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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Structural and dynamical changes in an alpha-subunit of a heterotrimeric G protein along the activation pathway
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Structural and dynamical changes in an alpha-subunit of a heterotrimeric G protein along the activation pathway

机译：沿激活途径异三聚体G蛋白的α亚基的结构和动力学变化

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摘要

The G alpha subunits of heterotrimeric G proteins (G alpha beta gamma) mediate signal transduction via activation by receptors and subsequent interaction with downstream effectors. Crystal structures indicate that conformational changes in "switch" sequences of Ga, controlled by the identity of the bound nucleotide (GDP and GTP), modulate binding affinities to the G beta gamma subunits, receptor, and effector proteins. To investigate the solution structure and dynamics of G alpha i1 through the G protein cycle, nitroxide side chains (1111) were introduced at sites in switch 11 and at a site in helix alpha 4, a putative effector binding region. In the inactive G alpha i1(GDP) state, the EPR spectra are compatible with conformational polymorphism in switch II. Upon complex formation with G beta gamma, motions of R1 are highly constrained, reflecting direct contact interactions at the G alpha i1-G/3 interface; remarkably, the presence of R1 at the sites investigated does not substantially affect the binding affinity. Complex formation between the heterotrimer and activated rhodopsin leads to a dramatic change in R1 motion at residue 217 in the receptor-binding alpha 2/beta 4 loop and smaller allosteric changes at the G alpha i1-G beta gamma interface distant from the receptor binding surface. Upon addition of GTP gamma S, the activated G alpha i1(GTP) subunit dissociates from the complex, and switch 11 is transformed to a unique conformation similar to that in crystal structures but with a flexible backbone. A previously unreported activation -dependent change in alpha 4, distant from the interaction surface, supports a role for this helix in effector binding.
机译：异源三聚体G蛋白（G alpha beta gamma）的G alpha亚基通过受体激活以及随后与下游效应子的相互作用介导信号转导。晶体结构表明，Ga的“转换”序列的构象变化受结合核苷酸（GDP和GTP）的身份控制，可调节与Gβγ亚基，受体和效应蛋白的结合亲和力。为了研究G蛋白i1通过G蛋白循环的溶液结构和动力学，在开关11的位点和螺旋α4的位点（假定的效应子结合区）引入了氮氧化物侧链（1111）。在非活动G alpha i1（GDP）状态下，EPR谱与开关II中的构象多态性兼容。与Gβγ形成复合物后，R1的运动受到高度限制，反映了G alpha i1-G / 3界面的直接接触相互作用。值得注意的是，在所研究的位点R1的存在基本上不影响结合亲和力。异源三聚体和活化的视紫红质之间的复合物形成导致受体结合α2 /β4环中残基217的R1运动发生剧烈变化，并在远离受体结合表面的Gαi1-Gβγ界面处发生较小的变构变化。 。添加GTPγS后，活化的G alpha i1（GTP）亚基从复合物中解离，开关11转变为与晶体结构相似但具有柔性主链的独特构象。远离相互作用表面的先前未报道的α4活化依赖性变化支持了这种螺旋在效应子结合中的作用。

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