CN107286223B - 一种用于检测组蛋白位点乙酰化的重组蛋白及其应用 - Google Patents
一种用于检测组蛋白位点乙酰化的重组蛋白及其应用 Download PDFInfo
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- CN107286223B CN107286223B CN201710581878.2A CN201710581878A CN107286223B CN 107286223 B CN107286223 B CN 107286223B CN 201710581878 A CN201710581878 A CN 201710581878A CN 107286223 B CN107286223 B CN 107286223B
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Abstract
本发明提供一种用于检测组蛋白位点乙酰化的重组蛋白及其应用。本发明的氨基酸序列中包括串联2个或2个以上Bromo结构域序列,其中,Bromo结构域序列为:a)SEQ ID NO.1所示的氨基酸序列;或b)SEQ ID NO.1所示的氨基酸序列经替换、缺失和/或添加一个或几个氨基酸残基形成的具有同等功能的氨基酸序列。本发明的重组蛋白对H3K14AC的亲和力强,可用于替代商业化抗体来进行Western Blot实验,灵敏度高,没有交叉结合发生,且预期成本低,批次质量十分稳定,可以快速实现批量化生产。
Description
技术领域
本发明涉及蛋白修饰化检测技术领域,更具体地,涉及一种用于检测组蛋白位点乙酰化的重组蛋白及其应用。
背景技术
调控细胞过程和疾病进展的翻译后修改分子解剖学是后基因组生物学研究的主要目标之一。迄今为止,已发现300多种翻译后修饰。这是使蛋白基本结构甚至功能发生改变的有效方式。赖氨酸侧链上的修饰证明了分子网络的巨大复杂性。赖氨酸是由15个核糖体编码并已知可被修饰的氨基酸残基。赖氨酸侧链具有两种特性:电荷丰富和亲核性,适合翻译后修饰与不同的亲电底物以共价键结合。赖氨酸上可发生很多翻译后修饰,如甲基化,乙酰化,生物素化,泛素化,豆蔻酰化和sumo化修饰等,这些修饰在细胞生理和病理中有重要作用。
组蛋白上的赖氨酸可被如甲基化,乙酰化,泛素化,sumo化、核糖体化和豆蔻酰化修饰。其中,赖氨酸乙酰化是一种丰度高,可逆的,并可高度调控的组蛋白编码。赖氨酸乙酰化在各种细胞过程,如调亡、代谢、转录和应激反应中发挥重要作用。除了在基础生物学方面的作用,赖氨酸乙酰化及其调控酶与衰老、癌症、神经变性疾病以及心血管疾病也紧密相关。
组蛋白的修饰方式主要有丝氨酸苏氨酸或丝氨酸磷酸化,赖氨酸乙酰化,赖氨酸或精氨酸甲基化,针对不同修饰及其不同位点,通常购买商业化抗组蛋白特定修饰位点的多抗,进行蛋白质印迹检测组蛋白修饰的程度,进而分析基因转录的激活或抑制水平,在表观遗传学上是一项必备的实验分析技术。
目前,针对组蛋白乙酰化修饰位点的商业化抗体价格昂贵,而且批次质量不稳定,交叉反应明显,特定位点修饰的抗体制备周期很长,产量低。
发明内容
(一)要解决的技术问题
本发明要解决的技术问题是针对组蛋白乙酰化修饰位点的商业化抗体价格昂贵,各批次质量不稳定,交叉反应严重,特定位点修饰的抗体制备周期长,产量低。
(二)技术方案
为了解决上述技术问题或者至少部分地解决上述问题,本发明提供了一种重组蛋白,重组蛋白的氨基酸序列包括串联2个或2个以上Bromo结构域序列,其中,该Bromo结构域序列,记为BBM1,为:
a)SEQ ID NO.1所示的氨基酸序列;或
b)SEQ ID NO.1所示的氨基酸序列经替换、缺失和/或添加一个或几个氨基酸残基形成的具有同等功能的氨基酸序列。
本发明优化了Bromo结构域,并将2个或2个以上优化后的结构域串联,实验测定Kd值为6.75uM,亲和力提高20倍。
在本发明中,较为优选地是,将2个优化后的Bromo结构域串联。当使用2个优化的Bromo结构域串联时,记为BBM2,当使用3个优化的Bromo结构域串联时,记为BBM3,依此类推。
应当理解,本领域技术人员可根据本发明公开的SEQ ID NO.1片段,在不影响其活性的前提下,本发明的Bromo结构域序列还包括SEQ ID NO.1所示氨基酸序列取代、缺失或增加一个或几个氨基酸,具有与该结构域序列同等活性的由该Bromo结构域序列衍生得到的蛋白质。
在本领域中,Bromodomain结构域是一进化上高度保守的氨基酸的蛋白质功能结构域,本发明通过对该结构进行优化使其具有多个且串联的SEQ ID NO.1的氨基酸序列,提高对特定位点乙酰化的亲和力,从而起到提高检测灵敏度,降低交叉反应的效果。
为了得到质量更加稳定的重组蛋白,在本发明一个优选实施方式中,重组蛋白的氨基酸序列还包括N端的GST融合蛋白。即该重组蛋白中包含了N端的GST融合蛋白和C端的优化后的Bromo串联结构域,即该重组蛋白的氨基酸序列为:
a)SEQ ID NO.2所示的氨基酸序列;或
b)SEQ ID NO.2所示的氨基酸序列经替换、缺失和/或添加一个或几个氨基酸残基形成的具有同等功能的氨基酸序列。
在实验规模即可方便的纯化得到大量的,质量稳定的重组蛋白。
应当理解,本领域技术人员可根据本发明公开的重组蛋白GST-BBM2的氨基酸序列SEQ ID NO.2片段,在不影响其活性的前提下,本发明的重组蛋白还包括SEQ ID NO.2所示氨基酸序列取代、缺失或增加一个或几个氨基酸,具有与重组蛋白GST-BBM2同等活性的由GST-BBM2衍生得到的蛋白质。
根据本发明的另一个方面,本发明还提供了上述含有GST片段的重组蛋白的制备方法,包括:
1)全基因优化合成SEQ ID NO.1所述的核苷酸序列由2个Bromo结构域序列串联组成,简称为BBM2;
2)构建且诱导表达质粒pGEX-4t-1-BBM2;
3)用步骤2)中pGEX-4t-1-BBM2转化大肠杆菌感受态细胞BL21,活化,低温诱导培养,即得。
其中,在一个优选实施方式中,步骤2)具体为:
根据步骤1)的BBM2序列合成引物,PCR扩增,亚克隆到pGEX-4t-1载体,重组后载体编码pGEX-4t-1-BBM2。
在一个优选实施方式中,步骤3)具体为:
重组载体pGEX-4t-1-BBM2转化大肠杆菌感受态细胞BL21,单克隆活化到LB液体培养基,当OD600=0.6时,加入IPTG,低温16度诱导15h,可以得到该重组蛋白的可溶性表达;从1L液体LB诱导表达的发酵液中获得约20mg GST-BBM2重组蛋白。
根据本发明的一个方面,本发明还提供了编码上述重组蛋白的基因。
当重组蛋白的氨基酸序列包括2个串联的Bromo结构域序列时,其核苷酸序列如SEQ ID NO.3所示的序列。
当该重组蛋白的氨基酸序列中包括SEQ ID NO.2所示的氨基酸序列时,其核苷酸序列如SEQ ID NO.4所示的序列
根据本发明的另一个方面,本发明还提供了提供含有上述基因的表达载体。
根据本发明的另一个方面,本发明还提供了含有上述表达载体的宿主细胞。
根据本发明的另一个方面,本发明还提供了含有上述重组蛋白的抗体。
根据本发明的另一个方面,本发明还提供了含有上述重组蛋白的检测试剂盒。
根据本发明的另一个方面,本发明还提供了使用上述重组蛋白、基因或是抗体在检测组蛋白位点乙酰化中的应用。
更优选地是,组蛋白位点为组蛋白H3中的位点。所述组蛋白位点更优选为H3K14。
较优选地是,在上述应用中使用蛋白质印迹检测组蛋白位点乙酰化程度。
在本发明中,组蛋白可以取自人、鼠、马、牛、猪、绵羊、山羊、鸡、狗、猫、果蝇、线虫和酵母等细胞中。
本发明涉及的SEQ ID No.2重组蛋白融合的GST蛋白,也可以方便使用抗GST通用的抗体,应用到蛋白免疫印记检测中。
根据本发明的另一个方面,本发明还提供了使用上述重组蛋白、基因或是抗体在检测组蛋白H3K14AC免疫印迹中的应用。
在该应用中,使用上述重组蛋白与抗GST通用单抗以及HRP标记的羊抗鼠多抗,经过3级结合和信号放大,灵敏度明显得到提高,可得到较为理想的检测效果。
在该应用中,检测方法具体为:
1)提取待检测蛋白质,并将其转移至硝酸纤维膜上,封闭,TBST洗涤;
2)使用PBS稀释后终浓度为1-10ug/mL的重组蛋白GST-BBM2孵育,加入抗GST单抗和带HRP的抗鼠IgG多抗孵育,观察免疫印迹结果。
(三)有益效果
1)本发明提出的重组蛋白优化了Bromo结构域,同时优选将2个或2个以上上述结构域串联,提高了与H3K14ac结合的亲和力,特异性识别强,将其替代商业化抗体,没有交叉结合发生,预期成本显著降低,批次质量十分稳定,可以快速实现批量化生产;
2)同时SEQ ID NO.2所述的重组蛋白融合了助溶蛋白GST,提高了结构域Bromo可溶性表达水平。更有优势的是,利用大肠杆菌表达系统制备重组蛋白的成本低,一次研发理论上可以无数次重复生产,容易实现标准化工艺和规模化生产,从而保证批次间同质性好,质量稳定;
3)使用商业化抗体时,每100次样品实验使用同样的抗体,在保证实验成功的基础上平均消耗100ug抗体,平均成本为4500元,在成千上万次的检测中,这样的抗体价格就十分昂贵。而使用重组的Bromo结构域作为替代抗体,在一个制备周期内,每mg重组蛋白生产的平均成本不超过150元,加上使用通用抗体的市场价格,每100ug为500元,可以预期检测成本至少降低5倍。因此将本发明的重组蛋白替代商业化抗体,实验检测成本将显著降低。
具体实施方式
下面结合实施例,对本发明的具体实施方式作进一步详细描述。以下实施例用于说明本发明,但不用来限制本发明的范围。
若未特别指明,实施例中所用的技术手段为本领域技术人员所熟知的常规技术手段。若未特别指明,实施例中所用的试剂为市售。
实施例1
重组蛋白GST-BBM2的制备
1)首先全基因优化合成SEQ ID No.1序列所述的核苷酸序列,翻译的氨基酸序列即为双结构域BBM2。基因两端分别引入了限制性酶切位点BamHI和XhoI,合成的基因克隆到pUC57载体中;
2)提取步骤1)中包含BBM2序列的载体,双酶切,连接到同样双酶切的pGEX-4t-1载体,经筛选鉴定得到重组后的载体,命名为pGEX-4t-1-BBM2;
3)重组载体pGEX-4t-1-BBM2转化大肠杆菌感受态细胞BL21,单克隆活化到5mlLB液体培养基,当OD600=0.6时,加入0.5mM IPTG,低温16度-20度诱导12-15个小时,可以得到该重组蛋白的可溶性表达;
4)从1L步骤3)中液体LB诱导表达的发酵液中获得约GST-BBM3重组蛋白。
实施例2
重组蛋白的特异性检测
ITC仪器设备:The titration was performed using MicroCal iTC200 system(GE Healthcare)
实验方法参考仪器使用说明和标准设置。
主要步骤:确定合适的反应物浓度,准备样品;滴定,收集热量数据;校正数据,拟合回归,计算热力学参数,最后分析模型。
1)所有检测样本置于恒温25℃反应;
2)合成待测的多肽10mg(组蛋白H3第14位赖氨酸上乙酰化修饰),使用ITC基础缓冲液溶解。母液浓度为0.5mg/ml。
多肽序列源于H3K14ac,为ARKSTGGKacAPRKQ
稀释溶液:20mM Tris-HCl,50mM NaCl,pH7.5,多肽工作浓度0.8-1.2mM;
3)重组蛋白使用紫外分光光度计测定,计算得到蛋白浓度为0.8mg/ml,使用上述缓冲液稀释,工作浓度0.05-0.1mM;
4)收集反应的热量数据,最终结果由Origin7拟合计算。
ITC实验测定和计算的Kd值反映了重组蛋白对相应模拟多肽的特异性结合。Kd越低,结合特异性越好。源于PB1蛋白的Bromo2结构域对H3K14ac的Kd值分别为150uM,具有很弱的特异性结合。
其中,实施例1的GST-BBM2对H3K14ac的Kd值为6.5uM,结合特异性提高了至少20倍。
其中,实施例1的GST-BBM2重组蛋白对H3K14ac:Kd值为6.45um。
实施例3
以SEQ ID No.2所述的重组蛋白GST-BBM2蛋白免疫印迹WB(Western Blot)检测
1)使用RIPA裂解液提取人肝组织细胞核蛋白.采用15%SDS-PAGE聚丙烯酰胺凝胶电泳分离样品中的蛋白质,随后电转移蛋白到硝酸纤维素膜上;
2)使用5%BSA或脱脂奶粉37度封闭1到2个小时,TBST洗涤3次,每次5min;用TBS洗涤3次,每次5min;
3)使用SEQ ID No.2所述的重组蛋白GST-BBM2孵育NC膜,工作浓度为20-200nM或0.5-5ug/ml,37℃孵育1到2个小时,使用TBST和TBS依次洗涤3次,每次5min;
4)加入小鼠抗GST单抗,按说明书稀释抗体(1:1000),37度孵育2h,TBST洗涤3次,每次5min.再用TBS洗涤3次,每次5min;
5)加入带HRP的羊抗鼠IgG多抗(1:2000),按说明书稀释抗体,37度孵育2h,TBST洗涤3次,每次5min,用TBS洗涤3次,每次5min;
6)加入ECL发光液,依次显影,定影,曝光1-5min。观察免疫印迹结果。
来源于人的其它组织和细胞样本均可以以同样的技术方案实施。
免疫印迹结果:
以GST-BBM2重组蛋白进行WB时,灵敏度是原始结构域的20倍。在可控灵敏度范围内,出现了与H3K14ac对应大小的明显条带,对不同组织样本检测时,交叉反应较少;最有效的使用浓度为60nM。
以GST-BBM2重组蛋白进行WB时,与商业化抗体的检测灵敏度相当,使用重组蛋白有显著的优势,明显减少了非特异性识别和交叉反应,使得实验结果有可靠性和预判性。
最后,本发明的方法仅为较佳的实施方案,并非用于限定本发明的保护范围。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
序列表
<110> 武汉博欧特生物科技有限公司
<120> 一种用于检测组蛋白位点乙酰化的重组蛋白及其应用
<130> KHP171111391.5
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Val Val Leu Tyr Met Asp Pro Met Cys Leu Asp Ala Phe Pro Lys Leu
165 170 175
Val Cys Phe Lys Lys Arg Ile Glu Ala Ile Pro Gln Ile Asp Lys Tyr
180 185 190
Leu Lys Ser Ser Lys Tyr Ile Ala Trp Pro Leu Gln Gly Trp Gln Ala
195 200 205
Thr Phe Gly Gly Gly Asp His Pro Pro Lys Ser Asp Leu Val Pro Arg
210 215 220
Gly Ser Gly Thr Val Thr Glu Gly Ser Ser Pro Ala Tyr Leu Lys Glu
225 230 235 240
Ile Leu Glu Gln Leu Leu Glu Ala Ile Val Val Ala Thr Asn Pro Ser
245 250 255
Gly Arg Leu Ile Ser Glu Val Phe Gln Lys Leu Pro Ser Lys Val Gln
260 265 270
Tyr Pro Asp Tyr Tyr Glu Ile Ile Lys Glu Pro Ile Asp Leu Lys Thr
275 280 285
Ile Ala Gln Arg Ile Gln Asn Gly Ser Tyr Lys Ser Ile His Ala Met
290 295 300
Ala Lys Asp Ile Asp Leu Leu Ala Lys Asn Ala Lys Thr Tyr Asn Glu
305 310 315 320
Pro Gly Ser Gln Ile Phe Lys Asp Ala Asn Ser Ile Lys Lys Ile Phe
325 330 335
Tyr Met Lys Lys Ala Glu Ile Glu His His Glu Met Ala Lys Ser Ser
340 345 350
Gly Gly Gly Gly Thr Val Thr Glu Gly Ser Ser Pro Ala Tyr Leu Lys
355 360 365
Glu Ile Leu Glu Gln Leu Leu Glu Ala Ile Val Val Ala Thr Asn Pro
370 375 380
Ser Gly Arg Leu Ile Ser Glu Val Phe Gln Lys Leu Pro Ser Lys Val
385 390 395 400
Gln Tyr Pro Asp Tyr Tyr Glu Ile Ile Lys Glu Pro Ile Asp Leu Lys
405 410 415
Thr Ile Ala Gln Arg Ile Gln Asn Gly Ser Tyr Lys Ser Ile His Ala
420 425 430
Met Ala Lys Asp Ile Asp Leu Leu Ala Lys Asn Ala Lys Thr Tyr Asn
435 440 445
Glu Pro Gly Ser Gln Ile Phe Lys Asp Ala Asn Ser Ile Lys Lys Ile
450 455 460
Phe Tyr Met Lys Lys Ala Glu Ile Glu His His Glu Met Ala Lys Ser
465 470 475 480
Ser
<210> 3
<211> 765
<212> DNA
<213> BBM2基因
<400> 3
gggactgtca cagaaggatc gagcccggcg tacttgaagg agattttaga gcaattatta 60
gaagccattg tagttgcaac taatccttcg ggccgtttga tttctgaggt ttttcaaaag 120
ttgcctagca aagtgcagta cccagactat tacgaaatca ttaaggaacc gatcgatttg 180
aagaccatcg cacaacgcat tcaaaatggt agctacaagt caatccacgc catggcaaaa 240
gacatcgatc ttcttgcgaa gaacgcaaag acttacaatg aaccgggtag tcagattttc 300
aaagacgcta actcaatcaa aaaaatcttc tacatgaaga aagcagagat cgagcaccac 360
gaaatggcta aatcctcagg cggaggtggt acggtgaccg aggggagcag cccggcatac 420
cttaaggaga ttttggagca actgcttgaa gcaatcgttg ttgcaacgaa tccatcgggg 480
cgtttgatca gcgaagtctt tcagaagttg cccagtaaag tgcaataccc ggactactac 540
gagatcatca aggagccaat cgacctgaag accattgctc aacgcattca aaatgggtcc 600
tacaagagta ttcatgctat ggccaaggat attgatctgt tagccaagaa tgctaaaact 660
tacaatgagc cgggtagtca aatcttcaaa gacgcaaata gtattaagaa aatcttctac 720
atgaagaaag cggaaatcga acaccatgaa atggcgaaat caagc 765
<210> 4
<211> 1443
<212> DNA
<213> GST-BBM2基因
<400> 4
atgtccccta tactaggtta ttggaaaatt aagggccttg tgcaacccac tcgacttctt 60
ttggaatatc ttgaagaaaa atatgaagag catttgtatg agcgcgatga aggtgataaa 120
tggcgaaaca aaaagtttga attgggtttg gagtttccca atcttcctta ttatattgat 180
ggtgatgtta aattaacaca gtctatggcc atcatacgtt atatagctga caagcacaac 240
atgttgggtg gttgtccaaa agagcgtgca gagatttcaa tgcttgaagg agcggttttg 300
gatattagat acggtgtttc gagaattgca tatagtaaag actttgaaac tctcaaagtt 360
gattttctta gcaagctacc tgaaatgctg aaaatgttcg aagatcgttt atgtcataaa 420
acatatttaa atggtgatca tgtaacccat cctgacttca tgttgtatga cgctcttgat 480
gttgttttat acatggaccc aatgtgcctg gatgcgttcc caaaattagt ttgttttaaa 540
aaacgtattg aagctatccc acaaattgat aagtacttga aatccagcaa gtatatagca 600
tggcctttgc agggctggca agccacgttt ggtggtggcg accatcctcc aaaatcggat 660
ctggttccgc gtggatccgg gactgtcaca gaaggatcga gcccggcgta cttgaaggag 720
attttagagc aattattaga agccattgta gttgcaacta atccttcggg ccgtttgatt 780
tctgaggttt ttcaaaagtt gcctagcaaa gtgcagtacc cagactatta cgaaatcatt 840
aaggaaccga tcgatttgaa gaccatcgca caacgcattc aaaatggtag ctacaagtca 900
atccacgcca tggcaaaaga catcgatctt cttgcgaaga acgcaaagac ttacaatgaa 960
ccgggtagtc agattttcaa agacgctaac tcaatcaaaa aaatcttcta catgaagaaa 1020
gcagagatcg agcaccacga aatggctaaa tcctcaggcg gaggtggtac ggtgaccgag 1080
gggagcagcc cggcatacct taaggagatt ttggagcaac tgcttgaagc aatcgttgtt 1140
gcaacgaatc catcggggcg tttgatcagc gaagtctttc agaagttgcc cagtaaagtg 1200
caatacccgg actactacga gatcatcaag gagccaatcg acctgaagac cattgctcaa 1260
cgcattcaaa atgggtccta caagagtatt catgctatgg ccaaggatat tgatctgtta 1320
gccaagaatg ctaaaactta caatgagccg ggtagtcaaa tcttcaaaga cgcaaatagt 1380
attaagaaaa tcttctacat gaagaaagcg gaaatcgaac accatgaaat ggcgaaatca 1440
agc 1443
Claims (8)
1.一种重组蛋白,其特征在于,所述重组蛋白的氨基酸序列包括串联2个Bromo结构域序列,其中,所述Bromo结构域序列为:
SEQ ID NO.1所示的氨基酸序列。
2.根据权利要求1所述的重组蛋白,其特征在于,所述重组蛋白的氨基酸序列还包括N端的GST融合蛋白,所述重组蛋白的氨基酸序列为:
SEQ ID NO.2所示的氨基酸序列。
3.一种制备权利要求2所述重组蛋白的方法,包括:
1)全基因优化合成串联2个Bromo结构域序列BBM2;
2)构建诱导表达质粒pGEX-4t-1-BBM2;
3)用步骤2)中pGEX-4t-1-BBM2转化大肠杆菌感受态细胞BL21,活化,低温诱导培养,即得。
4.编码权利要求1或2所述重组蛋白的基因。
5.含有权利要求1或2所述重组蛋白的抗体。
6.含有权利要求1或2所述重组蛋白的检测试剂盒或诊断试剂。
7.权利要求1或2所述重组蛋白或权利要求5所述抗体在制备用于检测组蛋白位点乙酰化的试剂盒中的应用。
8.根据权利要求7所述的应用,其特征在于,所述组蛋白位点为H3K14。
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1509336A (zh) * | 2001-05-17 | 2004-06-30 | 株式会社岛津制作所 | 肽的制备方法 |
CN102946732A (zh) * | 2010-05-27 | 2013-02-27 | 科罗拉多州立大学董事会 | 用作组蛋白脱乙酰酶抑制剂的大环化合物 |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1509336A (zh) * | 2001-05-17 | 2004-06-30 | 株式会社岛津制作所 | 肽的制备方法 |
CN102946732A (zh) * | 2010-05-27 | 2013-02-27 | 科罗拉多州立大学董事会 | 用作组蛋白脱乙酰酶抑制剂的大环化合物 |
Non-Patent Citations (1)
Title |
---|
《Autoregulation of the Rsc4 Tandem Bromodomain by Gcn5 Acetylation》;Andrew P. VanDemark等;《Molecular Cell》;20070907;第27卷(第5期);摘要 * |
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