Ubiquitin-like家族蛋白溶液结构与分子作用机制研究
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摘要
蛋白质翻译后修饰是蛋白质功能调节的重要手段之一,涉及到蛋白质降解、信号转导、染色体装配、DNA损伤修复等重要的生物学功能。目前已知的翻译后修饰包括磷酸化、乙酰化、糖基化、泛素化、甲基化等。在这些翻译后修饰中,泛素蛋白家族包含大约十几种相关的蛋白质,目前研究比较透彻的是泛素(ubiquitin)蛋白和SUMO (small ubiquitin-like proteins)蛋白。我们的研究工作主要集中在两个方面：一个是锥体虫Trypanosoma brucei中SUMO蛋白(Tb-SUMO)的溶液结构和人Ubc9的相互作用；另一个是原核生物中ubiquitin蛋白(Pup)的溶液结构及与Mpa相互作用的研究。
锥体虫Trypanosoma brucei是一种古老的单细胞的原生生物,主要寄生在人和牛的体内,造成人的嗜睡病和牛的那加那病。我们实验室的廖善晖同学通过RNAi的方法证明了SUMO蛋白在锥体虫中细胞有丝分裂中起重要作用。我们利用核磁共振方法研究Trypanosoma brucei中SUMO蛋白的三维溶液结构,这是第一个被解析出来的原生生物中SUMO蛋白的溶液结构。通过核磁的溶液结构研究发现,Tb-SUMO的溶液结构具有典型的ubiquitin折叠构像,由5个β折叠和两个α螺旋组成。与其他已知的SUMO蛋白结构相比,Tb-SUMO蛋白在氨基端含有一段较长的无规卷曲序列,长度达到32个氨基酸残基。为了研究Tb-SUMO和E2酶的相互作用,我们用化学微扰的方法研究了Tb-SUMO与人E2 (Trypanosoma brucei中的E2酶尚未找到)酶Ubc9的相互作用界面,发现Tb-SUMO与Ubc9的主要相互作用界面集中在β片层上,相互作用方式主要以疏水相互作用和静电相互作用为主。通过研究我们发现锥体虫中的SUMO蛋白在结构和Ubc9的结合方式在进化上是保守的。
Ubiquitin蛋白在真核生物中可以作为信号分子介导蛋白质到蛋白酶体中进行水解。已知在结核杆菌中有蛋白酶体复合物,但是一直以来在原核生物中都没有发现类似ubiquitin介导蛋白水解的方式,直到2008年人们首次在结核杆菌中发现了原核生物的ubiquitin蛋白(Pup)。并确定了Pup蛋白在结核杆菌中介导底物蛋白的水解。Pup是一个由64个氨基酸编码的小蛋白质,与真核生物中ubiquitin蛋白一样,在Pup的羧基端含有两个连续的甘氨酸残基。我们通过Pup与真核生物中ubiquitin的序列比对发现它与真核中ubiquitin蛋白的序列同源性非常低,二级结构预测也显示其具有不同于真核ubiquitin蛋白的二级结构。在实验方面我们利用CD和NMR方法显示Pup是一个天然无规蛋白(IDP),1H-15N NOE和CSI方法显示在Pup的羧基端有一些残留的二级结构。之后我们利用NMR方法确定了Pup蛋白中各氨基酸的化学位移,同时我们用SPR方法和化学微扰的方法研究了Pup蛋白与Mpa (mycobacterium proteasomal ATPase)蛋白的相互作用。Mpa是原核生物中蛋白酶体的具有ATPase功能的一个调节亚基,它能够与Pup相互作用把底物带到蛋白酶体中进行水解。研究结果表明Pup和Mpa是一种强疏水相互作用,作用区段主要集中在羧基端的30-59的氨基酸区域。同时我们还在进化角度上用进化树对Pup蛋白的进化进行分析,发现Pup蛋白是一个在进化树上独立的分支,这也可以解释为什么Pup蛋白的结构与真核的ubiquitin结构有很大的差别。这是在国际上首次发现的原核生物中ubiquitin的蛋白是一个天然无规蛋白质,这个研究为后续的原核中ubiquitin的功能研究和作用机制提供实验上的依据。
Post-translational modification is an important mechanism that regulates a wide variety of cellular events such as protein degradation, singal transduction, gene expression, cell cycle, and DNA repair. Post-translational modifications include phosphorylation, acetylation, methylation, glycosylation, ubiquitylation and so on. Ubiquitin proteins family includes more than ten proteins. So far, many studies have been focused on ubiquitin and SUMO (small ubiquitin-like proteins). Our studies can be devided into two parts:one is about the study of solution structure of SUMO of Trypanosoma brucei and its interaction with hUbc9; the other is about the structural study of Pup and its interaction with Mpa (mycobacterium proteasomal ATPase).
Trypanosoma brucei is the most ancient unicellular eukaryotic organism that causes sleeping sickness in human and nagana diseases in animals. In this study, we use NMR method to solve the solution structure of SUMO of Trypanosoma brucei (Tb-SUMO). This is the first structure of SUMO determined in protist. Tb-SUMO has the typical ubiquitin-fold containing five 13 stands and two a halix. Compared with other SUMO structures, Tb-SUMO has an extended region with a length of 32 amino acids at the N-terminus. We also study the interaction between Tb-SUMO and human Ubc9 (the E2 enzyme has not been identified in Trypanosoma brucei so far). On SUMO, the surface is composed byβsheet and some loops, which is highly complementary in its electrostatic potentials and hydrophobicity to the positively charged surface of Ubc9. The result shows that the structure and binding surface of Tb-SUMO is conserved.
In eukaryotic cells, ubiquitin is attached to substracts as a tag to bring proteins into proteasome for degradation. Proteasome in mycobacterial has been found for many years. Ubiquitin protein is not known in prokaryotae, until Pup is reported to be coupled to proteins, rendering them as substrates for proteasome-mediated degradation in mycobacterium in 2008. Pup is a small protein encoded by 64 amino acids. Like eukaryotic ubiquitin proteins, there are two glycines in the C-terminus of Pup. Sequence alignment shows that Pup and ubiquitin proteins share very low similarity. Diverse structure predictions combined with CD and NMR spectroscopic studies all demonstrate that Pup is an intrinsically disordered protein. Moreover, 1H-15N NOE (nuclear Overhauser effect) data and CSI (chemical shift index) analyses indicate that there is a residual secondary structure at the C-terminus of Pup. In M. tuberculosis, Mpa is the regulatory cap ATPase of the proteasome that interacts with Pup and brings the substrates to the proteasome for degradation. SPR (surface plasmon resonance) and NMR perturbation studies imply that the C-terminus of Pup, ranging from residue 30 to 59, binds to Mpa probably through a hydrophobic interface. In addition, phylogenetic analysis clearly shows that the Pup family belongs to a unique and divergent evolutionary branch, suggesting that it is the most ancient and deeply branched family among ubiquitinlike proteins. This might explain the structural distinction between Pup and other ubiquitin-like superfamily proteins.
锥体虫Trypanosoma brucei是一种古老的单细胞的原生生物,主要寄生在人和牛的体内,造成人的嗜睡病和牛的那加那病。我们实验室的廖善晖同学通过RNAi的方法证明了SUMO蛋白在锥体虫中细胞有丝分裂中起重要作用。我们利用核磁共振方法研究Trypanosoma brucei中SUMO蛋白的三维溶液结构,这是第一个被解析出来的原生生物中SUMO蛋白的溶液结构。通过核磁的溶液结构研究发现,Tb-SUMO的溶液结构具有典型的ubiquitin折叠构像,由5个β折叠和两个α螺旋组成。与其他已知的SUMO蛋白结构相比,Tb-SUMO蛋白在氨基端含有一段较长的无规卷曲序列,长度达到32个氨基酸残基。为了研究Tb-SUMO和E2酶的相互作用,我们用化学微扰的方法研究了Tb-SUMO与人E2 (Trypanosoma brucei中的E2酶尚未找到)酶Ubc9的相互作用界面,发现Tb-SUMO与Ubc9的主要相互作用界面集中在β片层上,相互作用方式主要以疏水相互作用和静电相互作用为主。通过研究我们发现锥体虫中的SUMO蛋白在结构和Ubc9的结合方式在进化上是保守的。
Ubiquitin蛋白在真核生物中可以作为信号分子介导蛋白质到蛋白酶体中进行水解。已知在结核杆菌中有蛋白酶体复合物,但是一直以来在原核生物中都没有发现类似ubiquitin介导蛋白水解的方式,直到2008年人们首次在结核杆菌中发现了原核生物的ubiquitin蛋白(Pup)。并确定了Pup蛋白在结核杆菌中介导底物蛋白的水解。Pup是一个由64个氨基酸编码的小蛋白质,与真核生物中ubiquitin蛋白一样,在Pup的羧基端含有两个连续的甘氨酸残基。我们通过Pup与真核生物中ubiquitin的序列比对发现它与真核中ubiquitin蛋白的序列同源性非常低,二级结构预测也显示其具有不同于真核ubiquitin蛋白的二级结构。在实验方面我们利用CD和NMR方法显示Pup是一个天然无规蛋白(IDP),1H-15N NOE和CSI方法显示在Pup的羧基端有一些残留的二级结构。之后我们利用NMR方法确定了Pup蛋白中各氨基酸的化学位移,同时我们用SPR方法和化学微扰的方法研究了Pup蛋白与Mpa (mycobacterium proteasomal ATPase)蛋白的相互作用。Mpa是原核生物中蛋白酶体的具有ATPase功能的一个调节亚基,它能够与Pup相互作用把底物带到蛋白酶体中进行水解。研究结果表明Pup和Mpa是一种强疏水相互作用,作用区段主要集中在羧基端的30-59的氨基酸区域。同时我们还在进化角度上用进化树对Pup蛋白的进化进行分析,发现Pup蛋白是一个在进化树上独立的分支,这也可以解释为什么Pup蛋白的结构与真核的ubiquitin结构有很大的差别。这是在国际上首次发现的原核生物中ubiquitin的蛋白是一个天然无规蛋白质,这个研究为后续的原核中ubiquitin的功能研究和作用机制提供实验上的依据。
Post-translational modification is an important mechanism that regulates a wide variety of cellular events such as protein degradation, singal transduction, gene expression, cell cycle, and DNA repair. Post-translational modifications include phosphorylation, acetylation, methylation, glycosylation, ubiquitylation and so on. Ubiquitin proteins family includes more than ten proteins. So far, many studies have been focused on ubiquitin and SUMO (small ubiquitin-like proteins). Our studies can be devided into two parts:one is about the study of solution structure of SUMO of Trypanosoma brucei and its interaction with hUbc9; the other is about the structural study of Pup and its interaction with Mpa (mycobacterium proteasomal ATPase).
Trypanosoma brucei is the most ancient unicellular eukaryotic organism that causes sleeping sickness in human and nagana diseases in animals. In this study, we use NMR method to solve the solution structure of SUMO of Trypanosoma brucei (Tb-SUMO). This is the first structure of SUMO determined in protist. Tb-SUMO has the typical ubiquitin-fold containing five 13 stands and two a halix. Compared with other SUMO structures, Tb-SUMO has an extended region with a length of 32 amino acids at the N-terminus. We also study the interaction between Tb-SUMO and human Ubc9 (the E2 enzyme has not been identified in Trypanosoma brucei so far). On SUMO, the surface is composed byβsheet and some loops, which is highly complementary in its electrostatic potentials and hydrophobicity to the positively charged surface of Ubc9. The result shows that the structure and binding surface of Tb-SUMO is conserved.
In eukaryotic cells, ubiquitin is attached to substracts as a tag to bring proteins into proteasome for degradation. Proteasome in mycobacterial has been found for many years. Ubiquitin protein is not known in prokaryotae, until Pup is reported to be coupled to proteins, rendering them as substrates for proteasome-mediated degradation in mycobacterium in 2008. Pup is a small protein encoded by 64 amino acids. Like eukaryotic ubiquitin proteins, there are two glycines in the C-terminus of Pup. Sequence alignment shows that Pup and ubiquitin proteins share very low similarity. Diverse structure predictions combined with CD and NMR spectroscopic studies all demonstrate that Pup is an intrinsically disordered protein. Moreover, 1H-15N NOE (nuclear Overhauser effect) data and CSI (chemical shift index) analyses indicate that there is a residual secondary structure at the C-terminus of Pup. In M. tuberculosis, Mpa is the regulatory cap ATPase of the proteasome that interacts with Pup and brings the substrates to the proteasome for degradation. SPR (surface plasmon resonance) and NMR perturbation studies imply that the C-terminus of Pup, ranging from residue 30 to 59, binds to Mpa probably through a hydrophobic interface. In addition, phylogenetic analysis clearly shows that the Pup family belongs to a unique and divergent evolutionary branch, suggesting that it is the most ancient and deeply branched family among ubiquitinlike proteins. This might explain the structural distinction between Pup and other ubiquitin-like superfamily proteins.
引文
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