酶连接等时)，普通技术人员将理解在那些情况下寡核苷酸或多核苷酸将不包含核苷间连接的某些类似物、糖部分或任何或一些位置处的碱基。多核苷酸的大小范围通常从几个单体单元开始(例如5-40个，此时它们通常被称为“寡核苷酸”)至几千个单体单元。每当多核苷酸或寡核苷酸通过字母序列(大写或小写，如“ATGCCTG”)表示时，应理解核苷酸从左到右按5’→3’顺序排列，并且“A”表示脱氧腺苷，“C”表示脱氧胞苷，“G”表示脱氧鸟苷，并且“T”表示胸苷，“I”表示脱氧肌苷，“U”表示尿苷，除非另有指示或从上下文中显而易见。除非另有说明，否则术语和原子编号约定将遵循Strachan和Read,Human Molecular Genetics 2(Wiley-Liss，纽约，1999)中所公开的那些。通常多核苷酸包含通过磷酸二酯键连接的四种天然核苷(例如对于DNA的脱氧腺苷、脱氧胞苷、脱氧鸟苷、脱氧胸苷，或对于RNA的它们的核糖对应物)；然而，它们也可以包含非天然核苷酸类似物(例如包括经修饰的碱基、糖或核苷间连接)。本领域技术人员清楚，酶对活性具有特定的寡核苷酸或多核苷酸底物要求(例如单链DNA、RNA/DNA双链体等)，则为寡核苷酸或多核苷酸底物选择合适的组成完全在普通技术人员的知识范围内，尤其是在论文(如Sambrook等人，Molecular Cloning，第2版(Cold Spring HarborLaboratory，纽约，1989))和类似参考资料的指导下。同样，寡核苷酸和多核苷酸可以指单链形式或双链形式(即寡核苷酸或多核苷酸及其相应互补物的双链体)。普通技术人员从术语使用的上下文中将清楚，旨在哪种形式或哪两种形式。
“引物”意指寡核苷酸，无论是天然的还是合成的，其在与多核苷酸模板形成双链体后，能够充当核酸合成的起始点并从其3’端沿模板延伸，使得形成延伸的双链体。引物的延伸通常用核酸聚合酶(如DNA或RNA聚合酶)进行。延伸过程中添加的核苷酸序列由模板多核苷酸的序列决定。通常引物由DNA聚合酶延伸。引物的长度通常在14至40个核苷酸的范围内，或在18至36个核苷酸的范围内。引物被用于多种核酸扩增反应，例如，使用单一引物的线性扩增反应，或采用两种或更多种引物的聚合酶链式反应。选择用于特定应用的引物长度和序列的指导对于本领域普通技术人员来说是众所周知的，如通过引用并入本文中的以下参考文献所证明的那样：Dieffenbach，编辑，PCR引物：实验室手册(PCR Primer:ALaboratory Manual)，第2版(Cold Spring Harbor Press，纽约，2003)。
“取代”意指一个氨基酸残基被另一个氨基酸残基代替。优选地，术语“取代”是指用选自以下的另一氨基酸代替一个氨基酸残基：天然存在的标准20种氨基酸残基、稀有天然存在的氨基酸残基(例如羟脯氨酸、羟赖氨酸、别羟基赖氨酸、6-N-甲基赖氨酸、N-乙基甘氨酸、N-甲基甘氨酸、N-乙基天冬酰胺、别异亮氨酸、N-甲基异亮氨酸、N-甲基缬氨酸、焦谷氨酰胺、氨基丁酸、鸟氨酸、正亮氨酸、正缬氨酸)和非天然存在的氨基酸残基，通常是合成的(例如环己基丙氨酸)。优选地，术语“取代”是指氨基酸残基被选自天然存在的标准20种氨基酸残基的另一氨基酸残基代替。符号“+”表示取代的组合。
本公开不旨在限制于所阐述的特定形式的范围，而是旨在涵盖本文描述的变化的可替代物、修改和等同物。此外，本公开的范围完全涵盖鉴于本公开对于本领域技术人员而言可能变得显而易见的其他变化。本发明的范围仅受所附权利要求的限制。
序列表
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Asn Glu Leu Ser Asp Ser Val Thr His Ile Val Ala Glu Asn Asn Ser
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Gly Ser Asp Val Leu Glu Trp Leu Gln Leu Gln Asn Ile Lys Ala Ser
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Ser Glu Leu Glu Leu Leu Asp Ile Ser Trp Leu Ile Glu Cys Met Gly
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Ala Gly Lys Pro Val Glu Met Met Gly Arg His Gln Leu Val Val Asn
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Arg Asn Ser Ser Pro Ser Pro Val Pro Gly Ser Gln Asn Val Pro Ala
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Pro Ala Val Lys Lys Ile Ser Gln Tyr Ala Cys Gln Arg Arg Thr Thr
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Leu Asn Asn Tyr Asn Gln Leu Phe Thr Asp Ala Leu Asp Ile Leu Ala
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Glu Asn Asp Glu Leu Arg Glu Asn Glu Gly Ser Cys Leu Ala Phe Met
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Arg Ala Ser Ser Val Leu Lys Ser Leu Pro Phe Pro Ile Thr Ser Met
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Lys Asp Thr Glu Gly Ile Pro Cys Leu Gly Asp Lys Val Lys Ser Ile
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Ile Glu Gly Ile Ile Glu Asp Gly Glu Ser Ser Glu Ala Lys Ala Val
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Leu Asn Asp Glu Arg Tyr Lys Ser Phe Lys Leu Phe Thr Ser Val Phe
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Gly Val Gly Leu Lys Thr Ala Glu Lys Trp Phe Arg Met Gly Phe Arg
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Thr Leu Ser Lys Ile Gln Ser Asp Lys Ser Leu Arg Phe Thr Gln Met
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Gln Lys Ala Gly Phe Leu Tyr Tyr Glu Asp Leu Val Ser Cys Val Asn
290 295 300
Arg Pro Glu Ala Glu Ala Val Ser Met Leu Val Lys Glu Ala Val Val
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Thr Phe Leu Pro Asp Ala Leu Val Thr Met Thr Gly Gly Phe Arg Arg
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Gly Lys Met Thr Gly His Asp Val Asp Phe Leu Ile Thr Ser Pro Glu
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Ala Thr Glu Asp Glu Glu Gln Gln Leu Leu His Lys Val Thr Asp Phe
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Trp Lys Gln Gln Gly Leu Leu Leu Tyr Cys Asp Ile Leu Glu Ser Thr
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Thr Lys Val Ser Gln Tyr Ser Cys Gln Arg Lys Thr Thr Leu Asn Asn
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Tyr Asn Lys Lys Phe Thr Asp Ala Phe Glu Val Met Ala Glu Asn Tyr
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Glu Phe Lys Glu Asn Glu Ile Phe Cys Leu Glu Phe Leu Arg Ala Ala
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Ser Leu Leu Lys Ser Leu Pro Phe Ser Val Thr Arg Met Lys Asp Ile
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Gln Gly Leu Pro Cys Met Gly Asp Gln Val Arg Asp Val Ile Glu Ile
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Ile Glu Glu Gly Glu Ser Ser Arg Val Lys Glu Val Leu Asn Asp Glu
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Arg Tyr Lys Ala Phe Lys Gln Phe Thr Ser Val Phe Gly Val Gly Val
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Val Lys Ala Asp Lys Thr Leu Lys Leu Ser Lys Met Gln Lys Ala Gly
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Phe Leu Tyr Tyr Glu Asp Leu Val Ser Cys Val Ser Lys Ala Glu Ala
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Asp Ala Leu Val Thr Ile Thr Gly Gly Phe Arg Arg Gly Lys Asn Ile
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Leu Leu Tyr Cys Asp Ile Ile Glu Ser Thr Phe Val Lys Glu Gln Leu
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Ile Ile Glu Glu Gly Glu Ser Ser Arg Val Lys Glu Val Leu Asn Asp
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Glu Arg Tyr Lys Ala Phe Lys Gln Phe Thr Ser Val Phe Gly Val Gly
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Arg Lys Thr Ser Glu Lys Trp Tyr Arg Met Gly Leu Arg Thr Val Glu
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Gly Phe Leu Tyr Tyr Glu Asp Leu Val Ser Arg Val Ser Lys Ala Glu
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Ala His Leu Gly Leu Asp Tyr Val Glu Pro Trp Glu Arg Asn Ala
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Ala Phe Glu Val Met Ala Glu Asn Tyr Glu Phe Lys Glu Asn Glu Glu
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Phe Pro Val Thr Arg Met Lys Asp Ile Gln Gly Leu Pro Cys Met Gly
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Asp Gln Val Arg Arg Ile Ile Glu Glu Ile Ile Glu Glu Gly Glu Ser
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Ser Arg Val Lys Glu Val Leu Asn Asp Glu Arg Tyr Lys Ala Phe Lys
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Gln Phe Thr Ser Val Phe Gly Val Gly Arg Lys Thr Ser Glu Lys Trp
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Tyr Arg Met Gly Leu Arg Thr Val Glu Glu Val Lys Ala Asp Lys Thr
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Leu Lys Leu Ser Lys Met Gln Lys Ala Gly Phe Leu Tyr Tyr Glu Asp
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Leu Val Ser Arg Val Ser Lys Ala Glu Ala Asp Ala Val Ser Leu Ile
195 200 205
Val Lys Asn Thr Val Val Thr Phe Leu Pro Asp Ala Leu Val Thr Ile
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Thr Gly Gly Phe Arg Leu Gly Lys Lys Ile Gly His Asp Ile Asp Phe
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Leu Ile Thr Asn Pro Gly Pro Arg Glu Asp Glu Glu Leu Leu His Lys
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Val Ile Asp Leu Trp Lys Lys Gln Gly Leu Leu Leu Tyr Cys Asp Ile
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Ile Glu Ser Thr Phe Val Lys Glu Gln Leu Pro Ser Arg Lys Val Asp
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Ala Met Asp His Phe Gln Lys Cys Phe Ala Ile Leu Lys Leu Tyr Gln
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Pro Arg Val Asp Asn Ser Thr Ser Asn Thr Ser Lys Lys Leu Glu Met
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Pro Phe Glu Gln Tyr Ala Tyr Ala Leu Leu Gly Trp Thr Gly Ser Ala
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Phe Phe Asn Arg Asp Leu Arg Arg Tyr Ala Ser His Glu Arg Lys Met
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Val Glu Pro Trp Glu Arg Asn Ala
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Phe Ile Ala Arg Lys Val Ser Gln Tyr Ser Cys Gln Arg Lys Thr Thr
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Gly Val Gly Val Lys Thr Ser Glu Lys Trp Tyr Arg Met Gly Leu Arg
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Thr Phe Leu Pro Asp Ala Leu Val Thr Ile Thr Gly Gly Phe Arg Arg
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Lys Gln Gly Leu Leu Leu Tyr Cys Asp Ile Ile Glu Ser Thr Phe Val
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Glu Glu Gln Leu Pro Ser Arg Lys Val Asp Ala Met Asp Asn Phe Gln
245 250 255
Lys Cys Phe Thr Ile Leu Lys Leu Tyr Gln Pro Gly Val Asp Asn Ser
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Ser Tyr Asn Met Ser Lys Lys Ser Asp Met Ala Glu Val Lys Asp Trp
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Lys Ala Ile Arg Val Asp Leu Val Ile Thr Pro Phe Glu Gln Tyr Ala
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Tyr Ala Leu Leu Gly Trp Thr Gly Ser Arg Glu Phe Gly Arg Asp Leu
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Arg Arg Tyr Ala Ser His Glu Arg Lys Met Ile Leu Asp Asn His Gly
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Leu Tyr Asp Arg Arg Lys Arg Ile Phe Leu Lys Ala Gly Ser Glu Glu
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Glu Ile Phe Ala His Leu Gly Leu Asp Tyr Val Glu Pro Trp Glu Arg
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Asn Ala
370
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Ser Ser Val Ser Lys Val Ser Gln Tyr Ser Cys Gln Arg Lys Thr Thr
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Glu Asn Tyr Glu Phe Lys Glu Asn Glu Ile Phe Cys Leu Glu Phe Arg
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Lys Asp Ile Gln Gly Leu Pro Cys Met Gly Asp Arg Val Arg Asp Val
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Ile Glu Glu Ile Ile Glu Glu Gly Glu Ser Ser Arg Val Lys Glu Val
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Leu Asn Asp Glu Arg Tyr Lys Ala Phe Lys Gln Phe Thr Ser Val Phe
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Gly Val Gly Arg Lys Thr Ser Glu Lys Trp Tyr Arg Met Gly Leu Arg
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Thr Leu Glu Glu Val Lys Ala Asp Lys Thr Leu Lys Leu Ser Lys Met
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Gln Lys Ala Gly Phe Leu Tyr Tyr Glu Asp Leu Ala Glu Arg Val Ser
145 150 155 160
Lys Ala Glu Ala Asp Ala Val Ser Leu Ile Val Lys Asn Thr Val Val
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Thr Phe Leu Pro Asp Ala Leu Val Thr Ile Thr Gly Gly Phe Arg Leu
180 185 190
Gly Lys Lys Ile Gly His Asp Ile Asp Phe Leu Ile Thr Asn Pro Gly
195 200 205
Pro Arg Glu Asp Glu Glu Leu Leu His Lys Val Val Asp Leu Trp Lys
210 215 220
Lys Gln Gly Leu Leu Leu Tyr Cys Asp Ile Ile Glu Ser Thr Phe Val
225 230 235 240
Lys Glu Gln Leu Pro Ser Arg Lys Val Asp Ala Met Asp Asn Phe Gln
245 250 255
Lys Cys Phe Ala Ile Leu Lys Leu Tyr Gln Pro Arg Val Asp Asn Ser
260 265 270
Ser Tyr Asn Thr Ser Lys Lys Phe Asp Met Ala Glu Val Lys Asp Trp
275 280 285
Lys Ala Ile Arg Val Asp Leu Val Ile Thr Pro Phe Glu Gln Tyr Ala
290 295 300
Tyr Ala Leu Leu Gly Trp Thr Gly Ser Pro Gln Phe Asn Arg Asp Leu
305 310 315 320
Arg Arg Tyr Ala Thr His Glu Arg Lys Met Ile Leu Asp Asn His Ala
325 330 335
Leu Tyr Asp Arg Arg Lys Arg Ile Phe Leu Lys Ala Gly Ser Glu Glu
340 345 350
Glu Ile Phe Ala His Leu Gly Leu Asp Tyr Val Glu Pro Arg Glu Arg
355 360 365
Asn Ala
370
<210> 7
<211> 395
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> B19
<400> 7
Met Ala Ser Ser His His His His His His Ser Ser Gly Ser Glu Asn
1 5 10 15
Leu Tyr Phe Gln Thr Gly Ser Ser Gly Ser Ser Val Ser Lys Val Ser
20 25 30
Gln Tyr Ser Cys Gln Arg Lys Thr Thr Leu Asn Asn Tyr Asn Lys Lys
35 40 45
Phe Thr Asp Ala Phe Glu Ile Met Ala Glu Asn Tyr Glu Phe Lys Glu
50 55 60
Asn Glu Ile Phe Cys Leu Glu Phe Arg Arg Ala Ala Ser Val Leu Lys
65 70 75 80
Phe Leu Pro Phe Pro Val Thr Arg Met Lys Asp Ile Gln Gly Leu Pro
85 90 95
Cys Met Gly Asp Arg Val Arg Asp Val Ile Glu Glu Ile Ile Glu Glu
100 105 110
Gly Glu Ser Ser Arg Val Lys Glu Val Leu Asn Asp Glu Arg Tyr Lys
115 120 125
Ala Phe Lys Gln Phe Thr Ser Val Phe Gly Val Gly Arg Lys Thr Ser
130 135 140
Glu Lys Trp Tyr Arg Met Gly Leu Arg Thr Leu Glu Glu Val Lys Ala
145 150 155 160
Asp Lys Thr Leu Lys Leu Ser Lys Met Gln Lys Ala Gly Phe Leu Tyr
165 170 175
Tyr Glu Asp Leu Ala Glu Arg Val Ser Lys Ala Glu Ala Asp Ala Val
180 185 190
Ser Leu Ile Val Lys Asn Thr Val Val Thr Phe Leu Pro Asp Ala Leu
195 200 205
Val Thr Ile Thr Gly Gly Phe Arg Leu Gly Lys Lys Ile Gly His Asp
210 215 220
Ile Asp Phe Leu Ile Thr Asn Pro Gly Pro Arg Glu Asp Glu Glu Leu
225 230 235 240
Leu His Lys Val Val Asp Leu Trp Lys Lys Gln Gly Leu Leu Leu Tyr
245 250 255
Cys Asp Ile Ile Glu Ser Thr Phe Val Lys Glu Gln Leu Pro Ser Arg
260 265 270
Lys Val Asp Ala Met Asp Asn Phe Gln Lys Cys Phe Ala Ile Leu Lys
275 280 285
Leu Tyr Gln Pro Arg Val Asp Asn Ser Ser Tyr Asn Thr Ser Lys Lys
290 295 300
Phe Asp Met Ala Glu Val Lys Asp Trp Lys Ala Ile Arg Val Asp Leu
305 310 315 320
Val Ile Thr Pro Phe Glu Gln Tyr Ala Tyr Ala Leu Leu Gly Trp Thr
325 330 335
Gly Ser Pro Gln Phe Asn Arg Asp Leu Arg Arg Tyr Ala Thr His Glu
340 345 350
Arg Lys Met Ile Leu Asp Asn His Ala Leu Tyr Asp Arg Arg Lys Arg
355 360 365
Ile Phe Leu Lys Ala Gly Ser Glu Glu Glu Ile Phe Ala His Leu Gly
370 375 380
Leu Asp Tyr Val Glu Pro Arg Glu Arg Asn Ala
385 390 395
<210> 8
<211> 383
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> B57截短的野生型(扬子鳄)
<400> 8
Ser Pro Ser Pro Val Pro Gly Ser Gln Asn Val Pro Ala Pro Ser Val
1 5 10 15
Asp Lys Val Ser Gln Tyr Ala Cys Gln Arg Arg Thr Thr Leu Asn Asn
20 25 30
Tyr Asn Lys Lys Phe Thr Asp Ala Phe Glu Ile Leu Ala Glu Asn Cys
35 40 45
Glu Phe Arg Glu Asn Arg Leu Gly Cys Leu Glu Phe Leu Arg Ala Ala
50 55 60
Ser Val Leu Lys Phe Leu Pro Phe Pro Ile Val Lys Met Lys Asn Ile
65 70 75 80
Glu Gly Leu Pro Cys Met Gly Asp Lys Val Lys Cys Val Ile Glu Glu
85 90 95
Ile Leu Glu Glu Gly Glu Ser Cys Gln Ala Lys Glu Ile Leu Asn Asp
100 105 110
Glu Arg Tyr Lys Ser Phe Lys Leu Phe Thr Ser Val Phe Gly Val Gly
115 120 125
Leu Lys Thr Thr Glu Lys Trp Tyr Arg Met Gly Phe Arg Thr Leu Glu
130 135 140
Glu Val Lys Ala Glu Lys Thr Leu Lys Leu Ser Arg Met Gln Ile Ala
145 150 155 160
Gly Phe Leu His Tyr Glu Asp Ile Ile Ser Tyr Val Ser Lys Ala Glu
165 170 175
Ala Asp Ala Val Ser Leu Leu Ile Lys Asp Thr Val Cys Met Phe Leu
180 185 190
Pro Asp Ala Leu Val Thr Ile Thr Gly Gly Phe Arg Arg Gly Lys Lys
195 200 205
Thr Gly His Asp Val Asp Phe Leu Ile Thr Asn Pro Gly Pro Glu Glu
210 215 220
Glu Lys Glu Leu Leu His Lys Val Val Asp Leu Trp Glu Lys Gln Gly
225 230 235 240
Leu Leu Leu Tyr Tyr Asp Val Ile Glu Ser Thr Phe Glu Lys Glu Lys
245 250 255
Arg Pro Ser Arg Lys Val Asp Ala Leu Asp His Phe Gln Lys Cys Phe
260 265 270
Ala Ile Leu Lys Leu His Gln Gln Arg Arg Gly Asn Ser Asn Ser Asn
275 280 285
Ile Ser Lys Glu Ser Asp Lys Ala Glu Val Lys Asp Trp Lys Ala Ile
290 295 300
Arg Val Asp Leu Val Ile Ser Pro Phe Glu Gln Tyr Ala Tyr Ala Leu
305 310 315 320
Leu Gly Trp Thr Gly Ser Arg Gln Phe Glu Arg Asp Leu Arg Arg Tyr
325 330 335
Ala Ser Arg Glu Arg Lys Met Met Leu Asp Asn His Ala Leu Tyr Asp
340 345 350
Lys Thr Lys Arg Thr Phe Leu Lys Ala Glu Ser Glu Glu Glu Ile Phe
355 360 365
Ala His Leu Gly Leu Asp Tyr Ile Glu Pro Trp Glu Arg Asn Ala
370 375 380
<210> 9
<211> 383
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> B57截短的新的
<400> 9
Ser Pro Ser Pro Val Pro Gly Ser Gln Asn Val Pro Ala Pro Ser Val
1 5 10 15
Asp Lys Ile Ser Gln Tyr Ala Cys Gln Arg Arg Thr Thr Leu Asn Asn
20 25 30
Tyr Asn Lys Lys Phe Thr Asp Ala Phe Glu Ile Leu Ala Glu Asn Tyr
35 40 45
Glu Phe Asn Glu Asn Lys Gly Phe Cys Leu Ala Phe Arg Arg Ala Ala
50 55 60
Ser Val Leu Lys Phe Leu Pro Phe Thr Ile Val Arg Met Asn Asp Ile
65 70 75 80
Gln Gly Leu Pro Trp Met Gly Asp Gln Val Lys Arg Val Ile Glu Glu
85 90 95
Ile Leu Glu Glu Gly Glu Ser Ser Lys Val Lys Glu Val Leu Asn Asp
100 105 110
Glu Lys Tyr Lys Ala Phe Lys Leu Phe Thr Ser Val Phe Gly Val Gly
115 120 125
Arg Lys Thr Ser Glu Lys Trp Tyr Arg Met Gly Leu Arg Thr Leu Glu
130 135 140
Glu Val Lys Ala Asp Lys Thr Leu Lys Leu Thr Lys Met Gln Lys Ala
145 150 155 160
Gly Phe Leu Tyr Tyr Glu Asp Leu Ile Ser Arg Val Ser Lys Ala Glu
165 170 175
Ala Asp Ala Val Ser Leu Ile Val Lys Asp Thr Val Trp Lys Phe Leu
180 185 190
Pro Asp Ala Leu Val Thr Leu Thr Gly Gly Phe Arg Leu Gly Lys Lys
195 200 205
Met Gly His Asp Val Asp Phe Leu Ile Thr Thr Pro Gly Pro Glu Glu
210 215 220
Glu Glu Glu Leu Leu His Lys Val Ile Asp Leu Trp Lys Lys Gln Gly
225 230 235 240
Leu Leu Leu Tyr Tyr Asp Ile Ile Glu Ser Thr Phe Glu Lys Thr Lys
245 250 255
Leu Pro Ser Arg Thr Val Asp Ala Leu Asp His Phe Gln Lys Cys Phe
260 265 270
Ala Ile Leu Lys Leu His Lys Gln Arg Val Asp Asn Gly Asn Ser Asn
275 280 285
Gln Ser Lys Glu Phe Asp Lys Glu Glu Thr Lys Asp Trp Lys Ala Ile
290 295 300
Arg Val Asp Leu Val Ile Thr Pro Phe Glu Gln Tyr Ala Tyr Ala Leu
305 310 315 320
Leu Gly Trp Thr Gly Ser Ala Phe Phe Asn Arg Asp Leu Arg Arg Tyr
325 330 335
Ala Thr His Glu Lys Lys Met Met Leu Asp Asn His Ala Leu Tyr Asp
340 345 350
Lys Thr Lys Arg Ile Phe Leu Lys Ala Ala Ser Glu Glu Glu Ile Phe
355 360 365
Ala His Leu Gly Leu Asp Tyr Leu Glu Pro Trp Glu Arg Asn Ala
370 375 380
<210> 10
<211> 408
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> B57
<400> 10
Met Ala Ser Ser His His His His His His Ser Ser Gly Ser Glu Asn
1 5 10 15
Leu Tyr Phe Gln Thr Gly Ser Ser Gly Ser Pro Ser Pro Val Pro Gly
20 25 30
Ser Gln Asn Val Pro Ala Pro Ser Val Asp Lys Ile Ser Gln Tyr Ala
35 40 45
Cys Gln Arg Arg Thr Thr Leu Asn Asn Tyr Asn Lys Lys Phe Thr Asp
50 55 60
Ala Phe Glu Ile Leu Ala Glu Asn Tyr Glu Phe Asn Glu Asn Lys Gly
65 70 75 80
Phe Cys Leu Ala Phe Arg Arg Ala Ala Ser Val Leu Lys Phe Leu Pro
85 90 95
Phe Thr Ile Val Arg Met Asn Asp Ile Gln Gly Leu Pro Trp Met Gly
100 105 110
Asp Gln Val Lys Arg Val Ile Glu Glu Ile Leu Glu Glu Gly Glu Ser
115 120 125
Ser Lys Val Lys Glu Val Leu Asn Asp Glu Lys Tyr Lys Ala Phe Lys
130 135 140
Leu Phe Thr Ser Val Phe Gly Val Gly Arg Lys Thr Ser Glu Lys Trp
145 150 155 160
Tyr Arg Met Gly Leu Arg Thr Leu Glu Glu Val Lys Ala Asp Lys Thr
165 170 175
Leu Lys Leu Thr Lys Met Gln Lys Ala Gly Phe Leu Tyr Tyr Glu Asp
180 185 190
Leu Ile Ser Arg Val Ser Lys Ala Glu Ala Asp Ala Val Ser Leu Ile
195 200 205
Val Lys Asp Thr Val Trp Lys Phe Leu Pro Asp Ala Leu Val Thr Leu
210 215 220
Thr Gly Gly Phe Arg Leu Gly Lys Lys Met Gly His Asp Val Asp Phe
225 230 235 240
Leu Ile Thr Thr Pro Gly Pro Glu Glu Glu Glu Glu Leu Leu His Lys
245 250 255
Val Ile Asp Leu Trp Lys Lys Gln Gly Leu Leu Leu Tyr Tyr Asp Ile
260 265 270
Ile Glu Ser Thr Phe Glu Lys Thr Lys Leu Pro Ser Arg Thr Val Asp
275 280 285
Ala Leu Asp His Phe Gln Lys Cys Phe Ala Ile Leu Lys Leu His Lys
290 295 300
Gln Arg Val Asp Asn Gly Asn Ser Asn Gln Ser Lys Glu Phe Asp Lys
305 310 315 320
Glu Glu Thr Lys Asp Trp Lys Ala Ile Arg Val Asp Leu Val Ile Thr
325 330 335
Pro Phe Glu Gln Tyr Ala Tyr Ala Leu Leu Gly Trp Thr Gly Ser Ala
340 345 350
Phe Phe Asn Arg Asp Leu Arg Arg Tyr Ala Thr His Glu Lys Lys Met
355 360 365
Met Leu Asp Asn His Ala Leu Tyr Asp Lys Thr Lys Arg Ile Phe Leu
370 375 380
Lys Ala Ala Ser Glu Glu Glu Ile Phe Ala His Leu Gly Leu Asp Tyr
385 390 395 400
Leu Glu Pro Trp Glu Arg Asn Ala
405
<210> 11
<211> 380
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> B59截短的野生型(非洲爪蟾)
<400> 11
Ser Pro Ser Pro Val Pro Gly Ser Gln Asn Val Pro Ala Pro Ser Glu
1 5 10 15
Val Lys Val Ser Gln Tyr Ala Cys Gln Arg Cys Thr Thr Leu Gln Asp
20 25 30
Thr Asn Arg Ile Phe Thr Asp Ala Phe Asp Ile Leu Ala Glu His Phe
35 40 45
Glu Phe Cys Glu Asn Lys Gly Arg Thr Val Ala Phe Leu Arg Ala Ser
50 55 60
Ser Leu Ile Lys Ser Leu Pro Phe Pro Ile Thr Ala Met Lys Glu Leu
65 70 75 80
Glu Gly Leu Pro Trp Leu Gly Asp Gln Met Lys Gly Ile Ile Glu Glu
85 90 95
Ile Leu Glu Glu Gly Lys Ser Tyr Lys Val Leu Glu Val Met Asn Glu
100 105 110
Glu Arg Tyr Lys Ser Phe Lys Gln Phe Thr Ser Val Phe Gly Val Gly
115 120 125
Leu Lys Thr Ser Asp Lys Trp Phe Arg Met Gly Phe Arg Thr Leu Glu
130 135 140
Glu Ile Lys Asn Glu Lys Glu Leu Lys Leu Thr Lys Met Gln Lys Cys
145 150 155 160
Gly Leu Leu Tyr Tyr Glu Asp Ile Thr Ser Tyr Val Ser Arg Ala Glu
165 170 175
Ala Glu Thr Thr Glu Gln Leu Ile Lys Ser Ile Val Trp Lys Phe Val
180 185 190
Pro Asp Ala Ile Val Thr Leu Thr Gly Gly Phe Arg Arg Gly Lys Lys
195 200 205
Lys Gly His Asp Val Asp Ile Leu Ile Thr Cys Ala Arg Lys Gly Lys
210 215 220
Glu Lys Asn Ile Leu His Asn Thr Met Ser Val Leu Lys Asn Arg Gly
225 230 235 240
Leu Leu Leu Phe Tyr Asn Ile Ile Glu Ser Thr Phe Asp Glu Thr Lys
245 250 255
Leu Pro Ser Arg His Val Asp Ala Leu Asp His Phe Gln Lys Cys Phe
260 265 270
Thr Ile Leu Lys Leu Pro Lys Arg Gln Met Asp Ile Gly Asn Ile Ile
275 280 285
Asp Pro His Glu Cys Glu Arg Lys Asn Trp Lys Ala Val Arg Leu Asp
290 295 300
Leu Val Ile Thr Pro Tyr Glu Gln Tyr Pro Tyr Ala Leu Leu Gly Trp
305 310 315 320
Thr Gly Ser Arg Gln Phe Glu Arg Asp Leu Arg Arg Tyr Ala Thr His
325 330 335
Glu Lys Arg Met Met Leu Asp Asn His Gly Leu Tyr Asp Lys Thr Lys
340 345 350
Asn Asn Phe Leu Lys Ala Asn Asn Glu Glu Asp Ile Phe Lys Gln Leu
355 360 365
Gly Leu Asp Tyr Leu Glu Pro Trp Glu Arg Asn Ala
370 375 380
<210> 12
<211> 380
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> B59截短的新的
<400> 12
Ser Pro Ser Pro Val Pro Gly Ser Gln Asn Val Pro Ala Pro Ser Glu
1 5 10 15
Val Lys Val Ser Gln Tyr Ala Cys Gln Arg Arg Thr Thr Leu Gln Asp
20 25 30
Thr Asn Arg Ile Phe Thr Asp Ala Phe Asp Ile Leu Ala Glu Asn Tyr
35 40 45
Glu Phe Asn Glu Asn Lys Gly Pro Cys Val Ala Phe Arg Arg Ala Ser
50 55 60
Ser Val Leu Lys Ser Leu Pro Phe Pro Ile Val Ala Met Lys Asp Leu
65 70 75 80
Glu Gly Leu Pro Trp Leu Gly Asp Gln Met Lys Arg Ile Ile Glu Glu
85 90 95
Ile Leu Glu Glu Gly Lys Ser Ser Lys Val Val Glu Val Met Asn Asp
100 105 110
Glu Arg Tyr Lys Ala Phe Lys Leu Phe Thr Ser Val Phe Gly Val Gly
115 120 125
Arg Lys Thr Ser Glu Lys Trp Phe Arg Met Gly Phe Arg Thr Leu Glu
130 135 140
Glu Ile Lys Ser Asp Lys Glu Leu Lys Leu Thr Lys Met Gln Lys Ala
145 150 155 160
Gly Leu Leu Tyr Tyr Glu Asp Ile Thr Ser Ala Val Ser Lys Ala Glu
165 170 175
Ala Glu Ala Val Glu Gln Leu Ile Lys Ser Ile Val Trp Lys Phe Val
180 185 190
Pro Asp Ala Ile Val Thr Leu Thr Gly Gly Phe Arg Leu Gly Lys Lys
195 200 205
Met Gly His Asp Val Asp Ile Leu Ile Thr Thr Pro Arg Lys Gly Glu
210 215 220
Lys Glu Glu Ile Leu His Lys Thr Ile Asn Val Leu Lys Lys Arg Gly
225 230 235 240
Leu Leu Leu Phe Tyr Asn Ile Ile Glu Ser Thr Phe Asp Glu Thr Lys
245 250 255
Leu Pro Ser Arg His Val Asp Ala Leu Asp His Phe Gln Lys Cys Phe
260 265 270
Thr Ile Leu Lys Leu Gln Lys Gln Gln Leu Asp Asn Gly Asn Ser Asn
275 280 285
Glu Pro Phe Glu Thr Glu Lys Lys Asn Trp Lys Ala Ile Arg Val Asp
290 295 300
Leu Val Ile Thr Pro Tyr Glu Gln Tyr Ala Tyr Ala Leu Leu Gly Trp
305 310 315 320
Thr Gly Ser Pro Gln Phe Asn Arg Asp Leu Arg Arg Tyr Ala Thr His
325 330 335
Glu Lys Arg Met Met Leu Asp Asn His Ala Leu Tyr Asp Lys Thr Lys
340 345 350
Asn Ile Phe Leu Lys Ala Asn Ser Glu Glu Asp Ile Phe Thr His Leu
355 360 365
Gly Leu Asp Tyr Leu Glu Pro Trp Glu Arg Asn Ala
370 375 380
<210> 13
<211> 405
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> B59
<400> 13
Met Ala Ser Ser His His His His His His Ser Ser Gly Ser Glu Asn
1 5 10 15
Leu Tyr Phe Gln Thr Gly Ser Ser Gly Ser Pro Ser Pro Val Pro Gly
20 25 30
Ser Gln Asn Val Pro Ala Pro Ser Glu Val Lys Val Ser Gln Tyr Ala
35 40 45
Cys Gln Arg Arg Thr Thr Leu Gln Asp Thr Asn Arg Ile Phe Thr Asp
50 55 60
Ala Phe Asp Ile Leu Ala Glu Asn Tyr Glu Phe Asn Glu Asn Lys Gly
65 70 75 80
Pro Cys Val Ala Phe Arg Arg Ala Ser Ser Val Leu Lys Ser Leu Pro
85 90 95
Phe Pro Ile Val Ala Met Lys Asp Leu Glu Gly Leu Pro Trp Leu Gly
100 105 110
Asp Gln Met Lys Arg Ile Ile Glu Glu Ile Leu Glu Glu Gly Lys Ser
115 120 125
Ser Lys Val Val Glu Val Met Asn Asp Glu Arg Tyr Lys Ala Phe Lys
130 135 140
Leu Phe Thr Ser Val Phe Gly Val Gly Arg Lys Thr Ser Glu Lys Trp
145 150 155 160
Phe Arg Met Gly Phe Arg Thr Leu Glu Glu Ile Lys Ser Asp Lys Glu
165 170 175
Leu Lys Leu Thr Lys Met Gln Lys Ala Gly Leu Leu Tyr Tyr Glu Asp
180 185 190
Ile Thr Ser Ala Val Ser Lys Ala Glu Ala Glu Ala Val Glu Gln Leu
195 200 205
Ile Lys Ser Ile Val Trp Lys Phe Val Pro Asp Ala Ile Val Thr Leu
210 215 220
Thr Gly Gly Phe Arg Leu Gly Lys Lys Met Gly His Asp Val Asp Ile
225 230 235 240
Leu Ile Thr Thr Pro Arg Lys Gly Glu Lys Glu Glu Ile Leu His Lys
245 250 255
Thr Ile Asn Val Leu Lys Lys Arg Gly Leu Leu Leu Phe Tyr Asn Ile
260 265 270
Ile Glu Ser Thr Phe Asp Glu Thr Lys Leu Pro Ser Arg His Val Asp
275 280 285
Ala Leu Asp His Phe Gln Lys Cys Phe Thr Ile Leu Lys Leu Gln Lys
290 295 300
Gln Gln Leu Asp Asn Gly Asn Ser Asn Glu Pro Phe Glu Thr Glu Lys
305 310 315 320
Lys Asn Trp Lys Ala Ile Arg Val Asp Leu Val Ile Thr Pro Tyr Glu
325 330 335
Gln Tyr Ala Tyr Ala Leu Leu Gly Trp Thr Gly Ser Pro Gln Phe Asn
340 345 350
Arg Asp Leu Arg Arg Tyr Ala Thr His Glu Lys Arg Met Met Leu Asp
355 360 365
Asn His Ala Leu Tyr Asp Lys Thr Lys Asn Ile Phe Leu Lys Ala Asn
370 375 380
Ser Glu Glu Asp Ile Phe Thr His Leu Gly Leu Asp Tyr Leu Glu Pro
385 390 395 400
Trp Glu Arg Asn Ala
405
<210> 14
<211> 383
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> B63截短的野生型(虎蛇)
<400> 14
Ser Pro Ser Pro Val Pro Gly Ser Gln Asn Val Pro Ala Pro Ser Val
1 5 10 15
Asp Ser Ile Ser Pro Tyr Ala Cys Gln Arg Arg Thr Thr Leu Lys Asn
20 25 30
Tyr Asn Gln Lys Phe Thr Asp Ala Phe Glu Ile Leu Val Glu Asn Tyr
35 40 45
Glu Phe Asn Glu Asn Lys Glu Phe Cys Leu Ala Phe Gly Arg Ala Ala
50 55 60
Ser Leu Leu Lys Cys Leu Pro Phe Thr Val Val Arg Val Asn Asp Ile
65 70 75 80
Glu Gly Leu Pro Trp Met Gly Lys Gln Val Arg Glu Ile Ile Glu Asp
85 90 95
Ile Leu Glu Glu Gly Glu Ser Ser Lys Val Lys Ala Val Leu Asn Asp
100 105 110
Glu Asn Tyr Arg Ser Ile Lys Leu Phe Thr Ser Val Phe Gly Val Gly
115 120 125
Leu Arg Thr Ser Glu Lys Trp Tyr Arg Met Gly Leu Arg Thr Leu Glu
130 135 140
Glu Val Lys Cys Asn Lys Asn Leu Thr Leu Thr Arg Met Gln Lys Ala
145 150 155 160
Gly Phe Phe Tyr Tyr Asp Asp Leu Ile Ser Ser Val Ser Lys Ala Glu
165 170 175
Ala Asp Ala Ala Thr Gln Ile Val Gln Asp Thr Val Trp Lys Ile Leu
180 185 190
Pro Asn Ala Val Val Thr Leu Thr Gly Gly Phe Arg Arg Gly Lys Gln
195 200 205
Thr Gly His Asp Val Asp Phe Leu Ile Thr Val Pro Gly Ser Arg Gln
210 215 220
Glu Glu Glu Leu Leu His Pro Val Ile Asp Ile Trp Lys Lys Gln Glu
225 230 235 240
Leu Leu Leu Tyr Tyr Asp Leu Ile Glu Ser Thr Phe Glu Asn Thr Lys
245 250 255
Leu Pro Ser Arg Lys Val Asp Ala Leu Asp His Phe Gln Lys Cys Phe
260 265 270
Ala Ile Leu Lys Val His Lys Glu Arg Val Asn Lys Gly Ser Ala Val
275 280 285
Gln Ser Asn Val Phe Ala Glu Glu Gly Thr Lys Asp Trp Lys Ala Ile
290 295 300
Arg Val Asp Leu Val Val Thr Pro Phe Gln His Tyr Ala Phe Ala Leu
305 310 315 320
Leu Gly Trp Thr Gly Ser Arg Gln Phe Glu Arg Asp Leu Arg Arg Tyr
325 330 335
Ala Thr Gln Glu Lys Lys Met Met Leu Asp Asn His Ala Leu Tyr Asp
340 345 350
Lys Thr Lys Lys Ile Phe Leu Ser Ala Ala Asn Glu Glu Glu Ile Phe
355 360 365
Ser His Leu Gly Leu Asp Tyr Leu Glu Pro Trp Glu Arg Asn Ala
370 375 380
<210> 15
<211> 384
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> B63截短的新的
<400> 15
Ser Pro Ser Pro Val Pro Gly Ser Gln Asn Val Pro Ala Pro Ser Val
1 5 10 15
Asp Ser Ile Ser Gln Tyr Ala Cys Gln Arg Arg Thr Thr Leu Asn Asn
20 25 30
Tyr Asn Lys Lys Phe Thr Asp Ala Phe Glu Ile Leu Ala Glu Asn Tyr
35 40 45
Glu Phe Asn Glu Asn Lys Gly Phe Cys Leu Ala Phe Arg Arg Ala Ala
50 55 60
Ser Val Leu Lys Phe Leu Pro Phe Thr Ile Val Arg Val Asn Asp Ile
65 70 75 80
Glu Gly Leu Pro Trp Met Gly Glu Gln Val Lys Arg Ile Ile Glu Asp
85 90 95
Ile Leu Glu Glu Gly Glu Ser Ser Lys Val Lys Ala Val Leu Asn Asn
100 105 110
Glu Asn Tyr Arg Ala Phe Lys Leu Phe Thr Ser Val Phe Gly Val Gly
115 120 125
Arg Lys Thr Ser Glu Lys Trp Tyr Arg Met Gly Leu Arg Thr Leu Glu
130 135 140
Glu Val Lys Ala Asp Lys Asn Leu Lys Leu Thr Arg Met Gln Lys Ala
145 150 155 160
Gly Phe Leu His Tyr Glu Asp Leu Ile Ser Arg Val Ser Lys Ala Glu
165 170 175
Ala Asp Ala Ala Ser Leu Ile Val Lys Asp Thr Val Trp Lys Phe Leu
180 185 190
Pro Asn Ala Leu Val Thr Leu Thr Gly Gly Phe Arg Leu Gly Lys Lys
195 200 205
Met Gly His Asp Val Asp Phe Leu Ile Thr Val Pro Gly Ser Arg Gln
210 215 220
Glu Glu Glu Glu Leu Leu His Thr Val Ile Asp Leu Trp Lys Lys Gln
225 230 235 240
Gly Leu Leu Leu Tyr Tyr Asp Leu Ile Glu Ser Thr Phe Glu Lys Thr
245 250 255
Lys Leu Pro Ser Arg Thr Val Asp Ala Leu Asp His Phe Gln Lys Cys
260 265 270
Phe Ala Ile Leu Lys Leu His Lys Glu Arg Val Asp Lys Gly Asn Ser
275 280 285
Ile Gln Ser Lys Ala Phe Ala Glu Glu Glu Thr Lys Asp Trp Lys Ala
290 295 300
Ile Arg Val Asp Leu Val Val Thr Pro Phe Glu Gln Tyr Ala Phe Ala
305 310 315 320
Leu Leu Gly Trp Thr Gly Ser Pro Phe Phe Asn Arg Asp Leu Arg Arg
325 330 335
Tyr Ala Thr His Glu Lys Lys Met Met Leu Asp Asn His Ala Leu Tyr
340 345 350
Asp Lys Thr Lys Lys Ile Phe Leu Lys Ala Ala Ser Glu Glu Glu Ile
355 360 365
Phe Ala His Leu Gly Leu Asp Tyr Leu Glu Pro Trp Glu Arg Asn Ala
370 375 380
<210> 16
<211> 409
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> B63
<400> 16
Met Ala Ser Ser His His His His His His Ser Ser Gly Ser Glu Asn
1 5 10 15
Leu Tyr Phe Gln Thr Gly Ser Ser Gly Ser Pro Ser Pro Val Pro Gly
20 25 30
Ser Gln Asn Val Pro Ala Pro Ser Val Asp Ser Ile Ser Gln Tyr Ala
35 40 45
Cys Gln Arg Arg Thr Thr Leu Asn Asn Tyr Asn Lys Lys Phe Thr Asp
50 55 60
Ala Phe Glu Ile Leu Ala Glu Asn Tyr Glu Phe Asn Glu Asn Lys Gly
65 70 75 80
Phe Cys Leu Ala Phe Arg Arg Ala Ala Ser Val Leu Lys Phe Leu Pro
85 90 95
Phe Thr Ile Val Arg Val Asn Asp Ile Glu Gly Leu Pro Trp Met Gly
100 105 110
Glu Gln Val Lys Arg Ile Ile Glu Asp Ile Leu Glu Glu Gly Glu Ser
115 120 125
Ser Lys Val Lys Ala Val Leu Asn Asn Glu Asn Tyr Arg Ala Phe Lys
130 135 140
Leu Phe Thr Ser Val Phe Gly Val Gly Arg Lys Thr Ser Glu Lys Trp
145 150 155 160
Tyr Arg Met Gly Leu Arg Thr Leu Glu Glu Val Lys Ala Asp Lys Asn
165 170 175
Leu Lys Leu Thr Arg Met Gln Lys Ala Gly Phe Leu His Tyr Glu Asp
180 185 190
Leu Ile Ser Arg Val Ser Lys Ala Glu Ala Asp Ala Ala Ser Leu Ile
195 200 205
Val Lys Asp Thr Val Trp Lys Phe Leu Pro Asn Ala Leu Val Thr Leu
210 215 220
Thr Gly Gly Phe Arg Leu Gly Lys Lys Met Gly His Asp Val Asp Phe
225 230 235 240
Leu Ile Thr Val Pro Gly Ser Arg Gln Glu Glu Glu Glu Leu Leu His
245 250 255
Thr Val Ile Asp Leu Trp Lys Lys Gln Gly Leu Leu Leu Tyr Tyr Asp
260 265 270
Leu Ile Glu Ser Thr Phe Glu Lys Thr Lys Leu Pro Ser Arg Thr Val
275 280 285
Asp Ala Leu Asp His Phe Gln Lys Cys Phe Ala Ile Leu Lys Leu His
290 295 300
Lys Glu Arg Val Asp Lys Gly Asn Ser Ile Gln Ser Lys Ala Phe Ala
305 310 315 320
Glu Glu Glu Thr Lys Asp Trp Lys Ala Ile Arg Val Asp Leu Val Val
325 330 335
Thr Pro Phe Glu Gln Tyr Ala Phe Ala Leu Leu Gly Trp Thr Gly Ser
340 345 350
Pro Phe Phe Asn Arg Asp Leu Arg Arg Tyr Ala Thr His Glu Lys Lys
355 360 365
Met Met Leu Asp Asn His Ala Leu Tyr Asp Lys Thr Lys Lys Ile Phe
370 375 380
Leu Lys Ala Ala Ser Glu Glu Glu Ile Phe Ala His Leu Gly Leu Asp
385 390 395 400
Tyr Leu Glu Pro Trp Glu Arg Asn Ala
405
<210> 17
<211> 367
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> F15截短的野生型(褐鳟)
<400> 17
Thr Ala Ala Ala Asn Val Ser Gln Tyr Ala Cys Leu Arg Arg Thr Thr
1 5 10 15
Thr Glu Asn His Asn Lys Ile Phe Thr Asp Val Leu Glu Glu Leu Ala
20 25 30
Glu Asn Ser Glu Phe Asn Glu Ser Lys Gly Pro Cys Leu Ala Phe Arg
35 40 45
Arg Ala Ala Ser Val Leu Lys Ser Leu Pro Ser Ala Val His Cys Leu
50 55 60
Gly Ala Ile Gln Gly Leu Pro Cys Leu Gly Glu His Thr Lys Ala Val
65 70 75 80
Met Glu Glu Ile Leu Ile Phe Gly Arg Ser Phe Lys Val Glu Glu Val
85 90 95
Gln Ser Asp Glu Arg Tyr Gln Ala Leu Lys Leu Phe Thr Ser Val Phe
100 105 110
Gly Val Gly Pro Lys Thr Ala Glu Lys Trp Tyr Arg Arg Gly Leu Arg
115 120 125
Ser Leu Lys Glu Ile Leu Ala Glu Pro Asn Ile Gln Leu Asn Arg Met
130 135 140
Gln Arg Ala Gly Phe Leu Tyr Tyr Arg Asp Ile Ser Lys Ala Val Ser
145 150 155 160
Lys Ala Glu Ala Lys Ala Leu Ser Ser Ile Ile Glu Glu Thr Ala His
165 170 175
Trp Ile Ala Pro Asp Ser Ile Leu Ala Leu Thr Gly Gly Phe Arg Arg
180 185 190
Gly Lys Glu Tyr Gly His Asp Val Asp Phe Leu Leu Thr Met Pro Glu
195 200 205
Met Gly Lys Glu Glu Gly Leu Leu Leu Arg Val Ile Asp Arg Leu Arg
210 215 220
Asp Gln Gly Ile Leu Leu Tyr Cys Glu His Gln Asp Ser Thr Phe Asp
225 230 235 240
Met Ser Lys Leu Pro Ser His Arg Phe Glu Ala Met Asp His Phe Glu
245 250 255
Lys Cys Phe Leu Ile Leu Arg Leu Glu Glu Gly Gln Val Glu Gly Asp
260 265 270
Gly Gly Leu Gln Lys Asp Pro Gly Glu Ser Arg Gly Trp Arg Ala Val
275 280 285
Arg Val Asp Leu Val Ala Pro Pro Val Asp Arg Tyr Ala Phe Val Leu
290 295 300
Leu Gly Trp Thr Gly Ser Arg Gln Phe Glu Arg Asp Leu Arg Arg Phe
305 310 315 320
Ala Ser Lys Glu Arg Gly Met Cys Leu Asp Asn His Ala Leu Tyr Asp
325 330 335
Lys Thr Lys Lys Leu Phe Leu Pro Ala Thr Ser Glu Glu Asp Ile Phe
340 345 350
Ala His Leu Gly Leu Glu Tyr Val Glu Pro Trp Gln Arg Asn Ala
355 360 365
<210> 18
<211> 367
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> F15截短的新的
<400> 18
Ser Ser Val Ala Thr Val Ser Gln Tyr Ala Cys Gln Arg Arg Thr Thr
1 5 10 15
Met Glu Asn His Asn Lys Ile Phe Thr Asp Ala Phe Glu Val Leu Ala
20 25 30
Glu Asn Ser Glu Phe Asn Glu Ser Lys Glu Ser Arg Asp Ala Phe Arg
35 40 45
Arg Ala Ala Ser Val Leu Lys Ser Leu Pro Ser Ala Val Arg Ser Leu
50 55 60
Gly Asp Thr Glu Gly Leu Pro Cys Leu Gly Glu His Thr Lys Arg Val
65 70 75 80
Ile Glu Glu Ile Leu Glu Tyr Gly Arg Ser Ser Lys Val Glu Asp Ile
85 90 95
Leu Ser Asp Glu Arg Tyr Gln Thr Met Lys Leu Phe Thr Ser Val Phe
100 105 110
Gly Val Gly Pro Lys Thr Ala Glu Lys Trp Tyr Arg Arg Gly Leu Arg
115 120 125
Ser Leu Glu Glu Val Arg Ala Glu Pro Ser Ile His Leu Asn Arg Met
130 135 140
Gln Arg Ala Gly Phe Leu Tyr Tyr Arg Asp Ile Ser Lys Arg Val Ser
145 150 155 160
Lys Ala Glu Ala Lys Ala Leu Gly Asn Ile Ile Glu Glu Thr Val His
165 170 175
Ala Ile Ala Pro Asp Ala Ile Val Thr Leu Thr Gly Gly Phe Arg Leu
180 185 190
Gly Lys Glu Phe Gly His Asp Val Asp Phe Ile Leu Thr Thr Pro Glu
195 200 205
Met Gly Lys Glu Glu Gly Leu Leu Pro Arg Val Ile Asp Arg Leu Arg
210 215 220
Asn Gln Gly Ile Leu Leu Tyr Cys Asp Tyr Gln Glu Ser Thr Phe Asp
225 230 235 240
Met Ser Lys Leu Pro Ser Arg Thr Phe Glu Ala Met Asp His Phe Gln
245 250 255
Lys Cys Phe Leu Ile Ile Lys Leu Lys Glu Gly Leu Val Glu Gly Glu
260 265 270
Gly Gly Leu Gln Ser Asp Pro Gly Asp Arg Arg Gly Trp Arg Ala Val
275 280 285
Arg Val Asp Leu Val Ala Pro Pro Val Asp Arg Tyr Ala Phe Ala Leu
290 295 300
Leu Gly Trp Thr Gly Ser Pro Gln Phe Asn Arg Asp Leu Arg Arg Phe
305 310 315 320
Ala Arg Leu Glu Arg Arg Met Leu Leu Asp Asn His Ala Leu Tyr Asp
325 330 335
Lys Thr Lys Lys Ile Phe Leu Pro Ala Lys Thr Glu Glu Asp Ile Phe
340 345 350
Ala His Leu Gly Leu Glu Tyr Ile Glu Pro Trp Gln Arg Asn Ala
355 360 365
<210> 19
<211> 392
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> F15
<400> 19
Met Ala Ser Ser His His His His His His Ser Ser Gly Ser Glu Asn
1 5 10 15
Leu Tyr Phe Gln Thr Gly Ser Ser Gly Ser Ser Val Ala Thr Val Ser
20 25 30
Gln Tyr Ala Cys Gln Arg Arg Thr Thr Met Glu Asn His Asn Lys Ile
35 40 45
Phe Thr Asp Ala Phe Glu Val Leu Ala Glu Asn Ser Glu Phe Asn Glu
50 55 60
Ser Lys Glu Ser Arg Asp Ala Phe Arg Arg Ala Ala Ser Val Leu Lys
65 70 75 80
Ser Leu Pro Ser Ala Val Arg Ser Leu Gly Asp Thr Glu Gly Leu Pro
85 90 95
Cys Leu Gly Glu His Thr Lys Arg Val Ile Glu Glu Ile Leu Glu Tyr
100 105 110
Gly Arg Ser Ser Lys Val Glu Asp Ile Leu Ser Asp Glu Arg Tyr Gln
115 120 125
Thr Met Lys Leu Phe Thr Ser Val Phe Gly Val Gly Pro Lys Thr Ala
130 135 140
Glu Lys Trp Tyr Arg Arg Gly Leu Arg Ser Leu Glu Glu Val Arg Ala
145 150 155 160
Glu Pro Ser Ile His Leu Asn Arg Met Gln Arg Ala Gly Phe Leu Tyr
165 170 175
Tyr Arg Asp Ile Ser Lys Arg Val Ser Lys Ala Glu Ala Lys Ala Leu
180 185 190
Gly Asn Ile Ile Glu Glu Thr Val His Ala Ile Ala Pro Asp Ala Ile
195 200 205
Val Thr Leu Thr Gly Gly Phe Arg Leu Gly Lys Glu Phe Gly His Asp
210 215 220
Val Asp Phe Ile Leu Thr Thr Pro Glu Met Gly Lys Glu Glu Gly Leu
225 230 235 240
Leu Pro Arg Val Ile Asp Arg Leu Arg Asn Gln Gly Ile Leu Leu Tyr
245 250 255
Cys Asp Tyr Gln Glu Ser Thr Phe Asp Met Ser Lys Leu Pro Ser Arg
260 265 270
Thr Phe Glu Ala Met Asp His Phe Gln Lys Cys Phe Leu Ile Ile Lys
275 280 285
Leu Lys Glu Gly Leu Val Glu Gly Glu Gly Gly Leu Gln Ser Asp Pro
290 295 300
Gly Asp Arg Arg Gly Trp Arg Ala Val Arg Val Asp Leu Val Ala Pro
305 310 315 320
Pro Val Asp Arg Tyr Ala Phe Ala Leu Leu Gly Trp Thr Gly Ser Pro
325 330 335
Gln Phe Asn Arg Asp Leu Arg Arg Phe Ala Arg Leu Glu Arg Arg Met
340 345 350
Leu Leu Asp Asn His Ala Leu Tyr Asp Lys Thr Lys Lys Ile Phe Leu
355 360 365
Pro Ala Lys Thr Glu Glu Asp Ile Phe Ala His Leu Gly Leu Glu Tyr
370 375 380
Ile Glu Pro Trp Gln Arg Asn Ala
385 390
<210> 20
<211> 377
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> F24截短的野生型(电鳗)
<400> 20
Ser Pro Ser Pro Val Pro Gly Ser Gln Asn Val Pro Ala Pro Ser Leu
1 5 10 15
Pro Thr Val Ser Gln Tyr Ala Cys Gln Arg Arg Thr Thr Leu Asp Asn
20 25 30
His Asn Lys Val Phe Thr Asp Ala Leu Glu Val Leu Ile Glu Asn Tyr
35 40 45
Glu Phe Ser Asp Asn Lys Gly Ala Cys Val Gly Phe Arg Arg Ala Ala
50 55 60
Ser Val Leu Lys Ser Leu Pro Lys Pro Leu Arg Cys Leu Lys Asp Met
65 70 75 80
Glu Gly Leu Pro Cys Leu Gly Asp Asp Thr Lys Ala Ile Ile Glu Glu
85 90 95
Ile Tyr Glu Cys Gly Ser Ser Ser Arg Val Glu Asn Ile Leu Ser Asp
100 105 110
Glu Lys Tyr Gln Thr Leu Lys Leu Phe Thr Ser Val Phe Gly Val Gly
115 120 125
Pro Lys Thr Gly Glu Lys Trp Tyr Arg Arg Gly Leu Arg Ala Leu Glu
130 135 140
Gln Val His Ser Glu Pro Ser Ile Gln Leu Asn Lys Met Gln Ala Ala
145 150 155 160
Gly Phe Leu Tyr Tyr Glu Asp Ile Ser Lys Pro Val Ser Arg Ala Glu
165 170 175
Ala Lys Ala Val Gly Cys Ile Ile Glu Glu Val Ala Ser Cys Phe Ser
180 185 190
Ser Ser Val Thr Ile Thr Leu Thr Gly Gly Phe Arg Arg Gly Lys Glu
195 200 205
Phe Gly His Asp Val Asp Phe Leu Leu Ser Ile Pro Glu Pro Gly Lys
210 215 220
Glu Asp Gly Leu Leu Pro Ala Val Ile Asp Arg Leu Arg Lys Gln Gly
225 230 235 240
Ile Leu Leu Tyr Ser Asp Leu Gln Glu Ser Thr Leu Gln Gln Trp Lys
245 250 255
Arg Pro Ser Arg Cys Phe Asp Ser Met Asp His Phe Gln Lys Cys Phe
260 265 270
Leu Ile Val Lys Leu Trp Thr Arg Leu Val Glu Gly His Arg Glu Asp
275 280 285
Pro Ser Ser Gln Arg Asp Trp Lys Ala Val Arg Val Asp Leu Val Val
290 295 300
Pro Pro Val Asp Cys Tyr Ala Phe Ala Leu Leu Gly Trp Ser Gly Ser
305 310 315 320
Thr Gln Phe Glu Arg Asp Leu Arg Arg Phe Ala Arg Leu Glu Arg Arg
325 330 335
Met Leu Leu Asp Asn His Ala Leu Tyr Asp Lys Thr Thr Asn Thr Phe
340 345 350
Leu Gln Ala Lys Thr Glu Glu Asp Ile Phe Ala His Leu Gly Leu Asp
355 360 365
Tyr Ile Glu Pro Trp Gln Arg Asn Ala
370 375
<210> 21
<211> 377
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> F24截短的新的
<400> 21
Ser Pro Ser Pro Val Pro Gly Ser Gln Asn Val Pro Ala Pro Ser Leu
1 5 10 15
Pro Thr Val Ser Gln Tyr Ala Cys Gln Arg Arg Thr Thr Leu Asp Asn
20 25 30
His Asn Lys Ile Phe Thr Asp Ala Leu Glu Val Leu Ala Glu Asn Tyr
35 40 45
Glu Phe Ser Asp Ser Lys Glu Ser Arg Asp Ala Phe Arg Arg Ala Ala
50 55 60
Ser Val Leu Lys Ser Leu Pro Thr Pro Leu Arg Ser Leu Gln Asp Thr
65 70 75 80
Glu Gly Leu Pro Cys Leu Gly Glu Glu Thr Lys Arg Val Ile Glu Glu
85 90 95
Ile Phe Glu Glu Gly Ser Ser Ser Arg Val Glu Asp Ile Leu Ser Asp
100 105 110
Glu Arg Tyr Gln Thr Leu Lys Leu Phe Thr Ser Val Phe Gly Val Gly
115 120 125
Pro Lys Thr Ala Glu Lys Trp Tyr Arg Arg Gly Leu Arg Ser Leu Glu
130 135 140
Gln Val Arg Ser Asp Pro Ser Ile His Leu Asn Arg Met Gln Thr Ala
145 150 155 160
Gly Phe Leu Tyr Tyr Glu Asp Ile Ser Lys Pro Val Ser Lys Ala Glu
165 170 175
Ala Lys Ala Leu Gly Asn Ile Ile Glu Glu Thr Ala Ser Ala Phe Ser
180 185 190
Pro Ser Val Thr Ile Thr Leu Thr Gly Gly Phe Arg Leu Gly Lys Glu
195 200 205
Phe Gly His Asp Val Asp Phe Leu Leu Thr Val Pro Glu Pro Gly Lys
210 215 220
Glu Asp Gly Leu Leu Pro Ala Val Ile Asp Arg Leu Arg Ser Gln Gly
225 230 235 240
Ile Leu Leu Tyr Ser Asp Phe Gln Glu Ser Thr Phe Asp Leu Ser Lys
245 250 255
Leu Pro Ser Arg Arg Phe Glu Ala Met Asp His Phe Gln Lys Cys Phe
260 265 270
Leu Ile Val Lys Leu Lys Ala Gly Leu Val Glu Gly Glu Gly Ala Asp
275 280 285
Pro Gly Asp Arg Arg Asp Trp Arg Ala Val Arg Val Asp Leu Val Ala
290 295 300
Pro Pro Val Asp Arg Tyr Ala Phe Ala Leu Leu Gly Trp Ser Gly Ser
305 310 315 320
Ala Phe Phe Asn Arg Asp Leu Arg Arg Phe Ala Arg Leu Glu Arg Gly
325 330 335
Met Leu Leu Asp Asn His Ala Leu Tyr Asp Lys Thr Thr Asn Thr Phe
340 345 350
Leu Gln Ala Lys Thr Glu Glu Asp Ile Phe Ala His Leu Gly Leu Asp
355 360 365
Tyr Ile Glu Pro Trp Gln Arg Asn Ala
370 375
<210> 22
<211> 402
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> F24
<400> 22
Met Ala Ser Ser His His His His His His Ser Ser Gly Ser Glu Asn
1 5 10 15
Leu Tyr Phe Gln Thr Gly Ser Ser Gly Ser Pro Ser Pro Val Pro Gly
20 25 30
Ser Gln Asn Val Pro Ala Pro Ser Leu Pro Thr Val Ser Gln Tyr Ala
35 40 45
Cys Gln Arg Arg Thr Thr Leu Asp Asn His Asn Lys Ile Phe Thr Asp
50 55 60
Ala Leu Glu Val Leu Ala Glu Asn Tyr Glu Phe Ser Asp Ser Lys Glu
65 70 75 80
Ser Arg Asp Ala Phe Arg Arg Ala Ala Ser Val Leu Lys Ser Leu Pro
85 90 95
Thr Pro Leu Arg Ser Leu Gln Asp Thr Glu Gly Leu Pro Cys Leu Gly
100 105 110
Glu Glu Thr Lys Arg Val Ile Glu Glu Ile Phe Glu Glu Gly Ser Ser
115 120 125
Ser Arg Val Glu Asp Ile Leu Ser Asp Glu Arg Tyr Gln Thr Leu Lys
130 135 140
Leu Phe Thr Ser Val Phe Gly Val Gly Pro Lys Thr Ala Glu Lys Trp
145 150 155 160
Tyr Arg Arg Gly Leu Arg Ser Leu Glu Gln Val Arg Ser Asp Pro Ser
165 170 175
Ile His Leu Asn Arg Met Gln Thr Ala Gly Phe Leu Tyr Tyr Glu Asp
180 185 190
Ile Ser Lys Pro Val Ser Lys Ala Glu Ala Lys Ala Leu Gly Asn Ile
195 200 205
Ile Glu Glu Thr Ala Ser Ala Phe Ser Pro Ser Val Thr Ile Thr Leu
210 215 220
Thr Gly Gly Phe Arg Leu Gly Lys Glu Phe Gly His Asp Val Asp Phe
225 230 235 240
Leu Leu Thr Val Pro Glu Pro Gly Lys Glu Asp Gly Leu Leu Pro Ala
245 250 255
Val Ile Asp Arg Leu Arg Ser Gln Gly Ile Leu Leu Tyr Ser Asp Phe
260 265 270
Gln Glu Ser Thr Phe Asp Leu Ser Lys Leu Pro Ser Arg Arg Phe Glu
275 280 285
Ala Met Asp His Phe Gln Lys Cys Phe Leu Ile Val Lys Leu Lys Ala
290 295 300
Gly Leu Val Glu Gly Glu Gly Ala Asp Pro Gly Asp Arg Arg Asp Trp
305 310 315 320
Arg Ala Val Arg Val Asp Leu Val Ala Pro Pro Val Asp Arg Tyr Ala
325 330 335
Phe Ala Leu Leu Gly Trp Ser Gly Ser Ala Phe Phe Asn Arg Asp Leu
340 345 350
Arg Arg Phe Ala Arg Leu Glu Arg Gly Met Leu Leu Asp Asn His Ala
355 360 365
Leu Tyr Asp Lys Thr Thr Asn Thr Phe Leu Gln Ala Lys Thr Glu Glu
370 375 380
Asp Ile Phe Ala His Leu Gly Leu Asp Tyr Ile Glu Pro Trp Gln Arg
385 390 395 400
Asn Ala
<210> 23
<211> 378
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> F32截短的野生型(攀鲈)
<400> 23
Ser Pro Ser Pro Val Pro Gly Ser Gln Asn Val Pro Ala Pro Ser Val
1 5 10 15
Ala Thr Val Ser Gln Tyr Ala Cys Gln Arg Arg Thr Thr Thr Glu Asn
20 25 30
Asn Asn Lys Ile Leu Thr Asp Ala Phe Glu Val Leu Ala Glu Ser Tyr
35 40 45
Glu Leu Asn Gln Leu Glu Gly Pro Cys Leu Ala Phe Arg Arg Ala Ala
50 55 60
Ser Val Leu Lys Ser Leu Pro Trp Ala Val Gln Cys Leu Gly Ala Thr
65 70 75 80
Gln Gly Leu Pro Cys Leu Gly Glu His Thr Lys Ala Leu Ile Glu Glu
85 90 95
Ile Leu Gln Tyr Gly His Ser Phe Glu Val Glu Lys Ile Leu Ser Asp
100 105 110
Glu Arg Tyr Gln Thr Leu Lys Leu Phe Thr Ser Val Phe Gly Val Gly
115 120 125
Pro Lys Thr Ala Glu Lys Trp Tyr Arg Arg Gly Leu Arg Ser Phe Ser
130 135 140
Asp Ile Leu Ala Glu Pro Ser Ile Gln Leu Asn Arg Met Gln Gln Ser
145 150 155 160
Gly Phe Leu His Tyr Gly Asp Ile Ser Arg Ala Val Ser Lys Ala Glu
165 170 175
Ala Arg Ala Leu Gly Asn Ile Ile Asp Glu Ala Val His Ala Ile Thr
180 185 190
Pro Asp Gly Ile Leu Ala Leu Thr Gly Gly Phe Arg Arg Gly Lys Glu
195 200 205
Phe Gly His Asp Val Asp Phe Ile Val Thr Thr Pro Glu Gln Gly Lys
210 215 220
Glu Glu Thr Leu Leu Pro Asn Ile Ile Asp Arg Leu Lys Glu Gln Gly
225 230 235 240
Ile Leu Leu Tyr Ser Asp Tyr Gln Thr Ser Thr Phe Asp Ile Ser Lys
245 250 255
Leu Pro Ser His Lys Phe Glu Ala Met Asp His Phe Ala Lys Cys Phe
260 265 270
Leu Ile Leu Arg Leu Glu Gly Ser Leu Val Asp Arg Gly Leu Asn Ser
275 280 285
Thr Glu Gly Asp Ser Arg Gly Trp Arg Ala Val Arg Val Asp Leu Val
290 295 300
Ser Pro Pro Met Glu Arg Tyr Ala Tyr Ala Leu Leu Gly Trp Thr Gly
305 310 315 320
Ser Arg Gln Phe Glu Arg Asp Leu Arg Arg Phe Ala Arg Leu Glu Gln
325 330 335
His Met Leu Leu Asp Asn His Ala Leu Tyr Asp Lys Thr Lys Lys Glu
340 345 350
Phe Leu Ala Ala Thr Thr Glu Arg Asp Ile Phe Ala His Leu Gly Leu
355 360 365
Glu Tyr Ile Glu Pro Trp Gln Arg Asn Ala
370 375
<210> 24
<211> 378
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> F32截短的新的
<400> 24
Ser Pro Ser Pro Val Pro Gly Ser Gln Asn Val Pro Ala Pro Ser Val
1 5 10 15
Ala Thr Val Ser Gln Tyr Ala Cys Gln Arg Arg Thr Thr Thr Glu Asn
20 25 30
Asn Asn Lys Ile Phe Thr Asp Ala Phe Glu Val Leu Ala Glu Ser Tyr
35 40 45
Glu Phe Asn Glu Met Glu Glu Ser Arg Asp Ala Phe Arg Arg Ala Ala
50 55 60
Ser Val Leu Lys Ser Leu Pro Trp Ala Val Gln Ser Leu Gly Ala Thr
65 70 75 80
Gln Asp Leu Pro Cys Leu Gly Glu His Thr Lys Arg Val Met Glu Glu
85 90 95
Ile Leu Gln Tyr Gly Arg Ser Phe Glu Val Glu Lys Ile Leu Ser Asp
100 105 110
Glu Arg Tyr Gln Thr Leu Lys Leu Phe Thr Ser Val Phe Gly Val Gly
115 120 125
Pro Lys Thr Ala Glu Lys Trp Tyr Arg Arg Gly Leu Arg Ser Phe Glu
130 135 140
Asp Ile Arg Ala Glu Pro Ser Ile His Leu Asn Arg Met Gln Gln Ser
145 150 155 160
Gly Phe Leu His Tyr Gly Asp Ile Ser Arg Ala Val Ser Lys Ala Glu
165 170 175
Ala Arg Ala Leu Gly Asn Ile Ile Asp Glu Ala Val His Ala Ile Thr
180 185 190
Pro Asp Ala Ile Leu Ala Leu Thr Gly Gly Phe Arg Leu Gly Lys Glu
195 200 205
Phe Gly His Asp Val Asp Phe Ile Val Thr Thr Pro Glu Leu Gly Lys
210 215 220
Glu Glu Ser Leu Leu Pro Asn Ile Ile Asp Arg Leu Lys Lys Gln Gly
225 230 235 240
Ile Leu Leu Tyr Ser Asp Tyr Gln Ala Ser Thr Phe Asp Met Ser Lys
245 250 255
Leu Pro Ser His Arg Phe Glu Ala Met Asp His Phe Ala Lys Cys Phe
260 265 270
Leu Ile Leu Arg Leu Glu Gly Ser Gln Val Glu Gly Gly Leu Asn Ser
275 280 285
Ala Glu Gly Asp Ser Arg Gly Trp Arg Ala Val Arg Val Asp Leu Val
290 295 300
Ser Pro Pro Met Asp Arg Tyr Ala Phe Ala Leu Leu Gly Trp Thr Gly
305 310 315 320
Ser Ala Phe Phe Asn Arg Asp Leu Arg Arg Phe Ala Arg Met Glu Arg
325 330 335
Arg Met Leu Leu Asp Asn His Ala Leu Tyr Asp Lys Thr Lys Lys Glu
340 345 350
Phe Leu Ala Ala Thr Thr Glu Lys Asp Ile Phe Ala His Leu Gly Leu
355 360 365
Glu Tyr Ile Glu Pro Trp Gln Arg Asn Ala
370 375
<210> 25
<211> 403
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> F32
<400> 25
Met Ala Ser Ser His His His His His His Ser Ser Gly Ser Glu Asn
1 5 10 15
Leu Tyr Phe Gln Thr Gly Ser Ser Gly Ser Pro Ser Pro Val Pro Gly
20 25 30
Ser Gln Asn Val Pro Ala Pro Ser Val Ala Thr Val Ser Gln Tyr Ala
35 40 45
Cys Gln Arg Arg Thr Thr Thr Glu Asn Asn Asn Lys Ile Phe Thr Asp
50 55 60
Ala Phe Glu Val Leu Ala Glu Ser Tyr Glu Phe Asn Glu Met Glu Glu
65 70 75 80
Ser Arg Asp Ala Phe Arg Arg Ala Ala Ser Val Leu Lys Ser Leu Pro
85 90 95
Trp Ala Val Gln Ser Leu Gly Ala Thr Gln Asp Leu Pro Cys Leu Gly
100 105 110
Glu His Thr Lys Arg Val Met Glu Glu Ile Leu Gln Tyr Gly Arg Ser
115 120 125
Phe Glu Val Glu Lys Ile Leu Ser Asp Glu Arg Tyr Gln Thr Leu Lys
130 135 140
Leu Phe Thr Ser Val Phe Gly Val Gly Pro Lys Thr Ala Glu Lys Trp
145 150 155 160
Tyr Arg Arg Gly Leu Arg Ser Phe Glu Asp Ile Arg Ala Glu Pro Ser
165 170 175
Ile His Leu Asn Arg Met Gln Gln Ser Gly Phe Leu His Tyr Gly Asp
180 185 190
Ile Ser Arg Ala Val Ser Lys Ala Glu Ala Arg Ala Leu Gly Asn Ile
195 200 205
Ile Asp Glu Ala Val His Ala Ile Thr Pro Asp Ala Ile Leu Ala Leu
210 215 220
Thr Gly Gly Phe Arg Leu Gly Lys Glu Phe Gly His Asp Val Asp Phe
225 230 235 240
Ile Val Thr Thr Pro Glu Leu Gly Lys Glu Glu Ser Leu Leu Pro Asn
245 250 255
Ile Ile Asp Arg Leu Lys Lys Gln Gly Ile Leu Leu Tyr Ser Asp Tyr
260 265 270
Gln Ala Ser Thr Phe Asp Met Ser Lys Leu Pro Ser His Arg Phe Glu
275 280 285
Ala Met Asp His Phe Ala Lys Cys Phe Leu Ile Leu Arg Leu Glu Gly
290 295 300
Ser Gln Val Glu Gly Gly Leu Asn Ser Ala Glu Gly Asp Ser Arg Gly
305 310 315 320
Trp Arg Ala Val Arg Val Asp Leu Val Ser Pro Pro Met Asp Arg Tyr
325 330 335
Ala Phe Ala Leu Leu Gly Trp Thr Gly Ser Ala Phe Phe Asn Arg Asp
340 345 350
Leu Arg Arg Phe Ala Arg Met Glu Arg Arg Met Leu Leu Asp Asn His
355 360 365
Ala Leu Tyr Asp Lys Thr Lys Lys Glu Phe Leu Ala Ala Thr Thr Glu
370 375 380
Lys Asp Ile Phe Ala His Leu Gly Leu Glu Tyr Ile Glu Pro Trp Gln
385 390 395 400
Arg Asn Ala
<210> 26
<211> 378
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> F57截短的野生型
<400> 26
Ser Pro Ser Pro Val Pro Gly Ser Gln Asn Val Pro Ala Pro Ser Val
1 5 10 15
Asp Lys Val Ser Gln Tyr Ala Cys Gln Arg Arg Thr Thr Val Glu Asn
20 25 30
Asn Asn Arg Ile Phe Thr Asp Ala Phe Glu Val Leu Ala Glu Asn Tyr
35 40 45
Glu Phe Asn Glu Ile Glu Gly Arg Cys Leu Ala Phe Arg Arg Ala Ala
50 55 60
Ser Val Leu Lys Ser Leu Pro Trp Ala Val Arg Ser Val Gly Ala Thr
65 70 75 80
Leu Asp Leu Pro Cys Leu Gly Glu His Thr Thr Ala Val Met Lys Glu
85 90 95
Ile Leu Gln Tyr Gly Arg Ser Phe Glu Val Glu Lys Ile Leu Ser Asp
100 105 110
Glu Arg Cys Gln Thr Leu Lys Leu Phe Thr Ser Val Phe Gly Val Gly
115 120 125
Pro Lys Thr Ala Glu Lys Trp Tyr Arg Arg Gly Leu Arg Ser Phe Ser
130 135 140
Asp Val Leu Ala Gln Pro Gly Ile His Leu Asn Arg Met Gln Gln Ser
145 150 155 160
Gly Phe Leu His Tyr Gly Asp Ile Ser Arg Ala Val Ser Lys Ala Glu
165 170 175
Ala Arg Ala Val Gly Asn Ile Ile Asp Glu Ala Val His Val Ile Thr
180 185 190
Pro Asn Ala Ile Leu Ala Leu Thr Gly Gly Phe Arg Arg Gly Lys Asp
195 200 205
Phe Gly His Asp Val Asp Phe Ile Val Thr Thr Thr Glu Leu Gly Lys
210 215 220
Glu Lys Asn Leu Leu Ile Ser Val Ile Glu Ser Leu Lys Lys Gln Gly
225 230 235 240
Leu Leu Leu Phe Ser Asp Tyr Gln Ala Ser Thr Phe Asp Ile Ser Lys
245 250 255
Leu Pro Ser His Arg Phe Glu Ala Met Asp His Phe Ala Lys Cys Phe
260 265 270
Leu Ile Leu Arg Leu Glu Gly Ser Arg Val Glu Gly Gly Leu Gln Arg
275 280 285
Ala Gln Ala Asp Gly Arg Gly Trp Arg Ala Val Arg Val Asp Leu Val
290 295 300
Ser Pro Pro Ala Asp Arg Phe Ala Phe Thr Met Leu Gly Trp Thr Gly
305 310 315 320
Ser Arg Met Phe Glu Arg Asp Leu Arg Arg Phe Ala Arg Leu Glu Arg
325 330 335
Gln Met Leu Leu Asp Asn His Ala Leu Tyr Asp Lys Thr Lys Lys Glu
340 345 350
Phe Leu Thr Ala Ala Thr Glu Lys Asp Ile Phe Asp His Leu Gly Leu
355 360 365
Glu Tyr Ile Glu Pro Trp Gln Arg Asn Ala
370 375
<210> 27
<211> 383
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> F57截短的新的 (孔雀花鳉)
<400> 27
Ser Pro Ser Pro Val Pro Gly Ser Gln Asn Val Pro Ala Pro Ser Val
1 5 10 15
Asp Lys Ile Ser Gln Tyr Ala Cys Gln Arg Arg Thr Thr Leu Asn Asn
20 25 30
Tyr Asn Lys Lys Phe Thr Asp Ala Phe Glu Ile Leu Ala Glu Asn Tyr
35 40 45
Glu Phe Asn Glu Asn Lys Gly Phe Cys Leu Ala Phe Arg Arg Ala Ala
50 55 60
Ser Val Leu Lys Phe Leu Pro Phe Thr Ile Val Arg Met Asn Asp Ile
65 70 75 80
Gln Gly Leu Pro Trp Met Gly Asp Gln Val Lys Arg Val Ile Glu Glu
85 90 95
Ile Leu Glu Glu Gly Glu Ser Ser Lys Val Lys Glu Val Leu Asn Asp
100 105 110
Glu Lys Tyr Lys Ala Phe Lys Leu Phe Thr Ser Val Phe Gly Val Gly
115 120 125
Arg Lys Thr Ser Glu Lys Trp Tyr Arg Met Gly Leu Arg Thr Leu Glu
130 135 140
Glu Val Lys Ala Asp Lys Thr Leu Lys Leu Thr Lys Met Gln Lys Ala
145 150 155 160
Gly Phe Leu Tyr Tyr Glu Asp Leu Ile Ser Arg Val Ser Lys Ala Glu
165 170 175
Ala Asp Ala Val Ser Leu Ile Val Lys Asp Thr Val Trp Lys Phe Leu
180 185 190
Pro Asp Ala Leu Val Thr Leu Thr Gly Gly Phe Arg Leu Gly Lys Lys
195 200 205
Met Gly His Asp Val Asp Phe Leu Ile Thr Thr Pro Gly Pro Glu Glu
210 215 220
Glu Glu Glu Leu Leu His Lys Val Ile Asp Leu Trp Lys Lys Gln Gly
225 230 235 240
Leu Leu Leu Tyr Tyr Asp Ile Ile Glu Ser Thr Phe Glu Lys Thr Lys
245 250 255
Leu Pro Ser Arg Thr Val Asp Ala Leu Asp His Phe Gln Lys Cys Phe
260 265 270
Ala Ile Leu Lys Leu His Lys Gln Arg Val Asp Asn Gly Asn Ser Asn
275 280 285
Gln Ser Lys Glu Phe Asp Lys Glu Glu Thr Lys Asp Trp Lys Ala Ile
290 295 300
Arg Val Asp Leu Val Ile Thr Pro Phe Glu Gln Tyr Ala Tyr Ala Leu
305 310 315 320
Leu Gly Trp Thr Gly Ser Ala Phe Phe Asn Arg Asp Leu Arg Arg Tyr
325 330 335
Ala Thr His Glu Lys Lys Met Met Leu Asp Asn His Ala Leu Tyr Asp
340 345 350
Lys Thr Lys Arg Ile Phe Leu Lys Ala Ala Ser Glu Glu Glu Ile Phe
355 360 365
Ala His Leu Gly Leu Asp Tyr Leu Glu Pro Trp Glu Arg Asn Ala
370 375 380
<210> 28
<211> 408
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUNECE)
<220>
<223> F57
<400> 28
Met Ala Ser Ser His His His His His His Ser Ser Gly Ser Glu Asn
1 5 10 15
Leu Tyr Phe Gln Thr Gly Ser Ser Gly Ser Pro Ser Pro Val Pro Gly
20 25 30
Ser Gln Asn Val Pro Ala Pro Ser Val Asp Lys Ile Ser Gln Tyr Ala
35 40 45
Cys Gln Arg Arg Thr Thr Leu Asn Asn Tyr Asn Lys Lys Phe Thr Asp
50 55 60
Ala Phe Glu Ile Leu Ala Glu Asn Tyr Glu Phe Asn Glu Asn Lys Gly
65 70 75 80
Phe Cys Leu Ala Phe Arg Arg Ala Ala Ser Val Leu Lys Phe Leu Pro
85 90 95
Phe Thr Ile Val Arg Met Asn Asp Ile Gln Gly Leu Pro Trp Met Gly
100 105 110
Asp Gln Val Lys Arg Val Ile Glu Glu Ile Leu Glu Glu Gly Glu Ser
115 120 125
Ser Lys Val Lys Glu Val Leu Asn Asp Glu Lys Tyr Lys Ala Phe Lys
130 135 140
Leu Phe Thr Ser Val Phe Gly Val Gly Arg Lys Thr Ser Glu Lys Trp
145 150 155 160
Tyr Arg Met Gly Leu Arg Thr Leu Glu Glu Val Lys Ala Asp Lys Thr
165 170 175
Leu Lys Leu Thr Lys Met Gln Lys Ala Gly Phe Leu Tyr Tyr Glu Asp
180 185 190
Leu Ile Ser Arg Val Ser Lys Ala Glu Ala Asp Ala Val Ser Leu Ile
195 200 205
Val Lys Asp Thr Val Trp Lys Phe Leu Pro Asp Ala Leu Val Thr Leu
210 215 220
Thr Gly Gly Phe Arg Leu Gly Lys Lys Met Gly His Asp Val Asp Phe
225 230 235 240
Leu Ile Thr Thr Pro Gly Pro Glu Glu Glu Glu Glu Leu Leu His Lys
245 250 255
Val Ile Asp Leu Trp Lys Lys Gln Gly Leu Leu Leu Tyr Tyr Asp Ile
260 265 270
Ile Glu Ser Thr Phe Glu Lys Thr Lys Leu Pro Ser Arg Thr Val Asp
275 280 285
Ala Leu Asp His Phe Gln Lys Cys Phe Ala Ile Leu Lys Leu His Lys
290 295 300
Gln Arg Val Asp Asn Gly Asn Ser Asn Gln Ser Lys Glu Phe Asp Lys
305 310 315 320
Glu Glu Thr Lys Asp Trp Lys Ala Ile Arg Val Asp Leu Val Ile Thr
325 330 335
Pro Phe Glu Gln Tyr Ala Tyr Ala Leu Leu Gly Trp Thr Gly Ser Ala
340 345 350
Phe Phe Asn Arg Asp Leu Arg Arg Tyr Ala Thr His Glu Lys Lys Met
355 360 365
Met Leu Asp Asn His Ala Leu Tyr Asp Lys Thr Lys Arg Ile Phe Leu
370 375 380
Lys Ala Ala Ser Glu Glu Glu Ile Phe Ala His Leu Gly Leu Asp Tyr
385 390 395 400
Leu Glu Pro Trp Glu Arg Asn Ala
405
<210> 29
<211> 366
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> N100截短的野生型(短褐家鼠)
<400> 29
Pro Leu Met Gln Lys Ile Ser Gln Tyr Ala Cys Gln Arg Arg Thr Thr
1 5 10 15
Leu Asn Asn His Asn Gln Leu Phe Thr Asp Ala Phe Asp Ile Leu Ala
20 25 30
Glu Asn Tyr Glu Phe Arg Glu Asn Glu Val Ser Cys Leu Pro Phe Met
35 40 45
Arg Ala Ala Ser Val Leu Lys Ser Leu Ser Phe Pro Ile Val Ser Met
50 55 60
Lys Asp Ile Glu Gly Ile Pro Cys Leu Gly Asp Lys Val Lys Cys Val
65 70 75 80
Ile Glu Gly Ile Ile Glu Asp Gly Glu Ser Ser Glu Val Lys Ala Val
85 90 95
Leu Asn Asp Glu Arg Tyr Lys Ser Phe Lys Leu Phe Thr Ser Val Phe
100 105 110
Gly Val Gly Leu Lys Thr Ala Glu Lys Trp Phe Arg Met Gly Phe Arg
115 120 125
Thr Leu Ser Lys Ile Lys Ser Asp Lys Ser Leu Arg Phe Thr His Met
130 135 140
Gln Lys Ala Gly Phe Leu Tyr Tyr Glu Asp Leu Val Ser Cys Val Asn
145 150 155 160
Arg Ala Glu Ala Glu Ala Val Ser Met Leu Val Lys Glu Ala Val Val
165 170 175
Ala Phe Leu Pro Asp Ala Leu Val Thr Met Thr Gly Gly Phe Arg Arg
180 185 190
Gly Lys Met Thr Gly His Asp Val Asp Phe Leu Ile Thr Ser Pro Glu
195 200 205
Ala Thr Glu Glu Glu Glu Gln Gln Leu Leu His Lys Val Thr Asn Phe
210 215 220
Trp Arg Gln Gln Gly Leu Leu Leu Tyr Cys Asp Ile Ile Glu Ser Thr
225 230 235 240
Phe Glu Lys Phe Lys Leu Pro Ser Arg Lys Val Asp Ala Leu Asp His
245 250 255
Phe Gln Lys Cys Phe Leu Ile Leu Lys Leu His Arg Gly Leu Val Arg
260 265 270
Ser Glu Glu Ser Gly Gln Gln Glu Gly Lys Asp Trp Lys Ala Ile Arg
275 280 285
Val Asp Leu Val Met Cys Pro Tyr Glu Arg Arg Ala Phe Ala Leu Leu
290 295 300
Gly Trp Thr Gly Ser Arg Gln Phe Glu Arg Asp Leu Arg Arg Tyr Ala
305 310 315 320
Thr His Glu Arg Lys Met Met Leu Asp Asn His Ala Leu Tyr Asp Lys
325 330 335
Thr Lys Arg Val Phe Leu Glu Ala Glu Ser Glu Glu Glu Ile Phe Ala
340 345 350
His Leu Gly Leu Asp Tyr Ile Glu Pro Trp Glu Arg Asn Ala
355 360 365
<210> 30
<211> 366
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> N100截短的新的
<400> 30
Ser Val Val Gln Lys Ile Ser Glu Tyr Ala Cys Gln Arg Arg Thr Thr
1 5 10 15
Leu Asn Asn His Asn Glu Val Phe Thr Arg Ala Phe Asp Ile Leu Ala
20 25 30
Glu Asn Tyr Glu Phe Arg Glu Asn Glu Glu Ser Arg Asp Ala Phe Arg
35 40 45
Arg Ala Ser Ser Val Leu Lys Ser Leu Pro Phe Pro Ile Ile Ser Met
50 55 60
Lys Asp Thr Glu Gly Ile Pro Cys Leu Gly Asp Lys Val Lys Arg Val
65 70 75 80
Ile Glu Glu Ile Ile Glu Asp Gly Glu Ser Ser Glu Val Lys Ala Val
85 90 95
Leu Asn Asp Glu Arg Tyr Lys Ala Phe Lys Leu Phe Thr Ser Val Phe
100 105 110
Gly Val Gly Arg Lys Thr Ala Glu Lys Trp Phe Arg Met Gly Phe Arg
115 120 125
Thr Leu Glu Lys Ile Lys Ser Asp Lys Ser Leu Arg Phe Thr Gln Met
130 135 140
Gln Lys Ala Gly Phe Leu Tyr Tyr Glu Asp Leu Ala Glu Arg Val Asn
145 150 155 160
Arg Ala Glu Ala Glu Ala Ile Glu Met Leu Val Lys Glu Ala Val Val
165 170 175
Ala Phe Leu Pro Asp Ala Leu Val Thr Met Thr Gly Gly Phe Arg Leu
180 185 190
Gly Lys Met Thr Gly His Asp Val Asp Phe Leu Ile Thr Ser Pro Glu
195 200 205
Ala Thr Glu Glu Glu Glu Gln Gln Leu Leu His Lys Val Thr Asp Phe
210 215 220
Trp Arg Gln Gln Gly Leu Leu Leu Tyr Cys Asp Ile Ile Glu Ser Thr
225 230 235 240
Phe Glu Lys Phe Lys Leu Pro Ser Arg Thr Val Asp Ala Leu Asp His
245 250 255
Phe Gln Lys Cys Phe Leu Ile Leu Lys Leu His His Gly Arg Val Val
260 265 270
Ser Glu Lys Ser Gly Gln Gln Glu Gly Lys Gly Trp Lys Ala Ile Arg
275 280 285
Val Asp Leu Val Met Cys Pro Tyr Glu Arg Arg Ala Phe Ala Leu Leu
290 295 300
Gly Trp Thr Gly Ser Pro Phe Phe Asn Arg Asp Leu Arg Arg Tyr Ala
305 310 315 320
Thr His Glu Arg Lys Met Met Leu Asp Asn His Ala Leu Tyr Asp Lys
325 330 335
Thr Lys Arg Val Phe Leu Glu Ala Glu Ser Glu Glu Glu Ile Phe Ala
340 345 350
His Leu Gly Leu Asp Tyr Ile Glu Pro Trp Glu Arg Asn Ala
355 360 365
<210> 31
<211> 391
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> N100
<400> 31
Met Ala Ser Ser His His His His His His Ser Ser Gly Ser Glu Asn
1 5 10 15
Leu Tyr Phe Gln Thr Gly Ser Ser Gly Ser Val Val Gln Lys Ile Ser
20 25 30
Glu Tyr Ala Cys Gln Arg Arg Thr Thr Leu Asn Asn His Asn Glu Val
35 40 45
Phe Thr Arg Ala Phe Asp Ile Leu Ala Glu Asn Tyr Glu Phe Arg Glu
50 55 60
Asn Glu Glu Ser Arg Asp Ala Phe Arg Arg Ala Ser Ser Val Leu Lys
65 70 75 80
Ser Leu Pro Phe Pro Ile Ile Ser Met Lys Asp Thr Glu Gly Ile Pro
85 90 95
Cys Leu Gly Asp Lys Val Lys Arg Val Ile Glu Glu Ile Ile Glu Asp
100 105 110
Gly Glu Ser Ser Glu Val Lys Ala Val Leu Asn Asp Glu Arg Tyr Lys
115 120 125
Ala Phe Lys Leu Phe Thr Ser Val Phe Gly Val Gly Arg Lys Thr Ala
130 135 140
Glu Lys Trp Phe Arg Met Gly Phe Arg Thr Leu Glu Lys Ile Lys Ser
145 150 155 160
Asp Lys Ser Leu Arg Phe Thr Gln Met Gln Lys Ala Gly Phe Leu Tyr
165 170 175
Tyr Glu Asp Leu Ala Glu Arg Val Asn Arg Ala Glu Ala Glu Ala Ile
180 185 190
Glu Met Leu Val Lys Glu Ala Val Val Ala Phe Leu Pro Asp Ala Leu
195 200 205
Val Thr Met Thr Gly Gly Phe Arg Leu Gly Lys Met Thr Gly His Asp
210 215 220
Val Asp Phe Leu Ile Thr Ser Pro Glu Ala Thr Glu Glu Glu Glu Gln
225 230 235 240
Gln Leu Leu His Lys Val Thr Asp Phe Trp Arg Gln Gln Gly Leu Leu
245 250 255
Leu Tyr Cys Asp Ile Ile Glu Ser Thr Phe Glu Lys Phe Lys Leu Pro
260 265 270
Ser Arg Thr Val Asp Ala Leu Asp His Phe Gln Lys Cys Phe Leu Ile
275 280 285
Leu Lys Leu His His Gly Arg Val Val Ser Glu Lys Ser Gly Gln Gln
290 295 300
Glu Gly Lys Gly Trp Lys Ala Ile Arg Val Asp Leu Val Met Cys Pro
305 310 315 320
Tyr Glu Arg Arg Ala Phe Ala Leu Leu Gly Trp Thr Gly Ser Pro Phe
325 330 335
Phe Asn Arg Asp Leu Arg Arg Tyr Ala Thr His Glu Arg Lys Met Met
340 345 350
Leu Asp Asn His Ala Leu Tyr Asp Lys Thr Lys Arg Val Phe Leu Glu
355 360 365
Ala Glu Ser Glu Glu Glu Ile Phe Ala His Leu Gly Leu Asp Tyr Ile
370 375 380
Glu Pro Trp Glu Arg Asn Ala
385 390
<210> 32
<211> 379
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUNECE)
<220>
<223> N100or截短的野生型(长褐家鼠)
<400> 32
Ser Leu Ser Pro Val Pro Gly Ser Gln Thr Val Pro Pro Pro Leu Met
1 5 10 15
Gln Lys Ile Ser Gln Tyr Ala Cys Gln Arg Arg Thr Thr Leu Asn Asn
20 25 30
His Asn Gln Leu Phe Thr Asp Ala Phe Asp Ile Leu Ala Glu Asn Tyr
35 40 45
Glu Phe Arg Glu Asn Glu Val Ser Cys Leu Pro Phe Met Arg Ala Ala
50 55 60
Ser Val Leu Lys Ser Leu Ser Phe Pro Ile Val Ser Met Lys Asp Ile
65 70 75 80
Glu Gly Ile Pro Cys Leu Gly Asp Lys Val Lys Cys Val Ile Glu Gly
85 90 95
Ile Ile Glu Asp Gly Glu Ser Ser Glu Val Lys Ala Val Leu Asn Asp
100 105 110
Glu Arg Tyr Lys Ser Phe Lys Leu Phe Thr Ser Val Phe Gly Val Gly
115 120 125
Leu Lys Thr Ala Glu Lys Trp Phe Arg Met Gly Phe Arg Thr Leu Ser
130 135 140
Lys Ile Lys Ser Asp Lys Ser Leu Arg Phe Thr His Met Gln Lys Ala
145 150 155 160
Gly Phe Leu Tyr Tyr Glu Asp Leu Val Ser Cys Val Asn Arg Ala Glu
165 170 175
Ala Glu Ala Val Ser Met Leu Val Lys Glu Ala Val Val Ala Phe Leu
180 185 190
Pro Asp Ala Leu Val Thr Met Thr Gly Gly Phe Arg Arg Gly Lys Met
195 200 205
Thr Gly His Asp Val Asp Phe Leu Ile Thr Ser Pro Glu Ala Thr Glu
210 215 220
Glu Glu Glu Gln Gln Leu Leu His Lys Val Thr Asn Phe Trp Arg Gln
225 230 235 240
Gln Gly Leu Leu Leu Tyr Cys Asp Ile Ile Glu Ser Thr Phe Glu Lys
245 250 255
Phe Lys Leu Pro Ser Arg Lys Val Asp Ala Leu Asp His Phe Gln Lys
260 265 270
Cys Phe Leu Ile Leu Lys Leu His Arg Gly Leu Val Arg Ser Glu Glu
275 280 285
Ser Gly Gln Gln Glu Gly Lys Asp Trp Lys Ala Ile Arg Val Asp Leu
290 295 300
Val Met Cys Pro Tyr Glu Arg Arg Ala Phe Ala Leu Leu Gly Trp Thr
305 310 315 320
Gly Ser Arg Gln Phe Glu Arg Asp Leu Arg Arg Tyr Ala Thr His Glu
325 330 335
Arg Lys Met Met Leu Asp Asn His Ala Leu Tyr Asp Lys Thr Lys Arg
340 345 350
Val Phe Leu Glu Ala Glu Ser Glu Glu Glu Ile Phe Ala His Leu Gly
355 360 365
Leu Asp Tyr Ile Glu Pro Trp Glu Arg Asn Ala
370 375
<210> 33
<211> 379
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> N100or截短的新的
<400> 33
Ser Pro Ser Pro Val Pro Gly Ser Gln Asn Val Pro Ala Pro Val Val
1 5 10 15
Gln Lys Ile Ser Glu Tyr Ala Cys Gln Arg Arg Thr Thr Leu Asn Asn
20 25 30
His Asn Glu Leu Phe Thr Arg Ala Phe Asp Ile Leu Ala Glu Asn Tyr
35 40 45
Glu Phe Arg Glu Asn Glu Glu Ser Arg Asp Ala Phe Arg Arg Ala Ala
50 55 60
Ser Val Leu Lys Ser Leu Ser Phe Pro Ile Val Ser Met Lys Asp Ile
65 70 75 80
Glu Gly Ile Pro Cys Leu Gly Asp Lys Val Lys Arg Ile Ile Glu Glu
85 90 95
Ile Ile Glu Asp Gly Glu Ser Ser Glu Val Lys Ala Val Leu Asn Asp
100 105 110
Glu Arg Tyr Lys Ala Phe Lys Leu Phe Thr Ser Val Phe Gly Val Gly
115 120 125
Arg Lys Thr Ala Glu Lys Trp Phe Arg Met Gly Phe Arg Thr Leu Glu
130 135 140
Lys Ile Arg Ser Asp Lys Ser Leu Arg Phe Thr His Met Gln Lys Ala
145 150 155 160
Gly Phe Leu Tyr Tyr Glu Asp Leu Val Ser Arg Val Asn Arg Ala Glu
165 170 175
Ala Glu Ala Val Ser Met Leu Val Lys Glu Ala Val Val Ala Phe Leu
180 185 190
Pro Asp Ala Leu Val Thr Met Thr Gly Gly Phe Arg Leu Gly Lys Met
195 200 205
Thr Gly His Asp Val Asp Phe Leu Ile Thr Ser Pro Glu Ala Thr Glu
210 215 220
Glu Glu Glu Gln Gln Leu Leu His Lys Val Thr Asn Phe Trp Arg Gln
225 230 235 240
Gln Gly Leu Leu Leu Tyr Cys Asp Ile Ile Glu Ser Thr Phe Glu Lys
245 250 255
Phe Lys Leu Pro Ser Arg Thr Val Asp Ala Leu Asp His Phe Gln Lys
260 265 270
Cys Phe Leu Ile Leu Lys Leu His Arg Gly Leu Val Arg Ser Glu Glu
275 280 285
Ser Gly Gln Gln Glu Gly Lys Asp Trp Lys Ala Ile Arg Val Asp Leu
290 295 300
Val Met Cys Pro Tyr Glu Arg Arg Ala Phe Ala Leu Leu Gly Trp Thr
305 310 315 320
Gly Ser Pro Phe Phe Asn Arg Asp Leu Arg Arg Tyr Ala Thr His Glu
325 330 335
Arg Lys Met Met Leu Asp Asn His Ala Leu Tyr Asp Lys Thr Lys Arg
340 345 350
Val Phe Leu Glu Ala Glu Ser Glu Glu Glu Ile Phe Ala His Leu Gly
355 360 365
Leu Asp Tyr Ile Glu Pro Trp Glu Arg Asn Ala
370 375
<210> 34
<211> 404
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> N100or
<400> 34
Met Ala Ser Ser His His His His His His Ser Ser Gly Ser Glu Asn
1 5 10 15
Leu Tyr Phe Gln Thr Gly Ser Ser Gly Ser Pro Ser Pro Val Pro Gly
20 25 30
Ser Gln Asn Val Pro Ala Pro Val Val Gln Lys Ile Ser Glu Tyr Ala
35 40 45
Cys Gln Arg Arg Thr Thr Leu Asn Asn His Asn Glu Leu Phe Thr Arg
50 55 60
Ala Phe Asp Ile Leu Ala Glu Asn Tyr Glu Phe Arg Glu Asn Glu Glu
65 70 75 80
Ser Arg Asp Ala Phe Arg Arg Ala Ala Ser Val Leu Lys Ser Leu Ser
85 90 95
Phe Pro Ile Val Ser Met Lys Asp Ile Glu Gly Ile Pro Cys Leu Gly
100 105 110
Asp Lys Val Lys Arg Ile Ile Glu Glu Ile Ile Glu Asp Gly Glu Ser
115 120 125
Ser Glu Val Lys Ala Val Leu Asn Asp Glu Arg Tyr Lys Ala Phe Lys
130 135 140
Leu Phe Thr Ser Val Phe Gly Val Gly Arg Lys Thr Ala Glu Lys Trp
145 150 155 160
Phe Arg Met Gly Phe Arg Thr Leu Glu Lys Ile Arg Ser Asp Lys Ser
165 170 175
Leu Arg Phe Thr His Met Gln Lys Ala Gly Phe Leu Tyr Tyr Glu Asp
180 185 190
Leu Val Ser Arg Val Asn Arg Ala Glu Ala Glu Ala Val Ser Met Leu
195 200 205
Val Lys Glu Ala Val Val Ala Phe Leu Pro Asp Ala Leu Val Thr Met
210 215 220
Thr Gly Gly Phe Arg Leu Gly Lys Met Thr Gly His Asp Val Asp Phe
225 230 235 240
Leu Ile Thr Ser Pro Glu Ala Thr Glu Glu Glu Glu Gln Gln Leu Leu
245 250 255
His Lys Val Thr Asn Phe Trp Arg Gln Gln Gly Leu Leu Leu Tyr Cys
260 265 270
Asp Ile Ile Glu Ser Thr Phe Glu Lys Phe Lys Leu Pro Ser Arg Thr
275 280 285
Val Asp Ala Leu Asp His Phe Gln Lys Cys Phe Leu Ile Leu Lys Leu
290 295 300
His Arg Gly Leu Val Arg Ser Glu Glu Ser Gly Gln Gln Glu Gly Lys
305 310 315 320
Asp Trp Lys Ala Ile Arg Val Asp Leu Val Met Cys Pro Tyr Glu Arg
325 330 335
Arg Ala Phe Ala Leu Leu Gly Trp Thr Gly Ser Pro Phe Phe Asn Arg
340 345 350
Asp Leu Arg Arg Tyr Ala Thr His Glu Arg Lys Met Met Leu Asp Asn
355 360 365
His Ala Leu Tyr Asp Lys Thr Lys Arg Val Phe Leu Glu Ala Glu Ser
370 375 380
Glu Glu Glu Ile Phe Ala His Leu Gly Leu Asp Tyr Ile Glu Pro Trp
385 390 395 400
Glu Arg Asn Ala
<210> 35
<211> 379
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> N14截短的野生型(乌干达红疣猴)
<400> 35
Ser Asp Ser Thr Asn Pro Gly Leu Pro Lys Thr Pro Pro Thr Ala Ile
1 5 10 15
Gln Lys Ile Ser Gln Tyr Ala Cys Gln Arg Arg Thr Thr Leu Asn Asn
20 25 30
Cys Asn Gln Ile Phe Thr Asp Ala Phe Asp Ile Leu Ala Glu Asn Cys
35 40 45
Glu Phe Arg Glu Asn Glu Asp Ser Cys Val Thr Phe Met Arg Ala Ala
50 55 60
Ser Val Leu Lys Ser Leu Pro Phe Thr Ile Ile Ser Met Lys Asp Thr
65 70 75 80
Glu Gly Ile Pro Cys Leu Gly Ser Lys Val Lys Cys Ile Ile Glu Glu
85 90 95
Ile Ile Glu Asp Gly Glu Ser Ser Glu Val Lys Ala Val Leu Asn Asp
100 105 110
Glu Arg Tyr Gln Ser Phe Lys Leu Phe Thr Ser Val Phe Gly Val Gly
115 120 125
Leu Lys Thr Ser Glu Lys Trp Phe Arg Met Gly Phe Arg Thr Leu Ser
130 135 140
Lys Val Arg Ser Asp Glu Ser Leu Lys Phe Thr Arg Met Gln Arg Ala
145 150 155 160
Gly Phe Leu Tyr Tyr Glu Asp Leu Val Ser Cys Val Thr Arg Ala Glu
165 170 175
Ala Glu Ala Val Ser Ala Leu Val Lys Glu Ala Val Trp Ala Phe Leu
180 185 190
Pro Asp Ala Phe Val Thr Met Thr Gly Gly Phe Arg Arg Gly Lys Lys
195 200 205
Met Gly His Asp Val Asp Phe Leu Ile Thr Ser Pro Gly Ser Thr Glu
210 215 220
Asp Glu Glu Gln Gln Leu Leu Gln Lys Val Met Asn Leu Trp Glu Lys
225 230 235 240
Lys Gly Leu Leu Leu Tyr Tyr Asp Leu Val Glu Ser Thr Phe Glu Lys
245 250 255
Leu Arg Leu Pro Ser Arg Lys Val Asp Ala Leu Asp His Phe Gln Lys
260 265 270
Cys Phe Leu Ile Phe Lys Leu Pro Leu Gln Arg Val Asp Ser Asp Gln
275 280 285
Ser Ser Trp Gln Gly Gly Lys Thr Trp Lys Ala Ile Arg Val Asp Leu
290 295 300
Val Met Cys Pro Tyr Glu Arg Arg Ala Phe Ala Leu Leu Gly Trp Thr
305 310 315 320
Gly Ser Arg Gln Phe Glu Arg Asp Leu Arg Arg Tyr Ala Thr His Glu
325 330 335
Arg Lys Met Ile Leu Asp Asn His Ala Leu Tyr Asp Lys Thr Lys Arg
340 345 350
Ile Phe Leu Lys Ala Glu Ser Glu Glu Glu Ile Phe Ala His Leu Gly
355 360 365
Leu Asp Tyr Ile Glu Pro Trp Glu Arg Asn Ala
370 375
<210> 36
<211> 379
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> N14截短的新的
<400> 36
Ser Pro Ser Pro Val Pro Gly Ser Gln Asn Val Pro Ala Pro Val Val
1 5 10 15
Gln Lys Ile Ser Gln Tyr Ala Cys Gln Arg Arg Thr Thr Leu Asn Asn
20 25 30
Tyr Asn Glu Ile Phe Thr Arg Ala Phe Asp Ile Leu Ala Glu Asn Ser
35 40 45
Glu Phe Arg Glu Asn Glu Asp Ser Tyr Val Thr Phe Arg Arg Ala Ala
50 55 60
Ser Val Leu Lys Ser Leu Pro Phe Thr Ile Ile Ser Met Lys Asp Thr
65 70 75 80
Glu Gly Ile Pro Cys Leu Gly Ser Lys Val Lys Arg Ile Ile Glu Glu
85 90 95
Ile Ile Glu Asp Gly Glu Ser Ser Glu Val Lys Ala Val Leu Asn Asp
100 105 110
Glu Arg Tyr Gln Ala Phe Lys Leu Phe Thr Ser Val Phe Gly Val Gly
115 120 125
Arg Lys Thr Ser Glu Lys Trp Phe Arg Met Gly Phe Arg Thr Leu Glu
130 135 140
Lys Val Arg Ser Asp Glu Ser Leu Lys Phe Thr Arg Met Gln Arg Ala
145 150 155 160
Gly Phe Leu Tyr Tyr Glu Asp Leu Val Ser Arg Val Thr Arg Ala Glu
165 170 175
Ala Glu Ala Val Ser Val Leu Val Lys Glu Ala Val Trp Ala Phe Leu
180 185 190
Pro Asp Ala Phe Val Thr Met Thr Gly Gly Phe Arg Leu Gly Lys Lys
195 200 205
Met Gly His Asp Val Asp Phe Leu Ile Thr Ser Pro Gly Ser Thr Glu
210 215 220
Asp Glu Glu Gln Gln Leu Leu Gln Lys Val Met Asn Leu Trp Glu Lys
225 230 235 240
Lys Gly Leu Leu Leu Tyr Tyr Asp Leu Val Glu Ser Thr Phe Glu Lys
245 250 255
Leu Arg Leu Pro Ser Arg Thr Val Asp Ala Leu Asp His Phe Gln Lys
260 265 270
Cys Phe Leu Ile Phe Lys Leu Pro Leu Gln Arg Val Gly Ser Asp Gln
275 280 285
Ser Ser Trp Gln Glu Gly Lys Thr Trp Lys Ala Ile Arg Val Asp Leu
290 295 300
Val Met Cys Pro Tyr Glu Arg Arg Ala Phe Ala Leu Leu Gly Trp Thr
305 310 315 320
Gly Ser Ala Phe Phe Asn Arg Asp Leu Arg Arg Tyr Ala Thr His Glu
325 330 335
Arg Lys Met Ile Leu Asp Asn His Ala Leu Tyr Asp Lys Thr Lys Arg
340 345 350
Ile Phe Leu Lys Ala Glu Ser Glu Glu Glu Ile Phe Ala His Leu Gly
355 360 365
Leu Asp Tyr Ile Glu Pro Trp Glu Arg Asn Ala
370 375
<210> 37
<211> 404
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUNECE)
<220>
<223> N14
<400> 37
Met Ala Ser Ser His His His His His His Ser Ser Gly Ser Glu Asn
1 5 10 15
Leu Tyr Phe Gln Thr Gly Ser Ser Gly Ser Pro Ser Pro Val Pro Gly
20 25 30
Ser Gln Asn Val Pro Ala Pro Val Val Gln Lys Ile Ser Gln Tyr Ala
35 40 45
Cys Gln Arg Arg Thr Thr Leu Asn Asn Tyr Asn Glu Ile Phe Thr Arg
50 55 60
Ala Phe Asp Ile Leu Ala Glu Asn Ser Glu Phe Arg Glu Asn Glu Asp
65 70 75 80
Ser Tyr Val Thr Phe Arg Arg Ala Ala Ser Val Leu Lys Ser Leu Pro
85 90 95
Phe Thr Ile Ile Ser Met Lys Asp Thr Glu Gly Ile Pro Cys Leu Gly
100 105 110
Ser Lys Val Lys Arg Ile Ile Glu Glu Ile Ile Glu Asp Gly Glu Ser
115 120 125
Ser Glu Val Lys Ala Val Leu Asn Asp Glu Arg Tyr Gln Ala Phe Lys
130 135 140
Leu Phe Thr Ser Val Phe Gly Val Gly Arg Lys Thr Ser Glu Lys Trp
145 150 155 160
Phe Arg Met Gly Phe Arg Thr Leu Glu Lys Val Arg Ser Asp Glu Ser
165 170 175
Leu Lys Phe Thr Arg Met Gln Arg Ala Gly Phe Leu Tyr Tyr Glu Asp
180 185 190
Leu Val Ser Arg Val Thr Arg Ala Glu Ala Glu Ala Val Ser Val Leu
195 200 205
Val Lys Glu Ala Val Trp Ala Phe Leu Pro Asp Ala Phe Val Thr Met
210 215 220
Thr Gly Gly Phe Arg Leu Gly Lys Lys Met Gly His Asp Val Asp Phe
225 230 235 240
Leu Ile Thr Ser Pro Gly Ser Thr Glu Asp Glu Glu Gln Gln Leu Leu
245 250 255
Gln Lys Val Met Asn Leu Trp Glu Lys Lys Gly Leu Leu Leu Tyr Tyr
260 265 270
Asp Leu Val Glu Ser Thr Phe Glu Lys Leu Arg Leu Pro Ser Arg Thr
275 280 285
Val Asp Ala Leu Asp His Phe Gln Lys Cys Phe Leu Ile Phe Lys Leu
290 295 300
Pro Leu Gln Arg Val Gly Ser Asp Gln Ser Ser Trp Gln Glu Gly Lys
305 310 315 320
Thr Trp Lys Ala Ile Arg Val Asp Leu Val Met Cys Pro Tyr Glu Arg
325 330 335
Arg Ala Phe Ala Leu Leu Gly Trp Thr Gly Ser Ala Phe Phe Asn Arg
340 345 350
Asp Leu Arg Arg Tyr Ala Thr His Glu Arg Lys Met Ile Leu Asp Asn
355 360 365
His Ala Leu Tyr Asp Lys Thr Lys Arg Ile Phe Leu Lys Ala Glu Ser
370 375 380
Glu Glu Glu Ile Phe Ala His Leu Gly Leu Asp Tyr Ile Glu Pro Trp
385 390 395 400
Glu Arg Asn Ala
<210> 38
<211> 379
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> N27截短的野生型(野猪)
<400> 38
Ser Ala Ser Pro Ser Pro Gly Ser Gln Asn Thr Leu Pro Pro Ala Val
1 5 10 15
Lys Lys Ile Ser Gln Tyr Ala Cys Gln Arg Arg Thr Thr Leu Asn Asn
20 25 30
Cys Asn His Ile Phe Thr Asp Ala Phe Glu Val Leu Ala Glu Asn Tyr
35 40 45
Glu Phe Arg Glu Asn Glu Thr Phe Cys Leu Ala Phe Met Arg Ala Ala
50 55 60
Ser Val Leu Lys Ser Leu Pro Phe Thr Ile Ile Ser Met Lys Asp Thr
65 70 75 80
Glu Gly Ile Pro Cys Leu Gly Asp Lys Val Lys Cys Val Ile Glu Glu
85 90 95
Ile Ile Glu Asp Gly Glu Ser Ser Glu Val Lys Ala Val Leu Asn Asp
100 105 110
Glu Arg Tyr Gln Ser Phe Lys Leu Phe Thr Ser Val Phe Gly Val Gly
115 120 125
Leu Lys Thr Ser Glu Arg Trp Phe Arg Met Gly Phe Arg Ser Leu Ser
130 135 140
Lys Ile Arg Ser Asp Lys Thr Leu Lys Phe Thr Arg Met Gln Lys Ala
145 150 155 160
Gly Phe Leu Tyr Tyr Glu Asp Leu Val Ser Cys Val Thr Arg Ala Glu
165 170 175
Ala Glu Ala Val Gly Val Leu Val Lys Glu Ala Val Gln Ala Phe Leu
180 185 190
Pro Asp Ala Phe Val Thr Met Thr Gly Gly Phe Arg Arg Gly Lys Lys
195 200 205
Met Gly His Asp Val Asp Phe Leu Ile Thr Ser Pro Gly Ser Thr Asp
210 215 220
Asp Glu Glu Gln Gln Leu Leu Pro Lys Val Val Asn Leu Trp Glu Arg
225 230 235 240
Glu Gly Leu Leu Leu Tyr Cys Asp Leu Val Glu Ser Thr Leu Glu Lys
245 250 255
Ser Lys Leu Pro Ser Arg Asn Val Asp Ala Leu Asp His Phe Gln Lys
260 265 270
Cys Phe Leu Ile Leu Lys Leu His His Gln Arg Val Asp Ser Gly Met
275 280 285
Ser Ser Gln Gln Glu Gly Lys Thr Trp Lys Ala Ile Arg Val Asp Leu
290 295 300
Val Met Cys Pro Tyr Glu Leu Arg Ala Phe Ala Leu Leu Gly Trp Thr
305 310 315 320
Gly Ser Arg Gln Phe Glu Arg Asp Leu Arg Arg Tyr Ala Thr His Glu
325 330 335
Arg Lys Met Ile Leu Asp Asn His Ala Leu Tyr Asp Lys Thr Lys Arg
340 345 350
Ile Phe Leu Lys Ala Glu Ser Glu Glu Glu Ile Phe Ala His Leu Gly
355 360 365
Leu Asp Tyr Leu Glu Pro Trp Glu Arg Asn Ala
370 375
<210> 39
<211> 379
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> N27截短的新的
<400> 39
Ser Pro Ser Pro Val Pro Gly Ser Gln Asn Val Pro Ala Pro Val Val
1 5 10 15
Lys Lys Ile Ser Gln Tyr Ala Cys Gln Arg Arg Thr Thr Leu Asn Asn
20 25 30
Tyr Asn Glu Ile Phe Thr Arg Ala Phe Glu Ile Leu Ala Glu Asn Tyr
35 40 45
Glu Phe Arg Glu Asn Glu Glu Ser Tyr Val Thr Phe Arg Arg Ala Ala
50 55 60
Ser Val Leu Lys Ser Leu Pro Phe Thr Ile Ile Ser Met Lys Asp Thr
65 70 75 80
Glu Gly Ile Pro Cys Leu Gly Asp Lys Val Lys Arg Val Ile Glu Glu
85 90 95
Ile Ile Glu Asp Gly Glu Ser Ser Glu Val Lys Ala Val Leu Asn Asp
100 105 110
Glu Arg Tyr Lys Ala Phe Lys Leu Phe Thr Ser Val Phe Gly Val Gly
115 120 125
Arg Lys Thr Ser Glu Lys Trp Phe Arg Met Gly Phe Arg Thr Leu Glu
130 135 140
Lys Ile Arg Ser Asp Lys Thr Leu Lys Phe Thr Arg Met Gln Lys Ala
145 150 155 160
Gly Phe Leu Tyr Tyr Glu Asp Leu Val Ser Arg Val Thr Arg Ala Glu
165 170 175
Ala Glu Ala Val Ser Val Leu Val Lys Glu Ala Val Trp Ala Phe Leu
180 185 190
Pro Asp Ala Phe Val Thr Met Thr Gly Gly Phe Arg Leu Gly Lys Lys
195 200 205
Ile Gly His Asp Val Asp Phe Leu Ile Thr Ser Pro Gly Ser Thr Glu
210 215 220
Glu Glu Glu Gln Gln Leu Leu His Lys Val Ile Asn Leu Trp Glu Lys
225 230 235 240
Lys Gly Leu Leu Leu Tyr Tyr Asp Leu Val Glu Ser Thr Phe Glu Lys
245 250 255
Leu Lys Leu Pro Ser Arg Thr Val Asp Ala Leu Asp His Phe Gln Lys
260 265 270
Cys Phe Leu Ile Leu Lys Leu His His Gln Arg Val Gly Ser Gly Lys
275 280 285
Ser Ser Gln Gln Glu Gly Lys Thr Trp Lys Ala Ile Arg Val Asp Leu
290 295 300
Val Met Cys Pro Tyr Glu Arg Arg Ala Phe Ala Leu Leu Gly Trp Thr
305 310 315 320
Gly Ser Pro Gln Phe Asn Arg Asp Leu Arg Arg Tyr Ala Thr His Glu
325 330 335
Arg Lys Met Met Leu Asp Asn His Ala Leu Tyr Asp Lys Thr Lys Arg
340 345 350
Ile Phe Leu Lys Ala Glu Ser Glu Glu Glu Ile Phe Ala His Leu Gly
355 360 365
Leu Asp Tyr Ile Glu Pro Trp Glu Arg Asn Ala
370 375
<210> 40
<211> 404
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> N27
<400> 40
Met Ala Ser Ser His His His His His His Ser Ser Gly Ser Glu Asn
1 5 10 15
Leu Tyr Phe Gln Thr Gly Ser Ser Gly Ser Pro Ser Pro Val Pro Gly
20 25 30
Ser Gln Asn Val Pro Ala Pro Val Val Lys Lys Ile Ser Gln Tyr Ala
35 40 45
Cys Gln Arg Arg Thr Thr Leu Asn Asn Tyr Asn Glu Ile Phe Thr Arg
50 55 60
Ala Phe Glu Ile Leu Ala Glu Asn Tyr Glu Phe Arg Glu Asn Glu Glu
65 70 75 80
Ser Tyr Val Thr Phe Arg Arg Ala Ala Ser Val Leu Lys Ser Leu Pro
85 90 95
Phe Thr Ile Ile Ser Met Lys Asp Thr Glu Gly Ile Pro Cys Leu Gly
100 105 110
Asp Lys Val Lys Arg Val Ile Glu Glu Ile Ile Glu Asp Gly Glu Ser
115 120 125
Ser Glu Val Lys Ala Val Leu Asn Asp Glu Arg Tyr Lys Ala Phe Lys
130 135 140
Leu Phe Thr Ser Val Phe Gly Val Gly Arg Lys Thr Ser Glu Lys Trp
145 150 155 160
Phe Arg Met Gly Phe Arg Thr Leu Glu Lys Ile Arg Ser Asp Lys Thr
165 170 175
Leu Lys Phe Thr Arg Met Gln Lys Ala Gly Phe Leu Tyr Tyr Glu Asp
180 185 190
Leu Val Ser Arg Val Thr Arg Ala Glu Ala Glu Ala Val Ser Val Leu
195 200 205
Val Lys Glu Ala Val Trp Ala Phe Leu Pro Asp Ala Phe Val Thr Met
210 215 220
Thr Gly Gly Phe Arg Leu Gly Lys Lys Ile Gly His Asp Val Asp Phe
225 230 235 240
Leu Ile Thr Ser Pro Gly Ser Thr Glu Glu Glu Glu Gln Gln Leu Leu
245 250 255
His Lys Val Ile Asn Leu Trp Glu Lys Lys Gly Leu Leu Leu Tyr Tyr
260 265 270
Asp Leu Val Glu Ser Thr Phe Glu Lys Leu Lys Leu Pro Ser Arg Thr
275 280 285
Val Asp Ala Leu Asp His Phe Gln Lys Cys Phe Leu Ile Leu Lys Leu
290 295 300
His His Gln Arg Val Gly Ser Gly Lys Ser Ser Gln Gln Glu Gly Lys
305 310 315 320
Thr Trp Lys Ala Ile Arg Val Asp Leu Val Met Cys Pro Tyr Glu Arg
325 330 335
Arg Ala Phe Ala Leu Leu Gly Trp Thr Gly Ser Pro Gln Phe Asn Arg
340 345 350
Asp Leu Arg Arg Tyr Ala Thr His Glu Arg Lys Met Met Leu Asp Asn
355 360 365
His Ala Leu Tyr Asp Lys Thr Lys Arg Ile Phe Leu Lys Ala Glu Ser
370 375 380
Glu Glu Glu Ile Phe Ala His Leu Gly Leu Asp Tyr Ile Glu Pro Trp
385 390 395 400
Glu Arg Asn Ala
<210> 41
<211> 379
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> N35截短的野生型(西伯利亚虎)
<400> 41
Tyr Ser Ala Ser Pro Asn Pro Glu Leu Gln Lys Thr Pro Pro Leu Val
1 5 10 15
Lys Lys Ile Pro Leu Tyr Ala Cys Gln Arg Arg Thr Thr Leu Asn Asn
20 25 30
Phe Asn His Val Phe Thr Asp Ala Phe Glu Val Leu Ala Glu Asn Tyr
35 40 45
Glu Phe Lys Glu Asn Glu Val Ser Ser Ala Thr Phe Met Arg Ala Ala
50 55 60
Ser Val Leu Lys Ser Leu Pro Phe Thr Ile Ile Ser Met Lys Asp Thr
65 70 75 80
Glu Gly Ile Pro Cys Leu Gly Asp Lys Val Lys Cys Val Ile Glu Glu
85 90 95
Ile Ile Glu Asp Gly Glu Ser Ser Glu Val Lys Ala Val Leu Asn Asp
100 105 110
Glu Arg Tyr Gln Ser Phe Lys Leu Phe Thr Ser Val Phe Gly Val Gly
115 120 125
Leu Lys Thr Ser Glu Lys Trp Phe Arg Met Gly Phe Arg Thr Leu Ser
130 135 140
Lys Ile Lys Ser Asp Lys Thr Leu Lys Phe Thr Gln Met Gln Lys Ala
145 150 155 160
Gly Phe Leu Tyr Tyr Glu Asp Leu Val Ser Cys Val Thr Arg Ala Glu
165 170 175
Ala Glu Ala Val Gly Val Leu Val Lys Glu Ala Val Trp Ala Phe Leu
180 185 190
Pro Asp Ala Phe Val Thr Met Thr Gly Gly Phe Arg Arg Gly Lys Lys
195 200 205
Ile Gly His Asp Val Asp Phe Leu Ile Thr Ser Pro Gly Ser Thr Asp
210 215 220
Glu Glu Glu Glu Glu Leu Leu Pro Lys Val Ile Asn Leu Trp Gln Arg
225 230 235 240
Lys Glu Leu Leu Leu Tyr Tyr Asp Leu Val Glu Ser Thr Phe Glu Lys
245 250 255
Leu Lys Leu Pro Ser Arg Lys Val Asp Ala Leu Asp His Phe Gln Lys
260 265 270
Cys Phe Leu Ile Leu Lys Leu His His Gln Arg Val Asp Ser Gly Lys
275 280 285
Cys Ser Gln Gln Glu Gly Lys Thr Trp Lys Ala Ile Arg Val Asp Leu
290 295 300
Val Met Cys Pro Tyr Glu Arg Arg Ala Phe Ala Leu Leu Gly Trp Thr
305 310 315 320
Gly Ser Arg Gln Phe Glu Arg Asp Leu Arg Arg Tyr Ala Thr His Glu
325 330 335
Arg Lys Met Ile Leu Asp Asn His Ala Leu Tyr Asp Lys Thr Lys Lys
340 345 350
Ile Phe Leu Lys Ala Glu Ser Glu Glu Glu Ile Phe Ala His Leu Gly
355 360 365
Leu Asp Tyr Ile Glu Pro Trp Glu Arg Asn Ala
370 375
<210> 42
<211> 379
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> N35截短的新的
<400> 42
Ser Pro Ser Pro Val Pro Gly Ser Gln Asn Val Pro Ala Pro Val Val
1 5 10 15
Lys Lys Ile Ser Gln Tyr Ala Cys Gln Arg Arg Thr Thr Leu Asn Asn
20 25 30
Tyr Asn Glu Ile Phe Thr Arg Ala Phe Glu Val Leu Ala Glu Asn Tyr
35 40 45
Glu Phe Arg Glu Asn Glu Glu Ser Tyr Val Thr Phe Arg Arg Ala Ala
50 55 60
Ser Val Leu Lys Ser Leu Pro Phe Thr Ile Ile Ser Met Lys Asp Thr
65 70 75 80
Glu Gly Ile Pro Cys Leu Gly Asp Lys Val Lys Arg Val Ile Glu Glu
85 90 95
Ile Ile Glu Asp Gly Glu Ser Ser Glu Val Lys Ala Val Leu Asn Asp
100 105 110
Glu Arg Tyr Gln Ala Phe Lys Leu Phe Thr Ser Val Phe Gly Val Gly
115 120 125
Arg Lys Thr Ser Glu Lys Trp Phe Arg Met Gly Phe Arg Thr Leu Glu
130 135 140
Lys Ile Arg Ser Asp Lys Thr Leu Lys Phe Thr Arg Met Gln Lys Ala
145 150 155 160
Gly Phe Leu Tyr Tyr Glu Asp Leu Ala Glu Arg Val Thr Arg Ala Glu
165 170 175
Ala Glu Ala Val Ser Val Leu Val Lys Glu Ala Val Trp Ala Phe Leu
180 185 190
Pro Asp Ala Phe Val Thr Met Thr Gly Gly Phe Arg Leu Gly Lys Lys
195 200 205
Ile Gly His Asp Val Asp Phe Leu Ile Thr Ser Pro Gly Ser Thr Glu
210 215 220
Glu Glu Glu Gln Gln Leu Leu Pro Lys Val Ile Asn Leu Trp Glu Arg
225 230 235 240
Lys Gly Leu Leu Leu Tyr Tyr Asp Leu Val Glu Ser Thr Phe Glu Lys
245 250 255
Leu Lys Leu Pro Ser Arg Lys Val Asp Ala Leu Asp His Phe Gln Lys
260 265 270
Cys Phe Leu Ile Leu Lys Leu His His Gln Arg Val Gly Ser Gly Lys
275 280 285
Ser Ser Gln Gln Glu Gly Lys Thr Trp Lys Ala Ile Arg Val Asp Leu
290 295 300
Val Met Cys Pro Tyr Glu Arg Arg Ala Phe Ala Leu Leu Gly Trp Thr
305 310 315 320
Gly Ser Ala Phe Phe Asn Arg Asp Leu Arg Arg Tyr Ala Thr His Glu
325 330 335
Arg Lys Met Ile Leu Asp Asn His Ala Leu Tyr Asp Lys Thr Lys Arg
340 345 350
Ile Phe Leu Lys Ala Glu Ser Glu Glu Glu Ile Phe Ala His Leu Gly
355 360 365
Leu Asp Tyr Ile Glu Pro Trp Glu Arg Asn Ala
370 375
<210> 43
<211> 410
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> N35
<400> 43
Met Ala Ser Ser His His His His His His Ser Ser Gly Ser Glu Asn
1 5 10 15
Leu Tyr Phe Gln Thr Gly Ser Ser Gly Ser Pro Ser Pro Val Pro Gly
20 25 30
Ser Gln Asn Val Pro Ala Pro Val Val Lys Lys Ile Ser Gln Tyr Ala
35 40 45
Cys Gln Arg Arg Thr Thr Leu Asn Asn Tyr Asn Glu Ile Phe Thr Arg
50 55 60
Ala Phe Glu Val Leu Ala Glu Asn Tyr Glu Phe Arg Glu Asn Glu Glu
65 70 75 80
Ser Tyr Val Thr Phe Arg Arg Ala Ala Ser Val Leu Lys Ser Leu Pro
85 90 95
Phe Thr Ile Ile Ser Met Lys Asp Thr Glu Gly Ile Pro Cys Leu Gly
100 105 110
Asp Lys Val Lys Arg Val Ile Glu Glu Ile Ile Glu Asp Gly Glu Ser
115 120 125
Ser Glu Val Lys Ala Val Leu Asn Asp Glu Arg Tyr Gln Ala Phe Lys
130 135 140
Leu Phe Thr Ser Val Phe Gly Val Gly Arg Lys Thr Ser Glu Lys Trp
145 150 155 160
Phe Arg Met Gly Phe Arg Thr Leu Glu Lys Ile Arg Ser Asp Lys Thr
165 170 175
Leu Lys Phe Thr Arg Met Gln Lys Ala Gly Phe Leu Tyr Tyr Glu Asp
180 185 190
Leu Ala Glu Arg Val Thr Arg Ala Glu Ala Glu Ala Val Ser Val Leu
195 200 205
Val Lys Glu Ala Val Trp Ala Phe Leu Pro Asp Ala Phe Val Thr Met
210 215 220
Thr Gly Gly Phe Arg Leu Gly Lys Lys Ile Gly His Asp Val Asp Phe
225 230 235 240
Leu Ile Thr Ser Pro Gly Ser Thr Glu Glu Glu Glu Gln Gln Leu Leu
245 250 255
Pro Lys Val Ile Asn Leu Trp Glu Arg Lys Gly Leu Leu Leu Tyr Tyr
260 265 270
Asp Leu Val Glu Ser Thr Phe Glu Lys Leu Lys Leu Pro Ser Arg Lys
275 280 285
Val Asp Ala Leu Asp His Phe Gln Lys Cys Phe Leu Ile Leu Lys Leu
290 295 300
His His Gln Arg Val Gly Ser Gly Lys Ser Ser Gln Gln Glu Gly Lys
305 310 315 320
Thr Trp Lys Ala Ile Arg Val Asp Leu Val Met Cys Pro Tyr Glu Arg
325 330 335
Arg Ala Phe Ala Leu Leu Gly Trp Thr Gly Ser Ala Phe Phe Asn Arg
340 345 350
Asp Leu Arg Arg Tyr Ala Thr His Glu Arg Lys Met Ile Leu Asp Asn
355 360 365
His Ala Leu Tyr Asp Lys Thr Lys Arg Ile Phe Leu Lys Ala Glu Ser
370 375 380
Glu Glu Glu Ile Phe Ala His Leu Gly Leu Asp Tyr Ile Glu Pro Trp
385 390 395 400
Glu Arg Asn Ala Ala Ala Ala Ile Gly Cys
405 410
<210> 44
<211> 365
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> N72截短的野生型(水牛)
<400> 44
Leu Ala Val Lys Lys Ile Ser Gln Tyr Ala Cys Gln Arg Lys Thr Thr
1 5 10 15
Leu Asn Asn Tyr Asn His Ile Phe Thr Asp Ala Phe Glu Ile Leu Ala
20 25 30
Glu Asn Ser Glu Phe Lys Glu Asn Glu Val Ser Tyr Val Thr Phe Met
35 40 45
Arg Ala Ala Ser Val Leu Lys Ser Leu Pro Phe Thr Ile Ile Ser Met
50 55 60
Lys Asp Thr Gln Gly Ile Pro Cys Leu Gly Asp Lys Val Lys Cys Val
65 70 75 80
Ile Glu Glu Ile Ile Glu Asp Gly Glu Ser Ser Glu Val Lys Ala Val
85 90 95
Leu Asn Asp Glu Arg Tyr Gln Ser Phe Lys Leu Phe Thr Ser Val Phe
100 105 110
Gly Val Gly Leu Lys Thr Ser Glu Lys Trp Phe Arg Met Gly Phe Arg
115 120 125
Ser Leu Ser Lys Ile Thr Ser Asp Lys Thr Leu Lys Phe Thr Lys Met
130 135 140
Gln Lys Ala Gly Phe Leu Tyr Tyr Glu Asp Leu Val Ser Cys Val Thr
145 150 155 160
Arg Ala Glu Ala Glu Ala Val Gly Val Leu Val Lys Glu Ala Val Trp
165 170 175
Ala Phe Leu Pro Asp Ala Phe Ile Thr Met Thr Gly Gly Phe Arg Arg
180 185 190
Gly Lys Lys Ile Gly His Asp Val Asp Phe Leu Ile Thr Ser Pro Gly
195 200 205
Ser Ala Glu Asp Glu Glu Gln Leu Leu Pro Lys Val Ile Asn Leu Trp
210 215 220
Glu Lys Lys Gly Leu Leu Leu Tyr Tyr Asp Leu Val Glu Ser Thr Phe
225 230 235 240
Glu Lys Phe Lys Leu Pro Ser Arg Gln Val Asp Thr Leu Asp His Phe
245 250 255
Gln Lys Cys Phe Leu Ile Leu Lys Leu His His Gln Arg Val Asp Ser
260 265 270
Gly Arg Ser Asn Gln Gln Glu Gly Lys Thr Trp Lys Ala Ile Arg Val
275 280 285
Asp Leu Val Met Cys Pro Tyr Glu Asn Arg Ala Phe Ala Leu Leu Gly
290 295 300
Trp Thr Gly Ser Arg Gln Phe Glu Arg Asp Ile Arg Arg Tyr Ala Thr
305 310 315 320
His Glu Arg Lys Met Met Leu Asp Asn His Ala Leu Tyr Asp Lys Thr
325 330 335
Lys Arg Val Phe Leu Lys Ala Glu Ser Glu Glu Glu Ile Phe Ala His
340 345 350
Leu Gly Leu Asp Tyr Ile Glu Pro Trp Glu Arg Asn Ala
355 360 365
<210> 45
<211> 366
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> N72截短的新的
<400> 45
Ser Val Val Lys Lys Ile Ser Gln Tyr Ala Cys Gln Arg Arg Thr Thr
1 5 10 15
Leu Asn Asn Tyr Asn Glu Ile Phe Thr Arg Ala Phe Glu Ile Leu Ala
20 25 30
Glu Asn Tyr Glu Phe Lys Glu Asn Glu Glu Ser Tyr Val Thr Phe Arg
35 40 45
Arg Ala Ala Ser Val Leu Lys Ser Leu Pro Phe Thr Ile Ile Ser Met
50 55 60
Lys Asp Thr Glu Gly Ile Pro Cys Leu Gly Asp Lys Val Lys Arg Val
65 70 75 80
Ile Glu Glu Ile Ile Glu Asp Gly Glu Ser Ser Glu Val Lys Ala Val
85 90 95
Leu Asn Asp Glu Arg Tyr Gln Ala Phe Lys Leu Phe Thr Ser Val Phe
100 105 110
Gly Val Gly Arg Lys Thr Ser Glu Lys Trp Phe Arg Met Gly Phe Arg
115 120 125
Ser Leu Glu Lys Ile Arg Ser Asp Lys Thr Leu Lys Phe Thr Arg Met
130 135 140
Gln Lys Ala Gly Phe Leu Tyr Tyr Glu Asp Leu Val Ser Arg Val Thr
145 150 155 160
Arg Ala Glu Ala Glu Ala Val Gly Val Leu Val Lys Glu Ala Val Trp
165 170 175
Ala Phe Leu Pro Asp Ala Phe Val Thr Met Thr Gly Gly Phe Arg Leu
180 185 190
Gly Lys Lys Ile Gly His Asp Val Asp Phe Leu Ile Thr Ser Pro Gly
195 200 205
Ser Thr Glu Asp Glu Glu Gln Gln Leu Leu Pro Lys Val Ile Asn Leu
210 215 220
Trp Glu Arg Lys Gly Leu Leu Leu Tyr Tyr Asp Leu Val Glu Ser Thr
225 230 235 240
Phe Glu Lys Phe Lys Leu Pro Ser Arg Gln Val Asp Ala Leu Asp His
245 250 255
Phe Gln Lys Cys Phe Leu Ile Leu Lys Leu His His Gln Arg Val Gly
260 265 270
Ser Gly Lys Ser Ser Gln Gln Glu Gly Lys Thr Trp Lys Ala Ile Arg
275 280 285
Val Asp Leu Val Met Cys Pro Tyr Glu Gln Arg Ala Phe Ala Leu Leu
290 295 300
Gly Trp Thr Gly Ser Ala Phe Phe Asn Arg Asp Leu Arg Arg Tyr Ala
305 310 315 320
Thr His Glu Arg Lys Met Met Leu Asp Asn His Ala Leu Tyr Asp Lys
325 330 335
Thr Lys Arg Ile Phe Leu Lys Ala Glu Ser Glu Glu Glu Ile Phe Ala
340 345 350
His Leu Gly Leu Asp Tyr Ile Glu Pro Arg Glu Arg Asn Ala
355 360 365
<210> 46
<211> 391
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> N72
<400> 46
Met Ala Ser Ser His His His His His His Ser Ser Gly Ser Glu Asn
1 5 10 15
Leu Tyr Phe Gln Thr Gly Ser Ser Gly Ser Val Val Lys Lys Ile Ser
20 25 30
Gln Tyr Ala Cys Gln Arg Arg Thr Thr Leu Asn Asn Tyr Asn Glu Ile
35 40 45
Phe Thr Arg Ala Phe Glu Ile Leu Ala Glu Asn Tyr Glu Phe Lys Glu
50 55 60
Asn Glu Glu Ser Tyr Val Thr Phe Arg Arg Ala Ala Ser Val Leu Lys
65 70 75 80
Ser Leu Pro Phe Thr Ile Ile Ser Met Lys Asp Thr Glu Gly Ile Pro
85 90 95
Cys Leu Gly Asp Lys Val Lys Arg Val Ile Glu Glu Ile Ile Glu Asp
100 105 110
Gly Glu Ser Ser Glu Val Lys Ala Val Leu Asn Asp Glu Arg Tyr Gln
115 120 125
Ala Phe Lys Leu Phe Thr Ser Val Phe Gly Val Gly Arg Lys Thr Ser
130 135 140
Glu Lys Trp Phe Arg Met Gly Phe Arg Ser Leu Glu Lys Ile Arg Ser
145 150 155 160
Asp Lys Thr Leu Lys Phe Thr Arg Met Gln Lys Ala Gly Phe Leu Tyr
165 170 175
Tyr Glu Asp Leu Val Ser Arg Val Thr Arg Ala Glu Ala Glu Ala Val
180 185 190
Gly Val Leu Val Lys Glu Ala Val Trp Ala Phe Leu Pro Asp Ala Phe
195 200 205
Val Thr Met Thr Gly Gly Phe Arg Leu Gly Lys Lys Ile Gly His Asp
210 215 220
Val Asp Phe Leu Ile Thr Ser Pro Gly Ser Thr Glu Asp Glu Glu Gln
225 230 235 240
Gln Leu Leu Pro Lys Val Ile Asn Leu Trp Glu Arg Lys Gly Leu Leu
245 250 255
Leu Tyr Tyr Asp Leu Val Glu Ser Thr Phe Glu Lys Phe Lys Leu Pro
260 265 270
Ser Arg Gln Val Asp Ala Leu Asp His Phe Gln Lys Cys Phe Leu Ile
275 280 285
Leu Lys Leu His His Gln Arg Val Gly Ser Gly Lys Ser Ser Gln Gln
290 295 300
Glu Gly Lys Thr Trp Lys Ala Ile Arg Val Asp Leu Val Met Cys Pro
305 310 315 320
Tyr Glu Gln Arg Ala Phe Ala Leu Leu Gly Trp Thr Gly Ser Ala Phe
325 330 335
Phe Asn Arg Asp Leu Arg Arg Tyr Ala Thr His Glu Arg Lys Met Met
340 345 350
Leu Asp Asn His Ala Leu Tyr Asp Lys Thr Lys Arg Ile Phe Leu Lys
355 360 365
Ala Glu Ser Glu Glu Glu Ile Phe Ala His Leu Gly Leu Asp Tyr Ile
370 375 380
Glu Pro Arg Glu Arg Asn Ala
385 390
<210> 47
<211> 379
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> N93or截短的野生型(黄腹旱獭)
<400> 47
Pro Asp His Ser Asn Ser Asp Pro Gln Arg Ile Pro Pro Pro Ala Val
1 5 10 15
Gln Thr Ile Ser Gln Tyr Ala Cys Gln Arg Arg Thr Thr Leu Asn Asn
20 25 30
Cys Asn Arg Val Phe Thr Asp Ala Phe Asp Val Leu Ala Glu Asn Tyr
35 40 45
Glu Phe Arg Glu Asn Glu Ser Cys Ser Val Val Phe Met Arg Ala Ala
50 55 60
Ser Val Leu Lys Ser Leu Pro Phe Thr Ile Ile Ser Met Arg Asp Leu
65 70 75 80
Glu Gly Ile Pro Cys Leu Glu Gly Lys Ala Lys Ser Ile Ile Glu Glu
85 90 95
Ile Ile Glu Asp Gly Glu Ser Ser Glu Val Lys Ala Val Leu Asn Asp
100 105 110
Glu Arg Tyr Lys Ser Phe Lys Leu Phe Thr Ser Val Phe Gly Val Gly
115 120 125
Leu Lys Thr Ser Glu Lys Trp Phe Arg Met Gly Phe Arg Thr Leu Ser
130 135 140
Lys Ile Arg Ser Asp Lys Ser Leu Lys Phe Thr His Met Gln Lys Ala
145 150 155 160
Gly Phe Leu Tyr Tyr Glu Asp Leu Val Ser Cys Val Thr Arg Ala Glu
165 170 175
Ala Glu Ala Val Ser Val Leu Val Lys Glu Ala Val Trp Ala Phe Leu
180 185 190
Pro Asp Ala Phe Ile Thr Met Thr Gly Gly Phe Arg Arg Gly Lys Asn
195 200 205
Ile Gly His Asp Val Asp Phe Leu Ile Thr Ser Ala Glu Ala Thr Glu
210 215 220
Glu Glu Glu Gln Gln Leu Leu His Lys Val Thr Asn Leu Trp Glu Lys
225 230 235 240
Lys Gly Leu Leu Leu Tyr Cys Asp Leu Val Glu Ser Thr Phe Glu Lys
245 250 255
Leu Lys Thr Pro Ser Arg Lys Val Asp Ala Leu Asp His Phe Gln Lys
260 265 270
Cys Phe Leu Ile Leu Lys Leu His His Gln Arg Val Asp Ser Asp Lys
275 280 285
Ala Ser Gln Gln Gly Gly Lys Asn Trp Lys Ala Ile Arg Val Asp Leu
290 295 300
Val Met Cys Pro Tyr Glu Arg Arg Ala Phe Ala Leu Leu Gly Trp Thr
305 310 315 320
Gly Ser Arg Gln Phe Glu Arg Asp Leu Arg Arg Tyr Ala Thr His Glu
325 330 335
Arg Lys Met Ile Leu Asp Asn His Ala Leu Tyr Asp Lys Thr Lys Arg
340 345 350
Ile Phe Leu Lys Ala Glu Ser Glu Glu Glu Ile Phe Ala His Leu Gly
355 360 365
Leu Asp Tyr Ile Glu Pro Trp Glu Arg Asn Ala
370 375
<210> 48
<211> 379
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> N93or截短的新的
<400> 48
Ser Pro Ser Pro Val Pro Gly Ser Gln Asn Val Pro Ala Pro Ala Val
1 5 10 15
Gln Thr Ile Ser Gln Tyr Ala Cys Gln Arg Arg Thr Thr Leu Asn Asn
20 25 30
Tyr Asn Arg Val Phe Thr Asp Ala Phe Asp Val Leu Ala Glu Asn Tyr
35 40 45
Glu Phe Arg Glu Asn Glu Glu Ser Ser Val Val Phe Arg Arg Ala Ala
50 55 60
Ser Val Leu Lys Ser Leu Pro Phe Thr Ile Ile Ser Met Arg Asp Leu
65 70 75 80
Glu Gly Ile Pro Cys Leu Glu Gly Lys Ala Lys Arg Ile Ile Glu Glu
85 90 95
Ile Ile Glu Asp Gly Glu Ser Ser Glu Val Lys Ala Val Leu Asn Asp
100 105 110
Glu Arg Tyr Lys Ala Phe Lys Leu Phe Thr Ser Val Phe Gly Val Gly
115 120 125
Arg Lys Thr Ser Glu Lys Trp Phe Arg Met Gly Phe Arg Thr Leu Glu
130 135 140
Lys Ile Arg Ser Asp Lys Ser Leu Lys Phe Thr His Met Gln Lys Ala
145 150 155 160
Gly Phe Leu Tyr Tyr Glu Asp Leu Val Ser Arg Val Thr Arg Ala Glu
165 170 175
Ala Glu Ala Val Ser Val Leu Val Lys Glu Ala Val Trp Ala Phe Leu
180 185 190
Pro Asp Ala Phe Ile Thr Met Thr Gly Gly Phe Arg Leu Gly Lys Asn
195 200 205
Ile Gly His Asp Val Asp Phe Leu Ile Thr Ser Ala Glu Ala Thr Glu
210 215 220
Glu Glu Glu Gln Gln Leu Leu His Lys Val Thr Asn Leu Trp Glu Lys
225 230 235 240
Lys Gly Leu Leu Leu Tyr Cys Asp Leu Val Glu Ser Thr Phe Glu Lys
245 250 255
Leu Lys Leu Pro Ser Arg Thr Val Asp Ala Leu Asp His Phe Gln Lys
260 265 270
Cys Phe Leu Ile Leu Lys Leu His His Gln Arg Val Asp Ser Asp Lys
275 280 285
Ala Ser Gln Gln Gly Gly Lys Asn Trp Lys Ala Ile Arg Val Asp Leu
290 295 300
Val Met Cys Pro Tyr Glu Arg Arg Ala Phe Ala Leu Leu Gly Trp Thr
305 310 315 320
Gly Ser Pro Gln Phe Asn Arg Asp Leu Arg Arg Tyr Ala Thr His Glu
325 330 335
Arg Lys Met Ile Leu Asp Asn His Ala Leu Tyr Asp Lys Thr Lys Arg
340 345 350
Ile Phe Leu Lys Ala Glu Ser Glu Glu Glu Ile Phe Ala His Leu Gly
355 360 365
Leu Asp Tyr Ile Glu Pro Arg Glu Arg Asn Ala
370 375
<210> 49
<211> 404
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> N93or
<400> 49
Met Ala Ser Ser His His His His His His Ser Ser Gly Ser Glu Asn
1 5 10 15
Leu Tyr Phe Gln Thr Gly Ser Ser Gly Ser Pro Ser Pro Val Pro Gly
20 25 30
Ser Gln Asn Val Pro Ala Pro Ala Val Gln Thr Ile Ser Gln Tyr Ala
35 40 45
Cys Gln Arg Arg Thr Thr Leu Asn Asn Tyr Asn Arg Val Phe Thr Asp
50 55 60
Ala Phe Asp Val Leu Ala Glu Asn Tyr Glu Phe Arg Glu Asn Glu Glu
65 70 75 80
Ser Ser Val Val Phe Arg Arg Ala Ala Ser Val Leu Lys Ser Leu Pro
85 90 95
Phe Thr Ile Ile Ser Met Arg Asp Leu Glu Gly Ile Pro Cys Leu Glu
100 105 110
Gly Lys Ala Lys Arg Ile Ile Glu Glu Ile Ile Glu Asp Gly Glu Ser
115 120 125
Ser Glu Val Lys Ala Val Leu Asn Asp Glu Arg Tyr Lys Ala Phe Lys
130 135 140
Leu Phe Thr Ser Val Phe Gly Val Gly Arg Lys Thr Ser Glu Lys Trp
145 150 155 160
Phe Arg Met Gly Phe Arg Thr Leu Glu Lys Ile Arg Ser Asp Lys Ser
165 170 175
Leu Lys Phe Thr His Met Gln Lys Ala Gly Phe Leu Tyr Tyr Glu Asp
180 185 190
Leu Val Ser Arg Val Thr Arg Ala Glu Ala Glu Ala Val Ser Val Leu
195 200 205
Val Lys Glu Ala Val Trp Ala Phe Leu Pro Asp Ala Phe Ile Thr Met
210 215 220
Thr Gly Gly Phe Arg Leu Gly Lys Asn Ile Gly His Asp Val Asp Phe
225 230 235 240
Leu Ile Thr Ser Ala Glu Ala Thr Glu Glu Glu Glu Gln Gln Leu Leu
245 250 255
His Lys Val Thr Asn Leu Trp Glu Lys Lys Gly Leu Leu Leu Tyr Cys
260 265 270
Asp Leu Val Glu Ser Thr Phe Glu Lys Leu Lys Leu Pro Ser Arg Thr
275 280 285
Val Asp Ala Leu Asp His Phe Gln Lys Cys Phe Leu Ile Leu Lys Leu
290 295 300
His His Gln Arg Val Asp Ser Asp Lys Ala Ser Gln Gln Gly Gly Lys
305 310 315 320
Asn Trp Lys Ala Ile Arg Val Asp Leu Val Met Cys Pro Tyr Glu Arg
325 330 335
Arg Ala Phe Ala Leu Leu Gly Trp Thr Gly Ser Pro Gln Phe Asn Arg
340 345 350
Asp Leu Arg Arg Tyr Ala Thr His Glu Arg Lys Met Ile Leu Asp Asn
355 360 365
His Ala Leu Tyr Asp Lys Thr Lys Arg Ile Phe Leu Lys Ala Glu Ser
370 375 380
Glu Glu Glu Ile Phe Ala His Leu Gly Leu Asp Tyr Ile Glu Pro Arg
385 390 395 400
Glu Arg Asn Ala
<210> 50
<211> 18
<212> DNA
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> 引物
<400> 50
aaaaaaaaaa aaaagggg 18
<210> 51
<211> 12
<212> DNA
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> 引物
<400> 51
cagttaaaaa ct 12
<210> 52
<211> 11
<212> DNA
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> 引物
<400> 52
gagttaaaac t 11
<210> 53
<211> 10
<212> DNA
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> 引物
<400> 53
cagcaaggct 10
<210> 54
<211> 25
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> 用于纯化TdT 变体的亲和标签
<400> 54
Met Ala Ser Ser His His His His His His Ser Ser Gly Ser Glu Asn
1 5 10 15
Leu Tyr Phe Gln Thr Gly Ser Ser Gly
20 25
<210> 55
<211> 403
<212> PRT
<213> 人工序列(ARTIFICIAL SEQUENCE)
<220>
<223> M57 (具有亲和标签)
<400> 55
Met Ala Ser Ser His His His His His His Ser Ser Gly Ser Glu Asn
1 5 10 15
Leu Tyr Phe Gln Thr Gly Ser Ser Gly Ser Pro Ser Pro Val Pro Gly
20 25 30
Ser Gln Asn Ala Pro Ala Pro Val Val Lys Lys Ile Ser Gln Tyr Ala
35 40 45
Cys Gln Arg Arg Thr Thr Leu Asn Asn Tyr Asn Glu Leu Phe Thr Arg
50 55 60
Ala Leu Asp Ile Leu Ala Glu Asn Asp Glu Phe Arg Glu Asn Glu Glu
65 70 75 80
Ser Arg Asp Ala Phe Arg Arg Ala Ser Ser Val Leu Lys Ser Leu Pro
85 90 95
Phe Pro Ile Thr Ser Met Lys Asp Thr Glu Gly Ile Pro Cys Leu Gly
100 105 110
Asp Lys Val Lys Arg Ile Ile Glu Glu Ile Ile Glu Asp Gly Glu Ser
115 120 125
Ser Glu Val Lys Ala Val Leu Asn Asp Glu Arg Tyr Lys Ala Phe Lys
130 135 140
Leu Phe Thr Ser Val Phe Gly Val Gly Arg Lys Thr Ala Glu Lys Trp
145 150 155 160
Phe Arg Met Gly Phe Arg Thr Leu Glu Lys Ile Arg Ser Asp Lys Ser
165 170 175
Leu Arg Phe Thr Gln Met Gln Lys Ala Gly Phe Leu Tyr Tyr Glu Asp
180 185 190
Leu Val Ser Gly Val Thr Arg Ala Glu Ala Glu Ala Val Gly Val Leu
195 200 205
Val Lys Glu Ala Val Trp Ala Phe Leu Pro Asp Ala Phe Val Thr Met
210 215 220
Thr Gly Gly Phe Arg Leu Gly Lys Lys Ile Gly His Asp Val Asp Phe
225 230 235 240
Leu Ile Thr Ser Pro Gly Ser Ala Glu Asp Glu Glu Gln Leu Leu Pro
245 250 255
Lys Val Ile Asn Leu Trp Glu Lys Lys Gly Leu Leu Leu Tyr Tyr Asp
260 265 270
Leu Val Glu Ser Thr Phe Glu Lys Phe Lys Leu Pro Ser Arg Gln Val
275 280 285
Asp Thr Leu Asp His Phe Gln Lys Cys Phe Leu Ile Leu Lys Leu His
290 295 300
His Gln Arg Val Asp Ser Ser Lys Ser Asn Gln Gln Glu Gly Lys Thr
305 310 315 320
Trp Lys Ala Ile Arg Val Asp Leu Val Met Cys Pro Tyr Glu Asn Arg
325 330 335
Ala Phe Ala Leu Leu Gly Trp Thr Gly Ser Pro Gln Phe Asn Arg Asp
340 345 350
Leu Arg Arg Tyr Ala Thr His Glu Arg Lys Met Met Leu Asp Asn His
355 360 365
Ala Leu Tyr Asp Lys Thr Lys Arg Val Phe Leu Glu Ala Glu Ser Glu
370 375 380
Glu Glu Ile Phe Ala His Leu Gly Leu Asp Tyr Ile Glu Pro Trp Glu
385 390 395 400
Arg Asn Ala
Claims (12)
1.末端脱氧核苷酸转移酶(TdT)变体，其包含与选自SEQ ID NO:2、5、8、11、14、17、20、23、26、29、32、35、38、41、44或47的氨基酸序列至少90％相同的氨基酸序列，其中：
对于SEQ ID NO:2，第61位的亮氨酸被取代，第170位的半胱氨酸被取代，第204位的精氨酸被取代，第326位的精氨酸被取代，和第329位的甘氨酸被取代；
对于SEQ ID NO:5，第48位的亮氨酸被取代，第158位的半胱氨酸被取代，第192位的精氨酸被取代，第314位的精氨酸被取代，和第317位的甘氨酸被取代；
对于SEQ ID NO:8，第61位的亮氨酸被取代，第171位的酪氨酸被取代，第205位的精氨酸被取代，第327位的精氨酸被取代，和第329位的谷氨酸被取代；
对于SEQ ID NO:11，第61位的亮氨酸被取代，第171位的酪氨酸被取代，第205位的精氨酸被取代，第324位的精氨酸被取代，和第327位的谷氨酸被取代；
对于SEQ ID NO:14，第61位的甘氨酸被取代，第205位的精氨酸被取代，第327位的精氨酸被取代，和第330位的谷氨酸被取代；
对于SEQ ID NO:17，第61位的精氨酸可以被取代或可以不被取代，第158位的丙氨酸被取代，第192位的精氨酸被取代，第311位的精氨酸被取代，和第314位的谷氨酸被取代；
对于SEQ ID NO:20，第61位的精氨酸可以被取代或可以不被取代，第171位的脯氨酸可以被取代或可以不被取代，第205位的精氨酸被取代，第321位的苏氨酸被取代，和第324位的谷氨酸被取代；
对于SEQ ID NO:23，第61位的精氨酸可以被取代或可以不被取代，第171位的丙氨酸可以被取代或可以不被取代，第205位的精氨酸被取代，第322位的丙氨酸可以被取代或可以不被取代，和第325位的谷氨酸被取代；
对于SEQ ID NO:26，第61位的精氨酸可以被取代或可以不被取代，第171位的丙氨酸可以被取代或可以不被取代，第205位的精氨酸被取代，第322位的精氨酸被取代，和第325位的谷氨酸被取代；
对于SEQ ID NO:29，第48位的甲硫氨酸被取代，第158位的半胱氨酸被取代，第192位的精氨酸被取代，第310位的精氨酸被取代，和第313位的谷氨酸被取代；
对于SEQ ID NO:32，第61位的甲硫氨酸被取代，第171位的半胱氨酸被取代，第205位的精氨酸被取代，第323位的精氨酸被取代，和第326位的谷氨酸被取代；
对于SEQ ID NO:35，第61位的甲硫氨酸被取代，第171位的半胱氨酸被取代，第205位的精氨酸被取代，第323位的精氨酸被取代，和第326位的谷氨酸被取代；
对于SEQ ID NO:38，第61位的甲硫氨酸被取代，第171位的半胱氨酸被取代，第205位的精氨酸被取代，第323位的精氨酸被取代，和第326位的谷氨酸被取代；
对于SEQ ID NO:41，第61位的甲硫氨酸被取代，第171位的半胱氨酸被取代，第205位的精氨酸被取代，第323位的精氨酸被取代，和第326位的谷氨酸被取代；
对于SEQ ID NO:44，第48位的甲硫氨酸被取代，第158位的半胱氨酸被取代，第192位的精氨酸被取代，第309位的精氨酸被取代，和第312位的谷氨酸被取代；以及
对于SEQ ID NO:47，第61位的甲硫氨酸被取代，第171位的半胱氨酸被取代，第205位的精氨酸被取代，第323位的精氨酸被取代，和第326位的谷氨酸被取代；以及
其中所述TdT变体(i)无需模板就能够合成核酸片段，和(ii)能够将3’-O-修饰的核苷酸掺入到核酸片段的游离3’-羟基上。
2.如权利要求1所述的TdT变体，其中：
对在以下位置处的亮氨酸的所述取代选自R或Q：SEQ ID NO:2、8或11中的第61位，或者SEQ ID NO:5中的第48位；
对在以下位置处的半胱氨酸的所述取代选自G、R、P、A、V、S、N、Q或D：SEQ ID NO:2中的第170位，或SEQ ID NO:5、29或44中的第158位，或SEQ ID NO:32、35、38、41或47中的第171位；并且在其它实施方案中，对在前述位置处的半胱氨酸的所述取代选自G或R；
对SEQ ID NO:8或11的第171位的酪氨酸的所述取代选自G、R、P、A、V、S、N、Q或D；并且在其它实施方案中，对在前述位置处的酪氨酸的所述取代选自G或R；
对在以下位置处的丙氨酸的所述取代选自G、R、P、V、S、N、Q或D：SEQ ID NO:17的第158位，或SEQ ID NO:23或26的第171位；并且在其它实施方案中，对在前述位置处的丙氨酸的所述取代选自G或R；
对SEQ ID NO:20的第171位的脯氨酸的所述取代选自G、R、A、V、S、N、Q或D；并且在其它实施方案中，对在前述位置处的酪氨酸的所述取代选自G或R；
对在以下位置处的精氨酸的所述取代选自L或N：SEQ ID NO：2的第204位，或SEQ IDNO：5、17、29或44的第192位，或SEQ ID NO：8、11、14、20、23、26、32、35、38、41或47的第205位；
对在以下位置处的精氨酸的所述取代选自P、N或A：SEQ ID NO:2的第326位，或SEQ IDNO:5的第314位，或SEQ ID NO:8或14的第327位，或SEQ ID NO:11的第324位，或SEQ ID NO:17的第311位，或SEQ ID NO:20的第321位，或SEQ ID NO:23或26的第322位，或SEQ ID NO:29的第310位，或SEQ ID NO:32、35、38、41或47的第323位，或SEQ ID NO:44的第309位；
对SEQ ID NO:20的第321位的苏氨酸的所述取代选自P、N或A；
对SEQ ID NO:2或5的第329位的甘氨酸的所述取代选自N、L、T或S；以及
对在以下位置处的谷氨酸的所述取代选自N、L、T或S：SEQ ID NO:8或14的第330位，或SEQ ID NO:11的第327位，或SEQ ID NO:17的第311位，或SEQ ID NO:20的第324位，或SEQID NO:23或26的第325位，或SEQ ID NO:29的第313位，SEQ ID NO:32、35、38、41或47的第326位，或SEQ ID NO:44的第312位。
3.如权利要求1或2所述的TdT变体，其中：
对于SEQ ID NO:2，第327位的谷氨酰胺被取代；
对于SEQ ID NO:5，第315位的谷氨酸被取代；
对于SEQ ID NO:8，第328位的谷氨酰胺被取代；
对于SEQ ID NO:11，第325位的谷氨酰胺被取代；
对于SEQ ID NO:14，第328位的谷氨酰胺被取代；
对于SEQ ID NO:17，第312位的谷氨酰胺被取代；
对于SEQ ID NO:20，第322位的谷氨酰胺被取代；
对于SEQ ID NO:23，第323位的谷氨酰胺被取代；
对于SEQ ID NO:26，第323位的甲硫氨酸被取代；
对于SEQ ID NO:29，第311位的谷氨酰胺被取代；
对于SEQ ID NO:32，第324位的谷氨酰胺被取代；
对于SEQ ID NO:35，第324位的谷氨酰胺被取代；
对于SEQ ID NO:38，第324位的谷氨酰胺被取代；
对于SEQ ID NO:41，第324位的谷氨酰胺被取代；
对于SEQ ID NO:44，第310位的谷氨酰胺被取代；和
对于SEQ ID NO:47，第324位的谷氨酰胺被取代。
4.如权利要求3所述的TdT变体，其中所述谷氨酰胺被选自以下的氨基酸取代：T、F、L、M、I、V和Y。
5.如权利要求1、2、3或4中任一项所述的TdT变体，其中所述3’-O-修饰的核苷酸选自：3’-O-氨基-2’-三磷酸脱氧核苷、3’-O-叠氮基甲基-2’-三磷酸脱氧核苷和3’-O-烯丙基-2’-三磷酸脱氧核苷。
6.末端脱氧核苷酸转移酶(TdT)变体，其包含与选自SEQ ID NO:3、6、9、12、15、18、21、24、27、30、33、36、39、42、45或48的氨基酸序列至少90％相同的氨基酸序列，其中：
对于SEQ ID NO:3，第61位的氨基酸是R，第171位的氨基酸是R，第205位的氨基酸是L，第327位的氨基酸是A，和第330位的氨基酸是N；
对于SEQ ID NO:6，第48位的氨基酸是R，第158位的氨基酸是R，第192位的氨基酸是L，第314位的氨基酸是P，和第317位的氨基酸是N；
对于SEQ ID NO:9，第61位的氨基酸是R，第171位的氨基酸是R，第205位的氨基酸是L，第327位的氨基酸是A，和第330位的氨基酸是N；
对于SEQ ID NO:12，第61位的氨基酸是R，第171位的氨基酸是A，第205位的氨基酸是L，第324位的氨基酸是P，和第327位的氨基酸是N；
对于SEQ ID NO:15，第61位的氨基酸是R，第171位的氨基酸是R，第205位的氨基酸是L，第328位的氨基酸是P，和第331位的氨基酸是N；
对于SEQ ID NO:18，第48位的氨基酸是R，第158位的氨基酸是R，第192位的氨基酸是L，第311位的氨基酸是P，和第314位的氨基酸是N；
对于SEQ ID NO:21，第61位的氨基酸是R，第171位的氨基酸是P，第205位的氨基酸是L，第321位的氨基酸是A，和第324位的氨基酸是N；
对于SEQ ID NO:24，第61位的氨基酸是R，第171位的氨基酸是A，第205位的氨基酸是L，第322位的氨基酸是A，和第325位的氨基酸是N；
对于SEQ ID NO:27，第61位的氨基酸是R，第171位的氨基酸是R，第205位的氨基酸是L，第327位的氨基酸是A，和第330位的氨基酸是N；
对于SEQ ID NO:30，第48位的氨基酸是R，第158位的氨基酸是R，第192位的氨基酸是L，第310位的氨基酸是P，和第313位的氨基酸是N；
对于SEQ ID NO:33，第61位的氨基酸是R，第171位的氨基酸是R，第205位的氨基酸是L，第323位的氨基酸是P，和第326位的氨基酸是N；
对于SEQ ID NO:36，第61位的氨基酸是R，第171位的氨基酸是R，第205位的氨基酸是L，第323位的氨基酸是A，和第326位的氨基酸是N；
对于SEQ ID NO:39，第61位的氨基酸是R，第171位的氨基酸是R，第205位的氨基酸是L，第323位的氨基酸是P，和第326位的氨基酸是N；
对于SEQ ID NO:42，第61位的氨基酸是R，第171位的氨基酸是R，第205位的氨基酸是L，第323位的氨基酸是A，和第326位的氨基酸是N；
对于SEQ ID NO:45，第48位的氨基酸是R，第158位的氨基酸是R，第192位的氨基酸是L，第310位的氨基酸是A，和第313位的氨基酸是N；
对于SEQ ID NO:48，第61位的氨基酸是R，第171位的氨基酸是R，第205位的氨基酸是L，第323位的氨基酸是P，和第326位的氨基酸是N；以及
其中所述TdT变体(i)无需模板就能够合成核酸片段，和(ii)能够将3’-O-修饰的核苷酸掺入到核酸片段的游离3’-羟基上。
7.如权利要求6所述的TdT变体，其中：
对于SEQ ID NO:3，第328位的氨基酸是Q或选自T、F、L或M；
对于SEQ ID NO:6，第315位的氨基酸是Q或选自T、F、L或M；
对于SEQ ID NO:9，第328位的氨基酸是Q或选自T、F、L或M；
对于SEQ ID NO:12，第325位的氨基酸是Q或选自T、F、L或M；
对于SEQ ID NO:15，第329位的氨基酸是Q或选自T、F、L或M；
对于SEQ ID NO:18，第312位的氨基酸是Q或选自T、F、L或M；
对于SEQ ID NO:21，第322位的氨基酸是Q或选自T、F、L或M；
对于SEQ ID NO:24，第323位的氨基酸是Q或选自T、F、L或M；
对于SEQ ID NO:27，第328位的氨基酸是Q或选自T、F、L或M；
对于SEQ ID NO:30，第311位的氨基酸是Q或选自T、F、L或M；
对于SEQ ID NO:33，第324位的氨基酸是Q或选自T、F、L或M；
对于SEQ ID NO:36，第324位的氨基酸是Q或选自T、F、L或M；
对于SEQ ID NO:39，第324位的氨基酸是Q或选自T、F、L或M；
对于SEQ ID NO:42，第324位的氨基酸是Q或选自T、F、L或M；
对于SEQ ID NO:45，第311位的氨基酸是Q或选自T、F、L或M；以及
对于SEQ ID NO：48，第324位的氨基酸是Q或选自T、F、L或M。
8.如权利要求6或7中任一项所述的TdT变体，其中所述3’-O-修饰的核苷酸选自：3’-O-氨基-2’-三磷酸脱氧核苷、3’-O-叠氮基甲基-2’-三磷酸脱氧核苷和3’-O-烯丙基-2’-三磷酸脱氧核苷。
9.末端脱氧核苷酸转移酶(TdT)变体，其包含与选自SEQ ID NO:3、6、9、12、15、18、21、24、27、30、33、36、39、42、45或48的氨基酸序列至少90％相同的氨基酸序列，并且其中所述TdT变体(i)无需模板就能够合成核酸片段，和(ii)能够将掺入3’-O-修饰的核苷酸掺入到多核苷酸的游离3’-羟基上。
10.合成具有预定序列的多核苷酸的方法，所述方法包括以下步骤：
a)提供具有3’-末端核苷酸的起始子，所述3’-末端核苷酸具有游离3’-羟基；
b)重复以下循环：(i)在延长条件下使具有游离3’-O-羟基的起始子或延长的片段与权利要求1至9中任一项所述的3’-O-封闭的三磷酸核苷和TdT变体接触，使得所述起始子或延长的片段通过掺入3’-O-封闭的三磷酸核苷而被延长以形成3’-O-封闭的延长的片段，和(ii)使所述延长的片段去封闭以形成具有游离3’-羟基的延长的片段，直到形成所述多核苷酸。
11.如权利要求10所述的方法，其中所述3’-O-封闭的三磷酸核苷是3’-O-NH2-三磷酸核苷、3’-O-叠氮基甲基-三磷酸核苷或3’-O-烯丙基-三磷酸核苷。
12.用于进行核苷酸掺入反应的试剂盒，其包含：
a)权利要求1至9中任一项所述的TdT变体，b)一种或多种3’-O-保护的三磷酸核苷，和c)任选的至少一种起始子。
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| WO2019051250A1 (en) | 2017-09-08 | 2019-03-14 | Sigma-Aldrich Co. Llc | SYNTHESIS OF POLYNUCLEOTIDES DEPENDING ON A MATRIX AND POLYMERASE MEDIATION |
| CA3119845A1 (en) * | 2018-11-14 | 2020-05-22 | Dna Script | Terminal deoxynucleotidyl transferase variants and uses thereof |
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2021
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- 2021-04-16 AU AU2021260014A patent/AU2021260014A1/en active Pending
- 2021-04-16 US US17/919,649 patent/US20230159903A1/en active Pending
- 2021-04-16 EP EP21717925.8A patent/EP4139446A1/en active Pending
- 2021-04-16 WO PCT/EP2021/059861 patent/WO2021213903A1/en unknown
- 2021-04-16 JP JP2022563942A patent/JP2023522234A/ja active Pending
- 2021-04-16 CN CN202180029834.3A patent/CN115427559A/zh active Pending
- 2021-04-16 KR KR1020227040201A patent/KR20230002825A/ko unknown
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| US20190264248A1 (en) * | 2014-04-17 | 2019-08-29 | Dna Script | Method for Synthesizing Nucleic Acids, in particular Long Nucleic Acids, Use of Said Method and Kit for Implementing Said Method |
| CN110997907A (zh) * | 2017-05-26 | 2020-04-10 | 核酸有限公司 | 末端转移酶在核酸合成中的用途 |
| US20190211315A1 (en) * | 2018-01-08 | 2019-07-11 | Dna Script | Variants of Terminal Deoxynucleotidyl Transferase and Uses Thereof |
| WO2020120442A2 (en) * | 2018-12-13 | 2020-06-18 | Dna Script | Direct oligonucleotide synthesis on cells and biomolecules |
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| JAMIE A. E. REPASKY, ET AL.: "Mutational Analysis of Terminal Deoxynucleotidyltransferase- Mediated NNucleotide Addition in V(D)J Recombination", THE JOURNAL OF IMMUNOLOGY, vol. 172, no. 9, pages 5478 - 5488, XP055491764, DOI: 10.4049/jimmunol.172.9.5478 * |
| 无: "Genbank accession number:XP_030097130.1", GENBANK, pages 1 - 2 * |
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| AU2021260014A1 (en) | 2022-11-17 |
| US20230159903A1 (en) | 2023-05-25 |
| EP4139446A1 (en) | 2023-03-01 |
| CA3175780A1 (en) | 2021-10-28 |
| KR20230002825A (ko) | 2023-01-05 |
| IL297425A (en) | 2022-12-01 |
| WO2021213903A1 (en) | 2021-10-28 |
| JP2023522234A (ja) | 2023-05-29 |
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