人类MEKK3蛋白质PB1结构域及Mog1蛋白质的结构与功能研究
摘要
本论文的工作重点包括:人类MAPKs家族激酶MEKK3的N端PB1结构域的克隆,表达,纯化并用核磁共振的方法解析了溶液中MEKK3 PB1结构域的结构。在结构解析的过程中,我们发现了MEKK3 PB1中存在着有趣的脯氨酸顺反异构现象。基于结构,我们研究了MEKK3 PB1与其下游激酶MEK5的N端PB1结构域的相互作用。我们的另一项工作是解析了人类Mog1蛋白的溶液结构;并初步研究了其与核转运蛋白Ran的相互作用。
第一章是对MAPK信号通路家族及PB1结构域的一个综述。MAPK信号通路参与了许多生理和病理过程,其中ERK5信号通路是唯一由PB1结构域介导的MAPK信号通路,PB1结构域是新近发现的蛋白—蛋白相互作用结构域,它参与了很多信号通路的传递。
第二章中,我们解析了人类MEKK3 PB1结构域的溶液结构。MEKK3 PB1在大肠杆菌中表达,经Ni离子亲和层析柱纯化,用于核磁共振实验。MEKK3 PB1结构具有典型的ubiquitin-like折叠方式,包含5段β-折叠片和2段α-螺旋的紧密球状蛋白结构域。5段β-折叠片以平行和反平行的方式排列,2段α-螺旋以几乎互相垂直的方式排列,处于5段β-折叠的另一侧。整个结构中含有一个疏水核心,对稳定蛋白结构发挥重要的作用。令我们感兴趣的是,我们在HSQC谱图上意外地发现了一些强度相对较弱的峰,经过分析,我们认为MEKK3 PB1中存在着多种构象,且所占比例不同。在HSQC谱图上,越靠近Pro39的残基,两种构象间的化学位移差越大。考虑到以上这些,我们猜测很可能是Gln38-Pro39间肽键的顺反异构作用造成了MEKK3 PB1构象的多样性。NOE及化学位移的信息证实了我们的猜测。这种顺反异构的现象在PB1结构域中还是第一次发现。顺式与反式异构体主链之间最大的差别在Pro39所在的连接α1和β3的G37-L40转角区域。在顺式构象下,这一区域形成一个第六类bβ-转角(Ⅵbβ-turn)。反式构象下,该区域则不属于任何典型的β-转角。主链动力学研究揭示了MEKK3 PB1的β3/β4转角可能存在着毫秒到微秒时间尺度的运动。然后,我们进一步研究了MEKK3 PB1与MEK5 PB1的相互作用。ITC和SPR实验显示MEKK3 PB1与MEK5 PB1的解离常数达到了10~(-8)M,这是很强的相互作用。通过定点突变实验,我们发现了在MEKK3 PB1的作用界面上,不同的残基对结合的贡献是不一样的。Lys7作为高度保守的残基,在MEKK3 PB1结合MEK5 PB1发挥了非常重要的作用。K7A突变几乎完全阻断了MEKK3 PB1与MEK5 PB1的相互结合。R5A突变也使得它们的相互作用大幅减弱,与此相反的是,R14A和R76A仅仅使相互作用稍有减弱。因此,我们认为Lys7和Arg5在MEKK3 PB1与MEK5 PB1的相互作用中发挥着非常重要的作用。
第三章中,我们解析了人类Mog1蛋白的溶液结构。Mog1蛋白是一个186个氨基酸的与核转运相关的蛋白。我们用大肠杆菌表达了Mog1,经Ni离子亲和层析柱纯化,用于核磁实验。Mog1含有9段β折叠,2段α螺旋和2段3_(10)螺旋。其中7段β折叠以平行和反平行的方式依次排列,两段α螺旋分别处于这组β折叠的前面和后面,形成夹心结构。人Mog1与酵母Mog1最主要的一个差别是,在人Mog1蛋白中,146-164位的氨基酸形成一个很大的loop区,而在ScMog1中相对应的位置则是一段α螺旋。我们通过凝胶过滤色谱证实了Mog1可以与Ran形成稳定的复合物,然而,我们尚未确定它们相互作用的界面,这方面的信息需要进一步的工作来确定了。
Our work focuses on the cloning,expression,purification and determination of the solution structure of human MEKK3 PB1 domain by NMR method.In the process of structure determination,we have found an interesting proline isomerization in MEKK3 PB1.Based on the structure of MEKK3 PB1,we studied interaction between MEKK3 PB1 and PB1 domain of its downstream MAPK kinase MEK5.Another work we have conducted is,solving the solution structure of a human protein Mogl, and further studied its interaction with nucleocytoplasmic transport protein Ran.
Chapter 1 is a brief review of the MAPK signaling pathway superfamily and PB1 domain.MAPK signaling pathway has been found involved in various biological processes as well as pathological processes.ERK5 signaling pathway is unique among the MAPK signaling pathways in that it is PB1-dependent,PB1 domain is a recently found module mediating protein-protein interaction.PB1 participates in many signaling pathways.
In chapter 2,we have solved the solution structure of human MEKK3 PB1 domain. MEKK3 PB1 was expressed in E.coli,purified with a Ni-chelating column,then used for NMR experiments.MEKK3 PB1 adopts a typical ubiquitin-like fold,includes fiveβstrands and twoαhelices.The fiveβstrands are arranged in a twisted parallel and anti-parallelβ-sheet.The twoαhelices are nearly orthogonal to each other and lie at the opposite side of theβ-sheet.The structure is stabilized by a hydrophobic core consisting of a large number of residues.To our interest,the spectra exhibits a set of crosspeaks with relatively low-intensity in addition to the major ones,an intramolecular conformation exchange is the only possible reason for the lo(?)v-intensity signals in the spectra.The chemical shift differences for backbone amides between the minor and the major conformations become larger as the residues get more close to residue Pro39.Taking these into consideration,we speculated that cis/trans isomerization around Gln38-Pro39 imide bond may be the source of the conformational heterogeneity.Consistent with this hypothesis,characteristic NOEs and chemical shift difference between the ~(13)C_βand the ~(13)C_γnuclei for the cis and trans conformations of Pro39 supported our hypothesis.The major backbone differences between the cis and trans conformations lie in the G37-L40 turn connectingα1 andβ3, the region where Pro-39 is located.In cis form,it adopts a type Vlbβturn,whereas in trans conformation,this region does not belong to any typical type ofβturn. Backbone dynamics studies have unraveled internal motions inβ3/β4-turn on microsecond-millisecond timescale.Further we have investigated its binding property with MEK5 PB1.ITC and SPR experiments have demonstrated that MEKK3 PB1 binds MEK5 PB1 tightly with a K_d of about 10~(-8)M.Mutagenesis analysis revealed that residues in the basic cluster of MEKK3 PB1 contributes differently to the PB1-PB1 interaction.As a highly conserved residue,Lys7 plays an important role in the interaction between MEKK3 PB1 and MEK5 PB1.The interaction was disrupted by the mutation K7A.Similarly,R5A attenuated interaction dramatically.In contrast, the interaction exhibited much weaker decrease upon R14A or R76A mutations.So we proposed that Lys7 and Arg5 are critical to the interaction between MEKK3 PB1 and MEK5 PB1.
In chapter 3,we have solved the solution structure of human Mog1 protein.Mog1 is a 186-residue protein relating to the nucleocytoplasmic transportation.Mog1 was expressed in E.coli,purified with a Ni-chelating column,then used for NMR experiments.Mog1 contains 9βstrands,2αhelices and 2 3_(10)helices,of which 7βstrands are arranged in parallel and anti-parallelβ-sheets with twoαhelices lying at the opposite side of theβ-sheet.A major difference between hMog1 and ScMog1 is that,in hMog1,residues 146-164 form a big loop.while in the corresponding position in SeMog1,it adopts anαhelix.Gel filtration chromatogram demonstrated that Mog1 and Ran could form a heterodimer.However,further work is needed to determine the interface between Mog1 and Ran.
第一章是对MAPK信号通路家族及PB1结构域的一个综述。MAPK信号通路参与了许多生理和病理过程,其中ERK5信号通路是唯一由PB1结构域介导的MAPK信号通路,PB1结构域是新近发现的蛋白—蛋白相互作用结构域,它参与了很多信号通路的传递。
第二章中,我们解析了人类MEKK3 PB1结构域的溶液结构。MEKK3 PB1在大肠杆菌中表达,经Ni离子亲和层析柱纯化,用于核磁共振实验。MEKK3 PB1结构具有典型的ubiquitin-like折叠方式,包含5段β-折叠片和2段α-螺旋的紧密球状蛋白结构域。5段β-折叠片以平行和反平行的方式排列,2段α-螺旋以几乎互相垂直的方式排列,处于5段β-折叠的另一侧。整个结构中含有一个疏水核心,对稳定蛋白结构发挥重要的作用。令我们感兴趣的是,我们在HSQC谱图上意外地发现了一些强度相对较弱的峰,经过分析,我们认为MEKK3 PB1中存在着多种构象,且所占比例不同。在HSQC谱图上,越靠近Pro39的残基,两种构象间的化学位移差越大。考虑到以上这些,我们猜测很可能是Gln38-Pro39间肽键的顺反异构作用造成了MEKK3 PB1构象的多样性。NOE及化学位移的信息证实了我们的猜测。这种顺反异构的现象在PB1结构域中还是第一次发现。顺式与反式异构体主链之间最大的差别在Pro39所在的连接α1和β3的G37-L40转角区域。在顺式构象下,这一区域形成一个第六类bβ-转角(Ⅵbβ-turn)。反式构象下,该区域则不属于任何典型的β-转角。主链动力学研究揭示了MEKK3 PB1的β3/β4转角可能存在着毫秒到微秒时间尺度的运动。然后,我们进一步研究了MEKK3 PB1与MEK5 PB1的相互作用。ITC和SPR实验显示MEKK3 PB1与MEK5 PB1的解离常数达到了10~(-8)M,这是很强的相互作用。通过定点突变实验,我们发现了在MEKK3 PB1的作用界面上,不同的残基对结合的贡献是不一样的。Lys7作为高度保守的残基,在MEKK3 PB1结合MEK5 PB1发挥了非常重要的作用。K7A突变几乎完全阻断了MEKK3 PB1与MEK5 PB1的相互结合。R5A突变也使得它们的相互作用大幅减弱,与此相反的是,R14A和R76A仅仅使相互作用稍有减弱。因此,我们认为Lys7和Arg5在MEKK3 PB1与MEK5 PB1的相互作用中发挥着非常重要的作用。
第三章中,我们解析了人类Mog1蛋白的溶液结构。Mog1蛋白是一个186个氨基酸的与核转运相关的蛋白。我们用大肠杆菌表达了Mog1,经Ni离子亲和层析柱纯化,用于核磁实验。Mog1含有9段β折叠,2段α螺旋和2段3_(10)螺旋。其中7段β折叠以平行和反平行的方式依次排列,两段α螺旋分别处于这组β折叠的前面和后面,形成夹心结构。人Mog1与酵母Mog1最主要的一个差别是,在人Mog1蛋白中,146-164位的氨基酸形成一个很大的loop区,而在ScMog1中相对应的位置则是一段α螺旋。我们通过凝胶过滤色谱证实了Mog1可以与Ran形成稳定的复合物,然而,我们尚未确定它们相互作用的界面,这方面的信息需要进一步的工作来确定了。
Our work focuses on the cloning,expression,purification and determination of the solution structure of human MEKK3 PB1 domain by NMR method.In the process of structure determination,we have found an interesting proline isomerization in MEKK3 PB1.Based on the structure of MEKK3 PB1,we studied interaction between MEKK3 PB1 and PB1 domain of its downstream MAPK kinase MEK5.Another work we have conducted is,solving the solution structure of a human protein Mogl, and further studied its interaction with nucleocytoplasmic transport protein Ran.
Chapter 1 is a brief review of the MAPK signaling pathway superfamily and PB1 domain.MAPK signaling pathway has been found involved in various biological processes as well as pathological processes.ERK5 signaling pathway is unique among the MAPK signaling pathways in that it is PB1-dependent,PB1 domain is a recently found module mediating protein-protein interaction.PB1 participates in many signaling pathways.
In chapter 2,we have solved the solution structure of human MEKK3 PB1 domain. MEKK3 PB1 was expressed in E.coli,purified with a Ni-chelating column,then used for NMR experiments.MEKK3 PB1 adopts a typical ubiquitin-like fold,includes fiveβstrands and twoαhelices.The fiveβstrands are arranged in a twisted parallel and anti-parallelβ-sheet.The twoαhelices are nearly orthogonal to each other and lie at the opposite side of theβ-sheet.The structure is stabilized by a hydrophobic core consisting of a large number of residues.To our interest,the spectra exhibits a set of crosspeaks with relatively low-intensity in addition to the major ones,an intramolecular conformation exchange is the only possible reason for the lo(?)v-intensity signals in the spectra.The chemical shift differences for backbone amides between the minor and the major conformations become larger as the residues get more close to residue Pro39.Taking these into consideration,we speculated that cis/trans isomerization around Gln38-Pro39 imide bond may be the source of the conformational heterogeneity.Consistent with this hypothesis,characteristic NOEs and chemical shift difference between the ~(13)C_βand the ~(13)C_γnuclei for the cis and trans conformations of Pro39 supported our hypothesis.The major backbone differences between the cis and trans conformations lie in the G37-L40 turn connectingα1 andβ3, the region where Pro-39 is located.In cis form,it adopts a type Vlbβturn,whereas in trans conformation,this region does not belong to any typical type ofβturn. Backbone dynamics studies have unraveled internal motions inβ3/β4-turn on microsecond-millisecond timescale.Further we have investigated its binding property with MEK5 PB1.ITC and SPR experiments have demonstrated that MEKK3 PB1 binds MEK5 PB1 tightly with a K_d of about 10~(-8)M.Mutagenesis analysis revealed that residues in the basic cluster of MEKK3 PB1 contributes differently to the PB1-PB1 interaction.As a highly conserved residue,Lys7 plays an important role in the interaction between MEKK3 PB1 and MEK5 PB1.The interaction was disrupted by the mutation K7A.Similarly,R5A attenuated interaction dramatically.In contrast, the interaction exhibited much weaker decrease upon R14A or R76A mutations.So we proposed that Lys7 and Arg5 are critical to the interaction between MEKK3 PB1 and MEK5 PB1.
In chapter 3,we have solved the solution structure of human Mog1 protein.Mog1 is a 186-residue protein relating to the nucleocytoplasmic transportation.Mog1 was expressed in E.coli,purified with a Ni-chelating column,then used for NMR experiments.Mog1 contains 9βstrands,2αhelices and 2 3_(10)helices,of which 7βstrands are arranged in parallel and anti-parallelβ-sheets with twoαhelices lying at the opposite side of theβ-sheet.A major difference between hMog1 and ScMog1 is that,in hMog1,residues 146-164 form a big loop.while in the corresponding position in SeMog1,it adopts anαhelix.Gel filtration chromatogram demonstrated that Mog1 and Ran could form a heterodimer.However,further work is needed to determine the interface between Mog1 and Ran.
引文
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