Invited review: Activation of G proteins by GTP and the mechanism of Gα-catalyzed GTP hydrolysis.
Invited review: Activation of G proteins by GTP and the mechanism of Gα-catalyzed GTP hydrolysis.
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DOI：
10.1002/bip.22836
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发表时间：
2016-08
期刊：
影响因子：
2.9
通讯作者：
Sprang SR
中科院分区：
文献类型：
--
作者：
Sprang SR
本文综述了GTP与异源三聚体G蛋白α亚基（Gα）结合的调节作用、Gα催化GTP水解的反应机制以及GTP酶激活蛋白（GAP）刺激Gα GTP酶活性的途径。GTP结合的高能量用于抑制和稳定Gα开关片段（特别是开关II）的构象，以提供与Gα效应物表面的稳定互补，同时排除与Gβγ（GDP结合Gα的调节结合配偶体）的相互作用。在GTP水解时，这些构象约束的能量被耗散，并且两个开关区段，特别是开关II，变得柔性，并且能够采用适合于与Gβγ紧密结合的构象。催化位点预组织对Gα GTdR活性呈现显著的活化能势垒。开关II（Glncat）的N末端附近的谷氨酰胺残基必须采用一种构象，在这种构象中，它定向并稳定γ磷酸盐和亲核试剂，以进行在线攻击。过渡态可能是松散的解离性质，磷酰基转移可能是协调的。开关I（Argcat）中的催化精氨酸与来自磷酸结合环的酰胺氢键一起稳定离去基团的β-γ桥氧处的电荷。具有“蛋白质信号传导调节因子”（RGS）结构域的GAP，或G蛋白效应物中结构不相关的结构域，作为GAP，通过稳定Gα催化的GTP水解的过渡前状态来加速催化，主要是通过抑制Argcat和Glncat的催化构象。© 2016 Wiley Periodicals，Inc. Biopolymers 105：449-462，2016.
This review addresses the regulatory consequences of the binding of GTP to the alpha subunits (Gα) of heterotrimeric G proteins, the reaction mechanism of GTP hydrolysis catalyzed by Gα and the means by which GTPase activating proteins (GAPs) stimulate the GTPase activity of Gα. The high energy of GTP binding is used to restrain and stabilize the conformation of the Gα switch segments, particularly switch II, to afford stable complementary to the surfaces of Gα effectors, while excluding interaction with Gβγ, the regulatory binding partner of GDP‐bound Gα. Upon GTP hydrolysis, the energy of these conformational restraints is dissipated and the two switch segments, particularly switch II, become flexible and are able to adopt a conformation suitable for tight binding to Gβγ. Catalytic site pre‐organization presents a significant activation energy barrier to Gα GTPase activity. The glutamine residue near the N‐terminus of switch II (Glncat) must adopt a conformation in which it orients and stabilizes the γ phosphate and the water nucleophile for an in‐line attack. The transition state is probably loose with dissociative character; phosphoryl transfer may be concerted. The catalytic arginine in switch I (Argcat), together with amide hydrogen bonds from the phosphate binding loop, stabilize charge at the β‐γ bridge oxygen of the leaving group. GAPs that harbor “regulator of protein signaling” (RGS) domains, or structurally unrelated domains within G protein effectors that function as GAPs, accelerate catalysis by stabilizing the pre‐transition state for Gα‐catalyzed GTP hydrolysis, primarily by restraining Argcatand Glncatto their catalytic conformations. © 2016 Wiley Periodicals, Inc. Biopolymers 105: 449–462, 2016.