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PKA RIIβ 四聚体全酶的结构与别构调控。

Structure and allostery of the PKA RIIβ tetrameric holoenzyme.

机构信息

Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093-0654, USA.

出版信息

Science. 2012 Feb 10;335(6069):712-6. doi: 10.1126/science.1213979.

Abstract

In its physiological state, cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) is a tetramer that contains a regulatory (R) subunit dimer and two catalytic (C) subunits. We describe here the 2.3 angstrom structure of full-length tetrameric RIIβ(2):C(2) holoenzyme. This structure showing a dimer of dimers provides a mechanistic understanding of allosteric activation by cAMP. The heterodimers are anchored together by an interface created by the β4-β5 loop in the RIIβ subunit, which docks onto the carboxyl-terminal tail of the adjacent C subunit, thereby forcing the C subunit into a fully closed conformation in the absence of nucleotide. Diffusion of magnesium adenosine triphosphate (ATP) into these crystals trapped not ATP, but the reaction products, adenosine diphosphate and the phosphorylated RIIβ subunit. This complex has implications for the dissociation-reassociation cycling of PKA. The quaternary structure of the RIIβ tetramer differs appreciably from our model of the RIα tetramer, confirming the small-angle x-ray scattering prediction that the structures of each PKA tetramer are different.

摘要

在生理状态下,环腺苷酸单磷酸(cAMP)依赖性蛋白激酶(PKA)是一个包含调节(R)亚基二聚体和两个催化(C)亚基的四聚体。我们在这里描述全长四聚体 RIIβ(2):C(2)全酶的 2.3 埃结构。该结构显示二聚体的二聚体,为 cAMP 的变构激活提供了机制理解。异二聚体通过 RIIβ 亚基的β4-β5 环形成的界面彼此锚定,该界面与相邻 C 亚基的羧基末端尾巴对接,从而在没有核苷酸的情况下迫使 C 亚基完全关闭构象。镁腺苷三磷酸(ATP)向这些晶体中的扩散没有捕获 ATP,而是捕获了反应产物二磷酸腺苷和磷酸化的 RIIβ 亚基。这种复合物对 PKA 的解离-再结合循环具有影响。RIIβ 四聚体的四级结构与我们的 RIα 四聚体模型明显不同,这证实了小角度 X 射线散射的预测,即每个 PKA 四聚体的结构都不同。

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