施一公2014-04-14 5:13 PM

蛋白磷酸酶2A的去甲基化和去活性的结构机制   Structural Mechanism of Demethylation and Inaction of Protein Phosphatase 2A.

论文摘要

蛋白磷酸酶2APP2A)是一种在很多生物过程中扮演重要角色的丝氨酸/苏氨酸磷酸酶。PP2A催化亚基的可逆性羧基甲基化是对其功能来说非常重要的监管机制PP2A的去甲基化和负调控是通过在酵母到人类中都具有保守性的PP2A特异性甲酯酶PME – 1来介导的。然而PME - 1功能的基本机制依显神秘。在此我们展示了PME- 1本身以及它和PP2A异源二聚体核心酶形成的复形的晶体结构。该结构揭示了PME – 1 PP2A的活性位点的直接结合,且这种相互作用能通过将催化三联体重新排列成活性构象从而导致PME- 1的活化。值得注意的是这些相互作用也能通过逐出PP2A磷酸酶活性所必需的锰离子从而导致PP2A的失活。这些观察结果确定了PME- 1能调节细胞中PP2A的激活,甲基化,和全酶的双重作用。

Abstract
Protein phosphatase 2A (PP2A) is an important serine/threonine phosphatase that plays a role in many biological processes. Reversible carboxyl methylation of the PP2A catalytic subunit is an essential regulatory mechanism for its function. Demethylation and negative regulation of PP2A is mediated by a PP2A-specific methylesterase PME-1, which is conserved from yeast to humans. However, the underlying mechanism of PME-1 function remains enigmatic. Here we report the crystal structures of PME-1 by itself and in complex with a PP2A heterodimeric core enzyme. The structures reveal that PME-1 directly binds to the active site of PP2A and that this interaction results in the activation of PME-1 by rearranging the catalytic triad into an active conformation. Strikingly, these interactions also lead to inactivation of PP2A by evicting the manganese ions that are required for the phosphatase activity of PP2A. These observations identify a dual role of PME-1 that regulates PP2A activation, methylation, and holoenzyme assembly in cells.

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