CN111334512A - 含羟脯氨酸与羟赖氨酸的重组类人胶原蛋白及其生产方法 - Google Patents
含羟脯氨酸与羟赖氨酸的重组类人胶原蛋白及其生产方法 Download PDFInfo
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Abstract
本发明公开了含羟脯氨酸与羟赖氨酸的重组类人胶原蛋白及其生产方法。含羟脯氨酸与羟赖氨酸重组类人胶原蛋白的核苷酸序列如SEQ ID NO.1所示;所述含羟脯氨酸与羟赖氨酸重组类人胶原蛋白的氨基酸序列如SEQ ID NO.5所示。该重组类人胶原蛋白利用克鲁维酵母为底盘细胞,分别将四种不同的载体pKLAC1‑hlCOL、pKLC‑P4HA、pKLC‑PDI、pKLC‑LH进行共表达,经过一系列的发酵、纯化方法来获取。重组类人胶原蛋白脯氨酸与赖氨酸的羟化率与天然人源I型胶原相近,分别达到30.7%、43.1%。相比未羟基化的重组类人胶原蛋白,具有更好的促进细胞粘附以及促进伤口愈合的功能。
Description
技术领域
本发明涉及生物重组蛋白技术领域,特别涉及一种含羟脯氨酸与羟赖氨酸的重组类人胶原蛋白及其生产方法。
背景技术
胶原蛋白是脊椎动物的主要结构蛋白,约占生物体总蛋白的30%。人类肌腱、骨、以及皮肤超过一半的细胞外基质蛋白均由胶原蛋白组成。胶原蛋白以其特殊的结构与功能,作为一种重要的生物材料,在药物输送、外科缝合、组织填充、神经修复、皮肤美容等领域有着越来越广泛的应用。
时至今日,胶原蛋白主要来源依旧为动物源胶原,如鱼等海产品以及牛、猪等牲畜加工副产物,通过酸、碱、酶等提取工艺来获取,但动物源胶原存在以下明显不足:1)终产物成分复杂,活性成分结构不明确,在剧烈的提取工艺过程中活性结构容易被破坏;2)非人源蛋白,具有免疫原性,过敏反应风险不容忽视;3)存在疯牛病等朊病毒风险,且宗教信仰问题难解决。
随着生物科技的发展,利用微生物作为底盘细胞来实现胶原蛋白的表达生产,可以很好地解决动物源胶原固有的难题。首先,人源化可以大大提高生物组织相容性,解决了免疫原性问题;其次,重组蛋白结构设计目的性更强,成分更明确,可以大大提高胶原蛋白的生物活性;再次,不使用动物源成分,杜绝了朊病毒来源,且从根本上解决了宗教信仰问题。基于此,近年来关于重组胶原蛋白的研究和应用呈上升趋势。
中国发明专利申请CN201910091891.9公开了一种利用毕赤酵母生产重组人源II型胶原蛋白单链的方法。PCT/US2018/053601公开了一种利用多种微生物表达***表达重组类人胶原的方法。尽管以上方法取得了一定效益,但在重组胶原蛋白结构设计上依旧不是很清晰,尤其是对脯氨酸与赖氨酸的羟基化功能的缺失,也制约了重组胶原蛋白的进一步应用。
天然胶原蛋白结构复杂,分子量大,同动物源提取的胶原蛋白相比,目前重组胶原蛋白仍难以“以量取胜”,只有设计更为合理有效的结构才能更好地实现“以质取胜”。此外,天然胶原蛋白结构中含有约23%的羟脯氨酸与羟赖氨酸。这些羟基化位点与胶原结构形成、原纤维功能、组织发育、以及多种病理学密切相关。例如,羟赖氨酸的缺乏会造成爱唐综合征(Ehlers-Danlos syndrome type VI)、布鲁克综合征(Bruck syndrome,BS)、以及骨骼发育不良等疾病。随着年龄的增长,人类皮肤组织中赖氨酸羟化酶的含量会呈现大幅度地下降。
Christoph R等人在大肠杆菌中实现了重组胶原蛋白的羟基化(Recombinantexpression of hydroxylated human collagen in Escherichia coli,2013);中国发明专利申请CN201810707153.8公开了一种通过将源于囊孢菌RH1的脯氨酸羟基化酶与人源胶原基因在大肠杆菌中进行共表达,实现了胶原蛋白的脯氨酸羟基化的方法。此类方法虽在一定程度上解决了重组胶原蛋白的部分羟基化问题,但也存在以下不足:1)重组人源胶原蛋白结构功能设计依旧不明确;2)对于羟基化完全的大肠杆菌来说,大肠杆菌属于非GRAS表达宿主(Generally Recognized as Safe,为美国FDA评价食品添加剂的安全性指标),此外,下游纯化工艺复杂,去除内毒素难度大。3)对于其他表达宿主来说,羟基化仅限于脯氨酸羟基化,难以做到脯氨酸与赖氨酸的同步羟基化。
发明内容
鉴于上述现有技术的不足之处,本发明的目的在于提供一种结构域活性位点明确,实现脯氨酸与赖氨酸的同步羟基化,羟基化宿主为GRAS表达宿主的同时含羟脯氨酸与羟赖氨酸的重组类人胶原蛋白及其生产方法。
本发明首先对类人胶原蛋白的氨基酸序列进行设计组合,赋予其更紧凑的结构与更高效的生物活性。然后利用基因工程的方法,构建多个表达载体,将羟基化的外源基因以及类人胶原蛋白的基因成功导入克鲁维酵母中。最后,通过微生物发酵技术,以半乳糖为诱导剂,实现羟基化类人胶原蛋白的生产。
为了达到上述目的,本发明采取了以下技术方案:
含羟脯氨酸与羟赖氨酸重组类人胶原蛋白的核苷酸序列:所述核苷酸序列如SEQID NO.1所示。
含羟脯氨酸与羟赖氨酸重组类人胶原蛋白:所述含羟脯氨酸与羟赖氨酸重组类人胶原蛋白的氨基酸序列如SEQ ID NO.5所示。
一种表达重组类人胶原蛋白的乳酸克鲁维酵母(Kluyveromyces lactis):以食品级表达宿主克鲁维酵母为底盘细胞,通过将含有脯氨酸羟化酶α亚基、蛋白质二硫键异构酶、赖氨酸羟化酶L230、以及重组类人胶原蛋白表达载体进行共转化,实现羟基化重组类人胶原蛋白的分泌表达;羟基化重组类人胶原蛋白为含羟脯氨酸与羟赖氨酸重组类人胶原蛋白;其中,所述脯氨酸羟化酶α亚基,蛋白酶二硫键异构酶,以及赖氨酸羟化酶为胞内组成型表达,所述重组类人胶原蛋白为分泌表达;脯氨酸羟化酶α亚基的核苷酸序列如SEQ IDNo.2所示,氨基酸序列如SEQ ID No.6所示;蛋白酶二硫键异构酶的核苷酸序列如SEQ IDNo.3所示,氨基酸序列如SEQ ID No.7所示;赖氨酸羟化酶的核苷酸序列如SEQ ID No.4所示,氨基酸序列如SEQ ID No.8所示;表达重组类人胶原蛋白的乳酸克鲁维酵母(Kluyveromyces lactis)的保藏号为:GDMCC NO 60895。保藏地址为:广州市先列中路100号大院59号楼5楼,邮编为510070;保藏单位:广东省微生物研究所;保藏时间为2019年11月15日。
所述的表达重组类人胶原蛋白的克鲁维酵母的生产诱导方法,包括以下步骤:
1)接种:将构建好的克鲁维酵母菌挑单菌落于YPD培养基中,28-30℃,100-300rpm培养约16-30h,至OD600达到20-30范围;
2)发酵培养:将步骤1)种子液接种至发酵罐中,控制温度在28-30℃,溶氧不低于20%,pH在 5.8±0.1;
3)菌体生长:待葡萄糖耗尽后,补加葡萄糖;
4)半乳糖诱导:待步骤3)中的葡萄糖消耗完后,开始补加植物来源的半乳糖,至诱导结束;
5)离心,收集发酵液上清,得重组类人胶原蛋白发酵液。
优选地,步骤3)补加0.1%-12%葡萄糖。
优选地,步骤4)补加0.1%-10%的植物来源的半乳糖
优选地,步骤5)所述的离心为3000g-10000g离心2-30min。
所述的含羟脯氨酸与羟赖氨酸重组类人胶原蛋白在促进细胞粘附以及促进伤口愈合中的应用。
与现有技术相比,本发明具有如下优点和有益效果:
1)本发明以食品级表达宿主克鲁维酵母为底盘细胞,通过将人源化的脯氨酸羟化酶(P4H)的α亚基、蛋白质二硫键异构酶(PDI)、赖氨酸羟化酶L230、以及类人胶原蛋白进行共表达,成功地实现了羟基化重组类人胶原蛋白的分泌表达,脯氨酸与赖氨酸的羟化率分别达到30.7%、43.1%,解决了重组类人胶原蛋白的分泌表达以及羟基化问题。
2)本发明获得的重组类人胶原蛋白的结构域明确,脯氨酸与赖氨酸的羟基化率,与天然胶原蛋白相近,具有较好的促细胞增殖及促粘附活性。
3)本发明底盘细胞为GRAS表达宿主,并在其中实现了重组胶原蛋白的分泌表达,简化了生产工艺。
4)本发明获得的重组类人胶原蛋白成分单一,纯度高,不含内毒素。
5)本发明获得的重组类人胶原蛋白可用于促进表皮细胞修复,加速伤口止血愈合,强化皮肤屏障,充当组织填充物等药物或化妆品领域。
附图说明
图1为pKLAC1-hlCOL质粒物理图谱。
图2为pKLC1-P4HA质粒物理图谱。
图3为pKLC1-LH质粒物理图谱。
图4为pKLC1-PDI质粒物理图谱。
图5为阳性重组子诱导上清SDS-PAGE。
图6为实施例4发酵罐上发酵上清中强脯氨酸及羟赖氨酸含量变化图。
图7为实施例5羟基化的重组类人胶原蛋白HPLC纯度检测峰线图。
图8为实施例6各浓度的重组类人胶原蛋白样品对NIH/3T3细胞的粘附活性(n=6)。
图9为大鼠全皮缺损模型不同时间点伤口修复过程图(比例尺:5mm)。
具体实施方式
为使本发明的目的、技术方案及效果更加清楚、明确,下面结合实施例和附图对本发明做进一步的说明,但本发明的实施方式不限如此。
实施例1:重组类人胶原蛋白核苷酸和氨基酸序列设计,表达载体的构建
基于克鲁维酵母密码子偏好性,通过在线网站(http://www.jcat.de/)分别设计重组类人胶原蛋白 (hlCOL)、脯氨酸羟化酶(P4H)的α亚基、蛋白质二硫键异构酶(PDI)、赖氨酸羟化酶L230(赖氨酸羟化酶L230的代号为LH)的蛋白基因hlCOL、P4HA、PDI、LH。基因序列委托上海捷瑞生物工程有限公司合成,合成的重组类人胶原蛋白(hlCOL)的核苷酸序列如SEQ ID No.1所示,脯氨酸羟化酶 (P4H)的α亚基的核苷酸序列如SEQ ID No.2所示,的核苷酸序列如SEQ ID No.3所示,赖氨酸羟化酶的核苷酸序列如SEQ ID No.4所示。由重组类人胶原蛋白(hlCOL)、脯氨酸羟化酶(P4H)的α亚基、蛋白酶二硫键异构酶(PDI)、赖氨酸羟化酶L230的核苷酸序列编码表达获得的氨基酸序列如分别如SEQ ID No.5、SEQ ID No.6、SEQID No.7和SEQ ID No.8所示。重组类人胶原蛋白(hlCOL)、脯氨酸羟化酶(P4H)的α亚基、蛋白质二硫键异构酶(PDI)、赖氨酸羟化酶L230(赖氨酸羟化酶L230 的代号为LH)与类人胶原蛋白分别对应的基因序列、氨基酸序列如表1所示。
表1本发明所对应的基因序列与对应的氨基酸序列
分别合成重组类人胶原蛋白(hlCOL)、脯氨酸羟化酶(P4H)的α亚基、蛋白质二硫键异构酶(PDI)、赖氨酸羟化酶L230的蛋白(LH)基因对应的上游引物F和下游引物R(委托上海生物工程股份公司合成),如表2所示;hlCOL的上游引物hlCOL-F和下游引物hlCOL-R的序列分别如SEQ ID NO.9和SEQ ID NO.10所示;P4H的上游引物P4H-F和下游引物P4H-R的序列分别如SEQ ID NO.11和SEQ ID NO. 12所示;PDI的上游引物PDI-F和下游引物PDI-R的序列分别如SEQ ID NO.13和SEQ ID NO.14所示; LH的上游引物LH-F和下游引物LH-R的序列分别如SEQ ID NO.15和SEQ ID NO.16所示;表2中F 对应上游引物,R对应下游引物。通过PCR扩增相应基因片段,引入相应酶切位点HindIII(CTCGAG)、 NotI(GCGGCCGC)以及XhoI(AAGCTT)。PCR反应体系如表3。
表2
表3PCR反应体系
以pKALC1载体为骨架,分别通过HindIII-NotI酶切位点,XhoI-NotI酶切位点,将合成的基因片段引入载体中,构建的新载体分别命名为pKLAC1-hlCOL(质粒A,对应物理图谱为图1)、pKLC-P4HA (质粒B,对应物理图谱为图2)、pKLC-PDI(质粒C,对应物理图谱为图3)、pKLC-LH(质粒D,对应物理图谱为图4)。其中,质粒A为分泌表达载体,分泌表达类人胶原蛋白,质粒B、质粒C、质粒D为胞内表达载体,质粒B和质粒C表达蛋白亚基组合具有脯氨酸羟化酶活性,质粒D表达的蛋白具有赖氨酸羟化酶活性。
连接产物42℃热激转化至大肠杆菌JM109感受态,复苏后涂布于含氨苄抗性(100μg/mL)LB抗性平板,37℃过夜,挑单菌落,利用表3中对应引物进行PCR验证(反应体系同表3)。挑选阳性转化子进行测序。
实施例2:羟基化类胶原蛋白工程菌构建
如图1、2、3、4所示,利用限制性内切酶SacII(美国NEB公司)线性化质粒A、质粒B、质粒 C、质粒D,构建酶切反应体系如下表4:
表4酶切反应体系
反应条件为37℃,30min。酶切反应结束后,利用胶回收试剂盒(北京天根生物)割胶回收含有目的基因的载体片段,去除载体上的抗性基因片段。
将回收得到的高纯度质粒片段,加入克鲁维酵母感受态细胞中,置于冰上孵育2min,再进行电转化 (1.5kv-2.5kv)。然后涂布于含有乙酰胺(5mM)的YCB培养基,28℃培养2天,待平板上长出单菌落,得到的表达重组类人胶原蛋白的乳酸克鲁维酵母(Kluyveromyces lactis)的保藏号为:GDMCC NO 60895。保藏地址为:广州市先列中路100号大院59号楼5楼,邮编为510070;保藏单位:广东省微生物研究所;保藏时间为2019年11月15日。
挑取单菌落,利用菌落PCR进行验证。本实施例根据目的基因的不同,分别设计相应的上下游验证引物,如下表5(委托上海生物工程股份公司合成,F’表示上游引物,R’表示下游引物)。
表5
在PCR小管中加入25μL菌体裂解液(Takara公司),挑取不同的转化子,放入PCR小管中吹打后取出。然后将PCR小管在80℃变性15min,2000g离心1min,取3μL上清液作为PCR反应的模板。PCR 反应体系如下表6:
表6菌落PCR反应体系
将PCR产物进行核酸电泳,分析条带大小,实际值与理论值相符的进入下一步鉴定。
对确认阳性的转化子进行培养,取诱导24h的发酵上清进行聚丙烯酰胺凝胶电泳(SDS-PAGE),结果如图5所示。同时,对羟脯氨酸含量与羟赖氨酸含量的进行测定。
检测结果确认均为阳性后,割下电泳凝胶中与理论一致的条带,进行蛋白质胶条分析(委托上海中科新生命生物科技有限公司完成),氨基酸组成结果如表7所示。氨基酸组成与理论相符,同时脯氨酸与赖氨酸的羟基化率分别达到30.7%、43.1%,与天然人I型胶原相近。
人胶原胶条分析氨基酸组成
实施例3:羟脯氨酸及羟赖氨酸含量测定
羟脯氨酸按农业部行业标准《生乳中L-羟脯氨酸的测定》(NY/T 3130-2017)中分光光度计法进行。
羟赖氨酸采用羟赖氨酸ELISA检测试剂盒(购于上海一研生物科技有限公司)进行检测。步骤如下:将稀释好的标准品(试剂盒自带)或发酵上清(来源实施实例2)各取10μL,再加稀释液40μL;空白孔不加。除空白孔外,标准品孔和样本孔中每孔加入辣根过氧化物酶(HRP)标记的检测抗体100 μL,用封板膜封住反应孔,37℃水浴锅或恒温箱温育60min。弃去液体,吸水纸上拍干,每孔加满洗涤液,静置1min,甩去洗涤液,吸水纸上拍干,如此重复洗板5次。每孔加入底物A、B各50μL,37℃避光孵育15min。再加入终止液50μL,15min内,在450nm波长处测定各孔的OD值。依据结果绘制标准曲线:在Excel工作表中,以标准品浓度作横坐标,对应OD值作纵坐标,绘制出标准品线性回归曲线,按曲线方程计算各样本浓度值。
实施例4:重组类人胶原在5L发酵罐上的诱导生产过程
首先,实施例2中构建的表达重组类人胶原蛋白的乳酸克鲁维酵母(Kluyveromyces lactis)工程菌进行菌种活化。用接种环蘸取菌液在YPD固体平板上划线。30℃培养2天,挑单菌落于YPD培养基中, 30℃,200rpm培养约30h,至OD600达到20-30范围,此即为一级种子液,种子液可根据最终培养体积大小按1:10比例进行扩培。
将上述制备好的种子液按无菌接种方式接种至5L发酵罐中(CBM培养基,起始体积为2.4L),发酵条件为:温度为28℃,溶氧不低于20%,通过流加25%氨水控制pH为5.8±0.1。待葡萄糖耗尽后,继续补加5%-12%(w/v,体积为总发酵体积)灭菌葡萄糖;葡萄糖补加结束后,开始补加2%-5%(w/v,体积为总发酵体积)的植物来源的β-半乳糖(过滤除菌,购于浙江一新制药股份有限公司),至诱导结束。
其中,发酵培养基配方如下:
CBM培养基(按每升基础培养基添加4mL微量元素)
基础培养基:85%磷酸28mL/L,硫酸钙1g/L,硫酸钾18g/L,七水硫酸镁14g/L,氢氧化钾4g/L,酵母抽提物,1%,葡萄糖2%(分开单独灭菌)。
微量元素:五水硫酸铜6.0g/L,碘化钠0.008g/L,一水硫酸锰3.0g/L,二水合钼酸钠0.2g/L,硼酸 0.02g/L,氯化钴0.5g/L,氯化锌20.0g/L,七水合硫酸亚铁65.0g/L,生物素0.2g/L,浓硫酸5mL/L发酵结束后,4000g离心10min,收集发酵液上清即为重组类人胶原蛋白发酵液。整个发酵诱导过程中,羟脯氨酸与羟赖氨酸含量变化见图6。图6显示,在诱导24h后,发酵液上清中的羟脯氨酸与羟赖氨酸开始快速积累,分析原因可能与导入的羟脯氨酸与羟赖氨酸的胞内活力有关,表明生产过程中羟脯氨酸与羟赖氨酸可以稳定积累。
实施例5:高纯重组类人胶原蛋白纯化
将离心收集的羟基化的重组类人胶原蛋白发酵液按体积比50:1与镍填料(常州天地人和公司)进行孵育5min,然后继续添加镍填料,直至上清中蛋白含量不再减少为止。
过滤收集填料,然后利用5倍体积0.1M PBS洗涤,再用0.5M咪唑洗涤填料,收集洗涤液,再经过G25分子筛(美国GE公司)将咪唑置换成0.1M PBS。纯化得到的蛋白经HPLC检测(HPLC条件:安捷伦1260高效液相色谱仪(配二级管阵列检测器);色谱柱:反相C18柱,Hedera ODS-2 4.6*250 5um。流动相:A 0.1%TFC水,B 0.1%TFC乙腈,梯度洗脱:0-40分钟,1%B--70%B,检测波长215nm。),结果如图7所示,纯度高达99.138%。
实施例6:重组类人胶原蛋白活性检测
将处于对数生长期的3T3细胞用含有10%FBS的1640(美国Gibco公司)常规培养至80%~90%,用 0.25%胰蛋白酶消化,以2.0×105个/mL的细胞数目接种于96孔板,培养24h后,换无血清1640培养基培养,24h后将培养基吸出后分别加入浓度为100、50、25、10μg/mL的重组类人胶原蛋白(所有样品均用PBS稀释,对照牛纤连蛋白为100μg/mL),每个浓度设3个孔计算误差。给药后放入二氧化碳培养箱培养24h,加入10μL MTT(0.5mg/mL),37℃培养箱中孵育4h后,吸出孔中溶液并加入100μL DMSO,振荡后于570/630nm波长下检测吸光值。
结果见图8,相比牛纤连蛋白,在100μg/mL同等添加量的情况下,重组类人胶原蛋白促细胞粘附活性为牛纤连蛋白的4倍,表明其具有更好的促细胞黏附活性。
实施例7:大鼠全皮缺损模型修复
取健康雌性清洁级SD大鼠96只,随机分为6组,每组16只。A组(PBS空白对照组),B组(EGF 对照组),C组(未羟基化的重组胶原蛋白),D组(100ng羟基化重组胶原蛋白),E组(500ng羟基化重组胶原蛋白),F组(1μg羟基化重组胶原蛋白)。
采用常规手术的方法于大鼠背部取全层皮肤形成圆形创面,直径2.5cm,创面止血后,以生理盐水纱布覆盖备用,建立动物全层皮肤缺损模型。根据上述分组,在创面喷雾给药(如上述A-F组对应的空白对照组、EGF对照组和不同类型的胶原蛋白)。术后动物单笼常规饲养,每间隔48h给药一次。分别用药5-14天。从图9来看,其中羟基化重组类人胶原蛋白伤口愈合情况明显优于生理盐水组(阴性对照)以及普通类人胶原蛋白。其加速伤口愈合,减少疤痕形成的效果更加显著。
序列表
<110> 肽源 (广州 )生物科技有限公司
<120> 含羟脯氨酸与羟赖氨酸的重组类人胶原蛋白及其生产方法
<160> 24
<170> SIPOSequenceListing 1.0
<210> 1
<211> 1764
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 1
ggtgttccag gtgacttggg tgctccaggt ccatctggtg ctagaggtga aagaggtttc 60
ccaggtgaaa gaggtgttca aggtccacca ggtccagctg gtccaagagg tgctaacggt 120
gctccaggta acgacggtgc taagggtgac gcgggtgctc caggtgctcc aggtctccac 180
ggtgaatttg gtttgccagg tccagctggt ccaagaggtg aaagaggtcc accaggtgaa 240
tctggtgctg ctggtccaac tggtccaatc ggttctagag gtccatctgg tccaccaggt 300
ccagacggta acaagggtga accaggtgtt gttggtgctg ttccaggtcc agctggtaag 360
gaaggtggta agggtccaag aggtgaaact ggtccagctg gtagaccagg tgaagttggt 420
ccaccaggtc caccaggtcc agctggtgaa aagggttctc caggtgctga cggtccagct 480
ggtgctccag gtactccagg tccacaaggt atcgctggtc aaagaggtgt tgttggtttg 540
ccaccaggtc cagctggtaa ggaaggtttg agaggtccaa gaggtgacca aggtccagtt 600
ggtagaactg gtgaagttgg tgctgtaggt ccaccaggct tcgctggtga aaagggtcca 660
tctggtgaag ctggtactgc tggtccacca ggtactccag gtccacaagg tttgttgggt 720
gctccaggca tattgggtct cccaggtttg ccaggtcaaa gaggtgaaag aggtttccca 780
ggtttgccag gtccatctgg tgaaccaggt aagcaaggtc catctggtgc ttctggtgaa 840
agaggtccac caggtccaat gggtccacca ggtttggctg gtccaccagg tgaatctggt 900
agagaaggtg ctccaggtgc tgaaggttct ccaggtagag acggttctcc aggtgctaag 960
ggtgacagag gtgaaactgg tccagctggt ccaccaggtg ctccaggtgc tccaggtgct 1020
ccaggtccag ttggtccagc tggtaagtct ggtgacagag gtgaaactgg tccagctggt 1080
ccaactggtc cagttggtcc agttggtgct agaggtccag ctggtccaca aggtccaaga 1140
ggtgacaagg gtgaaactgg tgaacaaggt gacagaggta tcaagggtca tcgtggtttc 1200
agcggtctcc aaggtccacc aggtccacca ggttctccag gtgaacaagg tccatctggt 1260
gcttctggtc cagctggtcc aagaggtcca ccaggttctg ctggtgctcc aggtaaggac 1320
ggtttgaacg gtttgccagg tccaatcggt ccaccaggtc caagaggtag aactggtgac 1380
gctggtccag ttggtccacc aggtccacca ggtccaccag gtccaccagg tccaccaggt 1440
gaaagaggtg acttgggtcc acaaggtatc gctggtcaaa gaggtgttgt tggtgaaaga 1500
ggtgaaagag gtgaaagagg tgcttctggt gaaagaggtg acttgggtcc acaaggtatc 1560
gctggtcaaa gaggtgttgt tggtgaaaga ggtgaaagag gtgaaagagg tgcttctggt 1620
gaaagaggtg acttgggtcc acaaggtatc gctggtcaaa gaggtgttgt tggtgaaaga 1680
ggtgaaagag gtgaaagagg tgcttctggt ccaccaggtc catgttgtgg cggcggtctc 1740
gaacaccacc atcaccacca ctaa 1764
<210> 2
<211> 1557
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 2
atgcacccag gtttcttcac ttctatcggt caaatgactg acttgatcca cactgaaaag 60
gacttggtta cttctttgaa ggactacatc aaggctgaag aagacaagtt ggaacaaatc 120
aagaagtggg ctgaaaagtt ggacagattg acttctactg ctactaagga cccagaaggt 180
ttcgttggtc acccagttaa cgctttcaag ttgatgaaga gattgaacac tgaatggtct 240
gaattggaaa acttggtttt gaaggacatg tctgacggtt tcatctctaa cttgactatc 300
caaagacaat acttcccaaa cgacgaagac caagttggtg ctgctaaggc tttgttgaga 360
ttgcaagaca cttacaactt ggacactgac actatctcta agggtaactt gccaggtgtt 420
aagcacaagt ctttcttgac tgctgaagac tgtttcgaat tgggtaaggt tgcttacact 480
gaagctgact actaccacac tgaattgtgg atggaacaag ctctcagaca attggacgaa 540
ggtgaaatct ctactatcga caaggtttct gttttggact acttgtctta cgctgtttac 600
caacaaggtg acttggacaa ggctttgttg ttgactaaga agttgttgga attggaccca 660
gaacaccaaa gagctaacgg taacttgaag tacttcgaat acatcatggc taaggaaaag 720
gacgttaaca agtctgcttc tgacgaccaa tctgaccaaa agactactcc aaagaagaag 780
ggtgttgctg ttgactactt gccagaaaga caaaagtacg aaatgttgtg tagaggtgaa 840
ggtatcaaga tgactccaag aagacaaaag aagttgttct gtagatacca cgacggtaac 900
agaaacccaa agttcatctt ggctccagct aagcaagaag acgaatggga caagccaaga 960
atcatcagat tccacgacat catctctgac gctgaaatcg aaatcgttaa ggacttggct 1020
aagccaagat tgtctagagc tactgttcac gacccagaaa ctggtaagtt gactactgct 1080
caatacagag tttctaagtc tgcttggttg tctggttacg aaaacccagt tgtttctaga 1140
atcaacatga gaatccaaga cttgactggt ttggacgttt ctactgctga agaattgcaa 1200
gttgctaact acggtgttgg tggtcaatac gaaccacact tcgacttcgc tagaaaggac 1260
gaaccagacg ctttcaagga attgggtact ggtaacagaa tcgctacttg gttgttctac 1320
atgtctgacg tttctgctgg tggtgctact gttttcccag aagttggcgc gtctgtatgg 1380
ccaaaaaagg gtactgctgt tttctggtac aacttgttcg cttctggtga aggtgactac 1440
tctactagac acgctgcttg cccagtcctc gttggcaata agtgggtaag caacaagtgg 1500
ttgcacgaaa gaggtcaaga attcagaaga ccatgtactt tgtctgaatt ggaataa 1557
<210> 3
<211> 1479
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 3
atggacgctc cagaagaaga agaccacgtt ttggttttga gaaagtctaa ctttgcggaa 60
gctctcgctg ctcacaagta cttgttggtt gaattctacg ctccatggtg tggtcactgt 120
aaggctttgg ctccagaata cgctaaggct gctggtaagt tgaaggctga aggttctgaa 180
atcagattgg ctaaggttga cgctactgaa gaatctgact tggctcaaca atacggtgtt 240
agaggttacc caactatcaa gttcttcaga aacggtgaca ctgcttctcc aaaggaatac 300
actgctggta gagaagctga cgacatcgtt aactggttga agaagagaac tggtccagct 360
gctactactt tgccagacgg tgctgctgct gaatctttgg ttgaatcttc tgaagttgct 420
gttatcggtt tcttcaagga cgttgaatct gactctgcta agcaattctt gcaagctgct 480
gaagctatcg acgacatccc attcggtatc acttctaact ctgacgtttt ctctaagtac 540
caattggaca aggacggtgt tgttttgttc aagaagttcg acgaaggtag aaacaacttc 600
gaaggtgaag ttactaagga aaacttgttg gacttcatca agcacaacca attgccattg 660
gttatcgaat tcactgaaca aactgctcca aagatcttcg gtggtgaaat caagactcac 720
atcttgttgt tcttgccaaa gtctgtttct gactacgacg gtaagttgtc taacttcaag 780
actgctgctg aatctttcaa gggtaagatc ttgttcatct tcatcgactc tgaccacact 840
gacaaccaaa gaatactcga attcttcgga ctcaagaagg aagagtgtcc agctgttaga 900
ttgatcactt tggaagaaga aatgactaag tacaagccag aatctgaaga attgactgct 960
gaaagaatca ctgaattctg tcacagattc ttggaaggta agatcaagcc acacttgatg 1020
tctcaagaat tgccagaaga ctgggacaag caaccagtta aggttttggt tggtaagaac 1080
ttcgaagacg ttgctttcga cgaaaagaag aacgttttcg ttgaattcta cgctccatgg 1140
tgtggtcact gtaagcaatt ggctccaatc tgggacaagt tgggtgaaac ttacaaggac 1200
cacgaaaaca tcgttatcgc taagatggac tctactgcta acgaagttga agctgttaag 1260
gttcactctt tcccaacttt gaagttcttc ccagcttctg ctgacagaac tgttatcgac 1320
tacaacggtg aaagaacttt ggacggtttc aagaagttct tggaatctgg tggtcaagac 1380
ggtgctggtg acgacgacga cttggaagac ttggaagaag ctgaagaacc agacatggaa 1440
gaagacgacg accaaaaggc tgttaaggac gaattgtaa 1479
<210> 4
<211> 2688
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 4
atgatctcta gaacttacgt tatcaacttg gctagaagac cagacaagaa ggacagaatc 60
ttggctgaat tcttgaagtt gaaggaaaag ggtgttgaat tgaactgtgt tatcttcgaa 120
gctgttgacg gtaacaaccc agaacacttg tctagattca acttcaagat cccaaactgg 180
actgacttga actctggtaa gccaatgact aacggtgaag ttggttgtgc tttgtctcac 240
tggtctgttt ggaaggacgt tgttgactgt gttgagaatg gtactctcga caaggactgc 300
agaatcttgg ttttggaaga cgacgttgtt ttcttggaca acttcatgga aagataccaa 360
acttacactt ctgaaatcac ttacaactgt gacttgttgt acttgcacag aaagccattg 420
aacccataca ctgaaactaa gatctctact cacatcgtta agccaaacaa gtcttactgg 480
gcttgtgctt acgttatcac ttaccaatgt gctaagaagt tcatgaacgc taactacttg 540
gaaaacttga tcccatctga cgaattcatc ccaatcatgc acggttgcaa tgtttacggc 600
ttcgaaaagt tgttttctaa ctgtgaaaag atcgactgtt acgctgttca accatctttg 660
gttaagttga cttctaacgc tttcaacgac tctgaaactt tccactctgg ttcttacgtt 720
ccatctaaca agttcaactt cgacactgac aagcaattca gaatcgttta catcggtcca 780
actaagggta actctttcca cagattcact gaatactgta agttgtactt gttgccatac 840
aaggttatcg acgaaaagga aactaacgac tttgttagct tgagatctga actccaatct 900
ttgtctgaac aagacttgaa cactactttg atgttggttg tttctgttaa ccacaacgac 960
ttctgtaaca ctatcccatg tgctccaact aacgaattca tcgacaagta caagcaattg 1020
actactgaca ctaactctat cgtttctgct gttcaaaacg gtactaacaa gactatgttc 1080
atcggttggg ctaacaagat ctctgaattc atcaaccact accaccaaaa gttgactgaa 1140
tctaacgctg aaactgacat caacttggct aacttgttgt tgatctcttc tatctcttct 1200
gacttcaact gtgttgttga agacgttgaa ggtaacttgt tccaattgat caacgaagaa 1260
tctgacatcg ttttctctac tactacttct agagttaaca acaagttggg taagactcca 1320
tctgttttgt acgctaactc tgactcttct gttatcgttt tgaacaaggt tgaaaactac 1380
actggttacg gttggaacga atactacggt taccacgttt acccagttaa gttcgacgtt 1440
ttgccaaaga tctacttgtc tatcagaatc gttaagaacg ctaacgttac taagatcgct 1500
gaaactttgg actacccaaa ggaattgatc actgtttcta tctctagatc tgaacacgac 1560
tctttctacc aagctgacat ccaaaagttc ttgttgtctg gtgctgacta ctacttctac 1620
atctctggtg actgtatcat cactagacca actatcttga aggaattgtt ggaattgaac 1680
aaggacttcg ttggtccatt gatgagaaag ggtactgaat cttggactaa ctactggggt 1740
gacatcgacc catctaacgg ttactacaag agatctttcg actacttcga catcatcggt 1800
agagacagag ttggttgttg gaacgttcca tacttggctt ctgtttactt gatcaagaag 1860
tctgttatcg aacaagttcc aaacttgttc actgaaaact ctcacatgtg gaacggttct 1920
aacatcgaca tgagattgtg tcacaacttg agaaagaaca acgttttcat gtacttgtct 1980
aacttgagac catacggtca catcgacgac tctatcaact tggaagtttt gtctggtgtt 2040
ccaactgaag ttactttgta cgacttgcca actagaaagg aagaatggga aaagaagtac 2100
ttgcacccag aattcttgtc tcacttgcaa aacttcaagg acttcgacta cactgaaatc 2160
tgtaacgacg tttactcttt cccattgttc actccagctt tctgtaagga agttatcgaa 2220
gttatggaca aggctaactt gtggtctaag ggtggtgact cttacttcga cccaagaatc 2280
ggtggtgttg aatcttaccc aactcaagac actcaattgt acgaagttgg tttggacaag 2340
caatggcact acgttgtttt caactacgtt gctccattcg ttagacactt gtacaacaac 2400
tacaagacta aggacatcaa cttggctttc gttgttaagt acgacatgga aagacaatct 2460
gaattggctc cacaccacga ctcttctact tacactttga acatcgcttt gaacgaatac 2520
ggtaaggaat acactgctgg tggttgtgaa ttcatcagac acaagttcat ctggcaaggt 2580
caaaaggttg gttacgctac tatccacgct ggtaagttgt tggcttacca cagagctttg 2640
ccaatcactt ctggtaagag atacatcttg gtttctttcg ttaactaa 2688
<210> 5
<211> 587
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 5
Gly Val Pro Gly Asp Leu Gly Ala Pro Gly Pro Ser Gly Ala Arg Gly
1 5 10 15
Glu Arg Gly Phe Pro Gly Glu Arg Gly Val Gln Gly Pro Pro Gly Pro
20 25 30
Ala Gly Pro Arg Gly Ala Asn Gly Ala Pro Gly Asn Asp Gly Ala Lys
35 40 45
Gly Asp Ala Gly Ala Pro Gly Ala Pro Gly Leu His Gly Glu Phe Gly
50 55 60
Leu Pro Gly Pro Ala Gly Pro Arg Gly Glu Arg Gly Pro Pro Gly Glu
65 70 75 80
Ser Gly Ala Ala Gly Pro Thr Gly Pro Ile Gly Ser Arg Gly Pro Ser
85 90 95
Gly Pro Pro Gly Pro Asp Gly Asn Lys Gly Glu Pro Gly Val Val Gly
100 105 110
Ala Val Pro Gly Pro Ala Gly Lys Glu Gly Gly Lys Gly Pro Arg Gly
115 120 125
Glu Thr Gly Pro Ala Gly Arg Pro Gly Glu Val Gly Pro Pro Gly Pro
130 135 140
Pro Gly Pro Ala Gly Glu Lys Gly Ser Pro Gly Ala Asp Gly Pro Ala
145 150 155 160
Gly Ala Pro Gly Thr Pro Gly Pro Gln Gly Ile Ala Gly Gln Arg Gly
165 170 175
Val Val Gly Leu Pro Pro Gly Pro Ala Gly Lys Glu Gly Leu Arg Gly
180 185 190
Pro Arg Gly Asp Gln Gly Pro Val Gly Arg Thr Gly Glu Val Gly Ala
195 200 205
Val Gly Pro Pro Gly Phe Ala Gly Glu Lys Gly Pro Ser Gly Glu Ala
210 215 220
Gly Thr Ala Gly Pro Pro Gly Thr Pro Gly Pro Gln Gly Leu Leu Gly
225 230 235 240
Ala Pro Gly Ile Leu Gly Leu Pro Gly Leu Pro Gly Gln Arg Gly Glu
245 250 255
Arg Gly Phe Pro Gly Leu Pro Gly Pro Ser Gly Glu Pro Gly Lys Gln
260 265 270
Gly Pro Ser Gly Ala Ser Gly Glu Arg Gly Pro Pro Gly Pro Met Gly
275 280 285
Pro Pro Gly Leu Ala Gly Pro Pro Gly Glu Ser Gly Arg Glu Gly Ala
290 295 300
Pro Gly Ala Glu Gly Ser Pro Gly Arg Asp Gly Ser Pro Gly Ala Lys
305 310 315 320
Gly Asp Arg Gly Glu Thr Gly Pro Ala Gly Pro Pro Gly Ala Pro Gly
325 330 335
Ala Pro Gly Ala Pro Gly Pro Val Gly Pro Ala Gly Lys Ser Gly Asp
340 345 350
Arg Gly Glu Thr Gly Pro Ala Gly Pro Thr Gly Pro Val Gly Pro Val
355 360 365
Gly Ala Arg Gly Pro Ala Gly Pro Gln Gly Pro Arg Gly Asp Lys Gly
370 375 380
Glu Thr Gly Glu Gln Gly Asp Arg Gly Ile Lys Gly His Arg Gly Phe
385 390 395 400
Ser Gly Leu Gln Gly Pro Pro Gly Pro Pro Gly Ser Pro Gly Glu Gln
405 410 415
Gly Pro Ser Gly Ala Ser Gly Pro Ala Gly Pro Arg Gly Pro Pro Gly
420 425 430
Ser Ala Gly Ala Pro Gly Lys Asp Gly Leu Asn Gly Leu Pro Gly Pro
435 440 445
Ile Gly Pro Pro Gly Pro Arg Gly Arg Thr Gly Asp Ala Gly Pro Val
450 455 460
Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly
465 470 475 480
Glu Arg Gly Asp Leu Gly Pro Gln Gly Ile Ala Gly Gln Arg Gly Val
485 490 495
Val Gly Glu Arg Gly Glu Arg Gly Glu Arg Gly Ala Ser Gly Glu Arg
500 505 510
Gly Asp Leu Gly Pro Gln Gly Ile Ala Gly Gln Arg Gly Val Val Gly
515 520 525
Glu Arg Gly Glu Arg Gly Glu Arg Gly Ala Ser Gly Glu Arg Gly Asp
530 535 540
Leu Gly Pro Gln Gly Ile Ala Gly Gln Arg Gly Val Val Gly Glu Arg
545 550 555 560
Gly Glu Arg Gly Glu Arg Gly Ala Ser Gly Pro Pro Gly Pro Cys Cys
565 570 575
Gly Gly Gly Leu Glu His His His His His His
580 585
<210> 6
<211> 587
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 6
Gly Val Pro Gly Asp Leu Gly Ala Pro Gly Pro Ser Gly Ala Arg Gly
1 5 10 15
Glu Arg Gly Phe Pro Gly Glu Arg Gly Val Gln Gly Pro Pro Gly Pro
20 25 30
Ala Gly Pro Arg Gly Ala Asn Gly Ala Pro Gly Asn Asp Gly Ala Lys
35 40 45
Gly Asp Ala Gly Ala Pro Gly Ala Pro Gly Leu His Gly Glu Phe Gly
50 55 60
Leu Pro Gly Pro Ala Gly Pro Arg Gly Glu Arg Gly Pro Pro Gly Glu
65 70 75 80
Ser Gly Ala Ala Gly Pro Thr Gly Pro Ile Gly Ser Arg Gly Pro Ser
85 90 95
Gly Pro Pro Gly Pro Asp Gly Asn Lys Gly Glu Pro Gly Val Val Gly
100 105 110
Ala Val Pro Gly Pro Ala Gly Lys Glu Gly Gly Lys Gly Pro Arg Gly
115 120 125
Glu Thr Gly Pro Ala Gly Arg Pro Gly Glu Val Gly Pro Pro Gly Pro
130 135 140
Pro Gly Pro Ala Gly Glu Lys Gly Ser Pro Gly Ala Asp Gly Pro Ala
145 150 155 160
Gly Ala Pro Gly Thr Pro Gly Pro Gln Gly Ile Ala Gly Gln Arg Gly
165 170 175
Val Val Gly Leu Pro Pro Gly Pro Ala Gly Lys Glu Gly Leu Arg Gly
180 185 190
Pro Arg Gly Asp Gln Gly Pro Val Gly Arg Thr Gly Glu Val Gly Ala
195 200 205
Val Gly Pro Pro Gly Phe Ala Gly Glu Lys Gly Pro Ser Gly Glu Ala
210 215 220
Gly Thr Ala Gly Pro Pro Gly Thr Pro Gly Pro Gln Gly Leu Leu Gly
225 230 235 240
Ala Pro Gly Ile Leu Gly Leu Pro Gly Leu Pro Gly Gln Arg Gly Glu
245 250 255
Arg Gly Phe Pro Gly Leu Pro Gly Pro Ser Gly Glu Pro Gly Lys Gln
260 265 270
Gly Pro Ser Gly Ala Ser Gly Glu Arg Gly Pro Pro Gly Pro Met Gly
275 280 285
Pro Pro Gly Leu Ala Gly Pro Pro Gly Glu Ser Gly Arg Glu Gly Ala
290 295 300
Pro Gly Ala Glu Gly Ser Pro Gly Arg Asp Gly Ser Pro Gly Ala Lys
305 310 315 320
Gly Asp Arg Gly Glu Thr Gly Pro Ala Gly Pro Pro Gly Ala Pro Gly
325 330 335
Ala Pro Gly Ala Pro Gly Pro Val Gly Pro Ala Gly Lys Ser Gly Asp
340 345 350
Arg Gly Glu Thr Gly Pro Ala Gly Pro Thr Gly Pro Val Gly Pro Val
355 360 365
Gly Ala Arg Gly Pro Ala Gly Pro Gln Gly Pro Arg Gly Asp Lys Gly
370 375 380
Glu Thr Gly Glu Gln Gly Asp Arg Gly Ile Lys Gly His Arg Gly Phe
385 390 395 400
Ser Gly Leu Gln Gly Pro Pro Gly Pro Pro Gly Ser Pro Gly Glu Gln
405 410 415
Gly Pro Ser Gly Ala Ser Gly Pro Ala Gly Pro Arg Gly Pro Pro Gly
420 425 430
Ser Ala Gly Ala Pro Gly Lys Asp Gly Leu Asn Gly Leu Pro Gly Pro
435 440 445
Ile Gly Pro Pro Gly Pro Arg Gly Arg Thr Gly Asp Ala Gly Pro Val
450 455 460
Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly Pro Pro Gly
465 470 475 480
Glu Arg Gly Asp Leu Gly Pro Gln Gly Ile Ala Gly Gln Arg Gly Val
485 490 495
Val Gly Glu Arg Gly Glu Arg Gly Glu Arg Gly Ala Ser Gly Glu Arg
500 505 510
Gly Asp Leu Gly Pro Gln Gly Ile Ala Gly Gln Arg Gly Val Val Gly
515 520 525
Glu Arg Gly Glu Arg Gly Glu Arg Gly Ala Ser Gly Glu Arg Gly Asp
530 535 540
Leu Gly Pro Gln Gly Ile Ala Gly Gln Arg Gly Val Val Gly Glu Arg
545 550 555 560
Gly Glu Arg Gly Glu Arg Gly Ala Ser Gly Pro Pro Gly Pro Cys Cys
565 570 575
Gly Gly Gly Leu Glu His His His His His His
580 585
<210> 7
<211> 491
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
Asp Ala Pro Glu Glu Glu Asp His Val Leu Val Leu Arg Lys Ser Asn
1 5 10 15
Phe Ala Glu Ala Leu Ala Ala His Lys Tyr Leu Leu Val Glu Phe Tyr
20 25 30
Ala Pro Trp Cys Gly His Cys Lys Ala Leu Ala Pro Glu Tyr Ala Lys
35 40 45
Ala Ala Gly Lys Leu Lys Ala Glu Gly Ser Glu Ile Arg Leu Ala Lys
50 55 60
Val Asp Ala Thr Glu Glu Ser Asp Leu Ala Gln Gln Tyr Gly Val Arg
65 70 75 80
Gly Tyr Pro Thr Ile Lys Phe Phe Arg Asn Gly Asp Thr Ala Ser Pro
85 90 95
Lys Glu Tyr Thr Ala Gly Arg Glu Ala Asp Asp Ile Val Asn Trp Leu
100 105 110
Lys Lys Arg Thr Gly Pro Ala Ala Thr Thr Leu Pro Asp Gly Ala Ala
115 120 125
Ala Glu Ser Leu Val Glu Ser Ser Glu Val Ala Val Ile Gly Phe Phe
130 135 140
Lys Asp Val Glu Ser Asp Ser Ala Lys Gln Phe Leu Gln Ala Ala Glu
145 150 155 160
Ala Ile Asp Asp Ile Pro Phe Gly Ile Thr Ser Asn Ser Asp Val Phe
165 170 175
Ser Lys Tyr Gln Leu Asp Lys Asp Gly Val Val Leu Phe Lys Lys Phe
180 185 190
Asp Glu Gly Arg Asn Asn Phe Glu Gly Glu Val Thr Lys Glu Asn Leu
195 200 205
Leu Asp Phe Ile Lys His Asn Gln Leu Pro Leu Val Ile Glu Phe Thr
210 215 220
Glu Gln Thr Ala Pro Lys Ile Phe Gly Gly Glu Ile Lys Thr His Ile
225 230 235 240
Leu Leu Phe Leu Pro Lys Ser Val Ser Asp Tyr Asp Gly Lys Leu Ser
245 250 255
Asn Phe Lys Thr Ala Ala Glu Ser Phe Lys Gly Lys Ile Leu Phe Ile
260 265 270
Phe Ile Asp Ser Asp His Thr Asp Asn Gln Arg Ile Leu Glu Phe Phe
275 280 285
Gly Leu Lys Lys Glu Glu Cys Pro Ala Val Arg Leu Ile Thr Leu Glu
290 295 300
Glu Glu Met Thr Lys Tyr Lys Pro Glu Ser Glu Glu Leu Thr Ala Glu
305 310 315 320
Arg Ile Thr Glu Phe Cys His Arg Phe Leu Glu Gly Lys Ile Lys Pro
325 330 335
His Leu Met Ser Gln Glu Leu Pro Glu Asp Trp Asp Lys Gln Pro Val
340 345 350
Lys Val Leu Val Gly Lys Asn Phe Glu Asp Val Ala Phe Asp Glu Lys
355 360 365
Lys Asn Val Phe Val Glu Phe Tyr Ala Pro Trp Cys Gly His Cys Lys
370 375 380
Gln Leu Ala Pro Ile Trp Asp Lys Leu Gly Glu Thr Tyr Lys Asp His
385 390 395 400
Glu Asn Ile Val Ile Ala Lys Met Asp Ser Thr Ala Asn Glu Val Glu
405 410 415
Ala Val Lys Val His Ser Phe Pro Thr Leu Lys Phe Phe Pro Ala Ser
420 425 430
Ala Asp Arg Thr Val Ile Asp Tyr Asn Gly Glu Arg Thr Leu Asp Gly
435 440 445
Phe Lys Lys Phe Leu Glu Ser Gly Gly Gln Asp Gly Ala Gly Asp Asp
450 455 460
Asp Asp Leu Glu Asp Leu Glu Glu Ala Glu Glu Pro Asp Met Glu Glu
465 470 475 480
Asp Asp Asp Gln Lys Ala Val Lys Asp Glu Leu
485 490
<210> 8
<211> 895
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 8
Met Ile Ser Arg Thr Tyr Val Ile Asn Leu Ala Arg Arg Pro Asp Lys
1 5 10 15
Lys Asp Arg Ile Leu Ala Glu Phe Leu Lys Leu Lys Glu Lys Gly Val
20 25 30
Glu Leu Asn Cys Val Ile Phe Glu Ala Val Asp Gly Asn Asn Pro Glu
35 40 45
His Leu Ser Arg Phe Asn Phe Lys Ile Pro Asn Trp Thr Asp Leu Asn
50 55 60
Ser Gly Lys Pro Met Thr Asn Gly Glu Val Gly Cys Ala Leu Ser His
65 70 75 80
Trp Ser Val Trp Lys Asp Val Val Asp Cys Val Glu Asn Gly Thr Leu
85 90 95
Asp Lys Asp Cys Arg Ile Leu Val Leu Glu Asp Asp Val Val Phe Leu
100 105 110
Asp Asn Phe Met Glu Arg Tyr Gln Thr Tyr Thr Ser Glu Ile Thr Tyr
115 120 125
Asn Cys Asp Leu Leu Tyr Leu His Arg Lys Pro Leu Asn Pro Tyr Thr
130 135 140
Glu Thr Lys Ile Ser Thr His Ile Val Lys Pro Asn Lys Ser Tyr Trp
145 150 155 160
Ala Cys Ala Tyr Val Ile Thr Tyr Gln Cys Ala Lys Lys Phe Met Asn
165 170 175
Ala Asn Tyr Leu Glu Asn Leu Ile Pro Ser Asp Glu Phe Ile Pro Ile
180 185 190
Met His Gly Cys Asn Val Tyr Gly Phe Glu Lys Leu Phe Ser Asn Cys
195 200 205
Glu Lys Ile Asp Cys Tyr Ala Val Gln Pro Ser Leu Val Lys Leu Thr
210 215 220
Ser Asn Ala Phe Asn Asp Ser Glu Thr Phe His Ser Gly Ser Tyr Val
225 230 235 240
Pro Ser Asn Lys Phe Asn Phe Asp Thr Asp Lys Gln Phe Arg Ile Val
245 250 255
Tyr Ile Gly Pro Thr Lys Gly Asn Ser Phe His Arg Phe Thr Glu Tyr
260 265 270
Cys Lys Leu Tyr Leu Leu Pro Tyr Lys Val Ile Asp Glu Lys Glu Thr
275 280 285
Asn Asp Phe Val Ser Leu Arg Ser Glu Leu Gln Ser Leu Ser Glu Gln
290 295 300
Asp Leu Asn Thr Thr Leu Met Leu Val Val Ser Val Asn His Asn Asp
305 310 315 320
Phe Cys Asn Thr Ile Pro Cys Ala Pro Thr Asn Glu Phe Ile Asp Lys
325 330 335
Tyr Lys Gln Leu Thr Thr Asp Thr Asn Ser Ile Val Ser Ala Val Gln
340 345 350
Asn Gly Thr Asn Lys Thr Met Phe Ile Gly Trp Ala Asn Lys Ile Ser
355 360 365
Glu Phe Ile Asn His Tyr His Gln Lys Leu Thr Glu Ser Asn Ala Glu
370 375 380
Thr Asp Ile Asn Leu Ala Asn Leu Leu Leu Ile Ser Ser Ile Ser Ser
385 390 395 400
Asp Phe Asn Cys Val Val Glu Asp Val Glu Gly Asn Leu Phe Gln Leu
405 410 415
Ile Asn Glu Glu Ser Asp Ile Val Phe Ser Thr Thr Thr Ser Arg Val
420 425 430
Asn Asn Lys Leu Gly Lys Thr Pro Ser Val Leu Tyr Ala Asn Ser Asp
435 440 445
Ser Ser Val Ile Val Leu Asn Lys Val Glu Asn Tyr Thr Gly Tyr Gly
450 455 460
Trp Asn Glu Tyr Tyr Gly Tyr His Val Tyr Pro Val Lys Phe Asp Val
465 470 475 480
Leu Pro Lys Ile Tyr Leu Ser Ile Arg Ile Val Lys Asn Ala Asn Val
485 490 495
Thr Lys Ile Ala Glu Thr Leu Asp Tyr Pro Lys Glu Leu Ile Thr Val
500 505 510
Ser Ile Ser Arg Ser Glu His Asp Ser Phe Tyr Gln Ala Asp Ile Gln
515 520 525
Lys Phe Leu Leu Ser Gly Ala Asp Tyr Tyr Phe Tyr Ile Ser Gly Asp
530 535 540
Cys Ile Ile Thr Arg Pro Thr Ile Leu Lys Glu Leu Leu Glu Leu Asn
545 550 555 560
Lys Asp Phe Val Gly Pro Leu Met Arg Lys Gly Thr Glu Ser Trp Thr
565 570 575
Asn Tyr Trp Gly Asp Ile Asp Pro Ser Asn Gly Tyr Tyr Lys Arg Ser
580 585 590
Phe Asp Tyr Phe Asp Ile Ile Gly Arg Asp Arg Val Gly Cys Trp Asn
595 600 605
Val Pro Tyr Leu Ala Ser Val Tyr Leu Ile Lys Lys Ser Val Ile Glu
610 615 620
Gln Val Pro Asn Leu Phe Thr Glu Asn Ser His Met Trp Asn Gly Ser
625 630 635 640
Asn Ile Asp Met Arg Leu Cys His Asn Leu Arg Lys Asn Asn Val Phe
645 650 655
Met Tyr Leu Ser Asn Leu Arg Pro Tyr Gly His Ile Asp Asp Ser Ile
660 665 670
Asn Leu Glu Val Leu Ser Gly Val Pro Thr Glu Val Thr Leu Tyr Asp
675 680 685
Leu Pro Thr Arg Lys Glu Glu Trp Glu Lys Lys Tyr Leu His Pro Glu
690 695 700
Phe Leu Ser His Leu Gln Asn Phe Lys Asp Phe Asp Tyr Thr Glu Ile
705 710 715 720
Cys Asn Asp Val Tyr Ser Phe Pro Leu Phe Thr Pro Ala Phe Cys Lys
725 730 735
Glu Val Ile Glu Val Met Asp Lys Ala Asn Leu Trp Ser Lys Gly Gly
740 745 750
Asp Ser Tyr Phe Asp Pro Arg Ile Gly Gly Val Glu Ser Tyr Pro Thr
755 760 765
Gln Asp Thr Gln Leu Tyr Glu Val Gly Leu Asp Lys Gln Trp His Tyr
770 775 780
Val Val Phe Asn Tyr Val Ala Pro Phe Val Arg His Leu Tyr Asn Asn
785 790 795 800
Tyr Lys Thr Lys Asp Ile Asn Leu Ala Phe Val Val Lys Tyr Asp Met
805 810 815
Glu Arg Gln Ser Glu Leu Ala Pro His His Asp Ser Ser Thr Tyr Thr
820 825 830
Leu Asn Ile Ala Leu Asn Glu Tyr Gly Lys Glu Tyr Thr Ala Gly Gly
835 840 845
Cys Glu Phe Ile Arg His Lys Phe Ile Trp Gln Gly Gln Lys Val Gly
850 855 860
Tyr Ala Thr Ile His Ala Gly Lys Leu Leu Ala Tyr His Arg Ala Leu
865 870 875 880
Pro Ile Thr Ser Gly Lys Arg Tyr Ile Leu Val Ser Phe Val Asn
885 890 895
<210> 9
<211> 26
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 9
ccctcgagaa aagaccacca ttcttg 26
<210> 10
<211> 28
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 10
taagcggccg cttattagtg gtggtggt 28
<210> 11
<211> 24
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 11
cccaagcttg aaaaaaatgc accc 24
<210> 12
<211> 24
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 12
taagcggccg cttattattc caat 24
<210> 13
<211> 23
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 13
cccaagcttg aaaaaaatgg acg 23
<210> 14
<211> 23
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 14
taagcggccg cttattacaa ttc 23
<210> 15
<211> 27
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 15
cccaagcttg aaaaaaatga tctctag 27
<210> 16
<211> 28
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 16
taagcggccg cttattagtt aacgaaag 28
<210> 17
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 17
ggtgttccag gtgacttggg 20
<210> 18
<211> 24
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 18
ttagtggtgg tgatggtggt gttc 24
<210> 19
<211> 28
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 19
atggacgctc cagaagaaga agaccacg 28
<210> 20
<211> 30
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 20
ctagtagaac ccttcaacaa catcaagaat 30
<210> 21
<211> 22
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 21
atggacgctc cagaagaaga ag 22
<210> 22
<211> 22
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 22
ttacaattcg tccttaacag cc 22
<210> 23
<211> 27
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 23
atgatctcta gaacttacgt tatcaac 27
<210> 24
<211> 28
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 24
tagttaacga aagaaaccaa gatgtatc 28
Claims (8)
1.含羟脯氨酸与羟赖氨酸重组类人胶原蛋白的核苷酸序列,其特征在于:所述核苷酸序列如SEQ ID NO.1所示。
2.含羟脯氨酸与羟赖氨酸重组类人胶原蛋白,其特征在于:所述含羟脯氨酸与羟赖氨酸重组类人胶原蛋白的氨基酸序列如SEQ ID NO.5所示。
3.一种表达重组类人胶原蛋白的克鲁维酵母,其特征在于:胞内组成型表达人源脯氨酸羟化酶α亚基,蛋白酶二硫键异构酶,以及赖氨酸羟化酶;其中,脯氨酸羟化酶α亚基的核苷酸序列如SEQ ID No.2所示,氨基酸序列如SEQ ID No.6所示;蛋白酶二硫键异构酶的核苷酸序列如SEQ ID No.3所示,氨基酸序列如SEQ ID No.7所示;赖氨酸羟化酶的核苷酸序列如SEQ ID No.4所示,氨基酸序列如SEQ ID No.8所示。
4.根据权利要求3所述的表达重组类人胶原蛋白的克鲁维酵母生产诱导方法,其特征在于包括以下步骤:
1)接种:将构建好的克鲁维酵母菌挑单菌落于YPD培养基中,28-30℃,100-300rpm培养约16-30h,至OD600达到20-30范围;
2)发酵培养:将步骤1)种子液接种至发酵罐中,控制温度在28-30℃,溶氧不低于20%,pH在5.8±0.1;
3)菌体生长:待葡萄糖耗尽后,补加葡萄糖;
4)半乳糖诱导:待步骤3)中的葡萄糖消耗完后,开始补加植物来源的半乳糖,至诱导结束;
5)离心,收集发酵液上清,得重组类人胶原蛋白发酵液。
5.根据权利要求4所述的表达重组类人胶原蛋白的克鲁维酵母生产诱导方法,其特征在于:步骤3)补加0.1%-12%葡萄糖。
6.根据权利要求4所述的表达重组类人胶原蛋白的克鲁维酵母生产诱导方法,其特征在于:步骤4)补加0.1%-10%的植物来源的半乳糖。
7.根据权利要求4所述的表达重组类人胶原蛋白的克鲁维酵母生产诱导方法,其特征在于:步骤5)所述的离心为3000g-10000g离心2-30min。
8.权利要求2所述的含羟脯氨酸与羟赖氨酸重组类人胶原蛋白在促进细胞粘附以及促进伤口愈合中的应用。
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CN118240735A (zh) * | 2024-05-21 | 2024-06-25 | 华南理工大学 | 一种能表达外源蛋白的菌株、重组人源胶原蛋白及合成方法与应用 |
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