保守GTP酶EF-G在蛋白质合成中的功能研究
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摘要
核桃体是蛋白质合成的中心,它是细胞内存在的一个大且复杂的分子机器。在翻译过程中,核桃体通过合成的多肽链将遗传信息传递出来。核糖体读取mRNA上的信息是按照既定的方向进行的,即从5’到3’端。核糖体的翻译过程是复杂的,为了保证这个过程的顺利进行,许多调控因子参与其中。GTPase是蛋白质合成过程中普遍存在的翻译因子,在这个过程中发挥重要作用。在多肽链的合成过程中,能量来自于GTP水解成GDP (?)释放无机磷的过程。核糖体上存在一个GTPase结合中心(GTPase-associated center, GAC)区域,GAC主要负责激活GTP酶的GTP水解活性。相关GTPase结合到GAC上调节蛋白质的翻译过程。
GTP酶广泛存在于生物体内,控制许多关键的生物过程如细胞分化、信号转导、蛋白质合成及运输、能量代谢等,发挥重要的生物学功能。GTP酶被称之为分子关蛋白,以循环形式发挥功能。延伸因子G和Tu(Elongation factor G and Tu, EF-G and EF-Tu),起始因子2(Initiation factor2, IF2)等是自然界中普遍存在的GTPase,在蛋白质合成过程中发挥相应的功能。EF-G是蛋白质翻译过程中的一个保守的GTPase。蛋白质的序列和结构显示,EF-G是由五个结构域组成的,结构域Ⅰ、Ⅱ、Ⅲ和Ⅴ分别与延伸因子4(EF4)的Ⅰ到Ⅳ对应相似。与EF4相比,EF-G多子一个G’结构域和结构域Ⅳ,但是EF4拥有一个特殊的C端结构域。EF-G能够催化肽基(?)-tRNA从A位点转移到P位点以及脱酰基-tRNA从P位点转移到E位点,从而促进mRNA-(tRNA)2复合物的转位。此外它能够结合核糖体循环因子(Ribosome recycling factor, RRF)参与核糖体的再循环过程,从而保证下一轮蛋白质合成的顺利进行。
本文通过同源模拟发现核糖体保护蛋白Tet(O)与EF-G具有相似的空问结构并且都包含五个结构域。通过序列比对发现E. coli EF-G和Campylobacter jejuni(空肠弯曲菌)Tet(O)结构域Ⅳ保守的两个环状区不同,从而通过分子克隆构建EF-G嵌合体。将突变基因克隆到pET-28a中,然后转化到E. coli BL21感受态细胞中进行蛋白质的表达纯化。纯化后的蛋白质突变体通过GTPase i活性检测、poly(U)指导的多聚苯丙氨酸的合成、多聚核糖体的解聚检测及相关的体内实验来检测EF-G在肽链合成中的作用。研究结果表明突变体能够影响肽链生成过程中mRNA-(tRNA)2复合物的移位但不影响核糖体的再循环过程。
本文通过对EF-G嵌合体在大肠杆菌蛋白翻译过程中的功能研究来进一步了解其转位过程的发生,从而为研究原核生物核糖体上的一些靶点抗生素的作用机制奠定了理论基础。
Ribosome, which is central to protein synthesis, is a big and complicated molecular machine in cells. During translation, the ribosome moves along with mRNA in a one-way direction from5' to3'and converts the genetic information into a polypeptide chain. A variety of regulated factors function in the process of ribosome translation which is complicated in order to ensure accurate protein synthesis. GTPase is a series of translation factors and plays a crucial role in ptotein synthesis. During the polypeptide chain synthesis, the energy is generated from the process of GTP hydrolysis into GDP and releasing inorganic Pi. There is a GTPase-associated center (GAC) to where many related GTPases bind to regulate the protein synthesis in the ribosome. GAC is responsible for stimulating the hydrolysis activity of GTPase.
GTPase is a large group of conservative enzymes in cell which is widely participated and plays an important biological function in cell differentiation, signal transduetion, protein synthesis and transport as well as energy metabolism. GTPase is called molecular switch protein with circulation form function. Elongation factor G (EF-G), elongation factor TU (EF-TU), initiation factor2(IF2) and others are common GTPase which function different in protein synthesis. EF-G is one of the conserved GTPases in protein translation. Sequence and structural data show that it is constituted of five structural domains, in which domains Ⅰ,Ⅱ,Ⅲ. and Ⅴ are homologous to domains Ⅰ to IV of elongation factor4(EF4). EF-G has regions of domains G' and IV to which EF4does not correspond,while it does not own a similar unique C-terminal domain of EF4. EF-G translocates the mRNA-(tRNA)2complex, moving the peptidyl-tRNA from the A to the P site and the deacylated-tRNA from the P to the E site. In addition, EF-G combines with RRF to participate in ribosome recycling, ensuring the next cycle of protein synthesis.
In our study, homology-modelling indicates that the structure of ribosome protection protein C. jejuni Tet(O) has a high similarity to E. coli EF-G and both contain five domains. The two conserved loops of domain Ⅳ in both proteins are different via sequence alignment. So we cloned the mutant gene of EF-G into pET-28a, expressed in E. coli BL21, and then purified proteins. Through C? IP hydrolysis, Poly(U)-dependent poly(Phe) Synthesis. Polysome breakdown assay as well as in vivo experiments, we concluded that EF-G mutants can affect the transloeation of mRNA-(tRNA)2complex, hut have no influence on ribosome recycling.
We learned more about the transloeation process through the function study of EF-G chimeras in E. coli protein synthesis in order to lay the theoretical basis lor researches on function mechanism of target antibiotics on prokaryotic ribosomes.
GTP酶广泛存在于生物体内,控制许多关键的生物过程如细胞分化、信号转导、蛋白质合成及运输、能量代谢等,发挥重要的生物学功能。GTP酶被称之为分子关蛋白,以循环形式发挥功能。延伸因子G和Tu(Elongation factor G and Tu, EF-G and EF-Tu),起始因子2(Initiation factor2, IF2)等是自然界中普遍存在的GTPase,在蛋白质合成过程中发挥相应的功能。EF-G是蛋白质翻译过程中的一个保守的GTPase。蛋白质的序列和结构显示,EF-G是由五个结构域组成的,结构域Ⅰ、Ⅱ、Ⅲ和Ⅴ分别与延伸因子4(EF4)的Ⅰ到Ⅳ对应相似。与EF4相比,EF-G多子一个G’结构域和结构域Ⅳ,但是EF4拥有一个特殊的C端结构域。EF-G能够催化肽基(?)-tRNA从A位点转移到P位点以及脱酰基-tRNA从P位点转移到E位点,从而促进mRNA-(tRNA)2复合物的转位。此外它能够结合核糖体循环因子(Ribosome recycling factor, RRF)参与核糖体的再循环过程,从而保证下一轮蛋白质合成的顺利进行。
本文通过同源模拟发现核糖体保护蛋白Tet(O)与EF-G具有相似的空问结构并且都包含五个结构域。通过序列比对发现E. coli EF-G和Campylobacter jejuni(空肠弯曲菌)Tet(O)结构域Ⅳ保守的两个环状区不同,从而通过分子克隆构建EF-G嵌合体。将突变基因克隆到pET-28a中,然后转化到E. coli BL21感受态细胞中进行蛋白质的表达纯化。纯化后的蛋白质突变体通过GTPase i活性检测、poly(U)指导的多聚苯丙氨酸的合成、多聚核糖体的解聚检测及相关的体内实验来检测EF-G在肽链合成中的作用。研究结果表明突变体能够影响肽链生成过程中mRNA-(tRNA)2复合物的移位但不影响核糖体的再循环过程。
本文通过对EF-G嵌合体在大肠杆菌蛋白翻译过程中的功能研究来进一步了解其转位过程的发生,从而为研究原核生物核糖体上的一些靶点抗生素的作用机制奠定了理论基础。
Ribosome, which is central to protein synthesis, is a big and complicated molecular machine in cells. During translation, the ribosome moves along with mRNA in a one-way direction from5' to3'and converts the genetic information into a polypeptide chain. A variety of regulated factors function in the process of ribosome translation which is complicated in order to ensure accurate protein synthesis. GTPase is a series of translation factors and plays a crucial role in ptotein synthesis. During the polypeptide chain synthesis, the energy is generated from the process of GTP hydrolysis into GDP and releasing inorganic Pi. There is a GTPase-associated center (GAC) to where many related GTPases bind to regulate the protein synthesis in the ribosome. GAC is responsible for stimulating the hydrolysis activity of GTPase.
GTPase is a large group of conservative enzymes in cell which is widely participated and plays an important biological function in cell differentiation, signal transduetion, protein synthesis and transport as well as energy metabolism. GTPase is called molecular switch protein with circulation form function. Elongation factor G (EF-G), elongation factor TU (EF-TU), initiation factor2(IF2) and others are common GTPase which function different in protein synthesis. EF-G is one of the conserved GTPases in protein translation. Sequence and structural data show that it is constituted of five structural domains, in which domains Ⅰ,Ⅱ,Ⅲ. and Ⅴ are homologous to domains Ⅰ to IV of elongation factor4(EF4). EF-G has regions of domains G' and IV to which EF4does not correspond,while it does not own a similar unique C-terminal domain of EF4. EF-G translocates the mRNA-(tRNA)2complex, moving the peptidyl-tRNA from the A to the P site and the deacylated-tRNA from the P to the E site. In addition, EF-G combines with RRF to participate in ribosome recycling, ensuring the next cycle of protein synthesis.
In our study, homology-modelling indicates that the structure of ribosome protection protein C. jejuni Tet(O) has a high similarity to E. coli EF-G and both contain five domains. The two conserved loops of domain Ⅳ in both proteins are different via sequence alignment. So we cloned the mutant gene of EF-G into pET-28a, expressed in E. coli BL21, and then purified proteins. Through C? IP hydrolysis, Poly(U)-dependent poly(Phe) Synthesis. Polysome breakdown assay as well as in vivo experiments, we concluded that EF-G mutants can affect the transloeation of mRNA-(tRNA)2complex, hut have no influence on ribosome recycling.
We learned more about the transloeation process through the function study of EF-G chimeras in E. coli protein synthesis in order to lay the theoretical basis lor researches on function mechanism of target antibiotics on prokaryotic ribosomes.
引文
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