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Cell:清华施一公解析甲基化酶晶体结构
【字体: 大 中 小 】 时间:2008年09月08日 来源:Cell
编辑推荐:
本篇文章中,将解析PME-1酶的晶体结构,以及人工合成的PP2A二聚体核心酶的结构。
蛋白质磷酸酶2A(Protein phosphatase 2A ,PP2A),是真核生物体内重要的的丝氨酸-苏氨酸磷酸酶,能拮抗绝大多数丝氨酸-苏氨酸蛋白激酶的活性。参与了体内众多信号通路和生理过程的调节。在物质代谢,基因表达,DNA复制与损伤修复,细胞分裂,细胞转化及细胞凋亡等生理过程中具有重要的调节作用。
蛋白质磷酸酶2A催化亚基的可逆性羧基甲基化是PP2A的发挥其功能的关键调节机制。蛋白质磷酸酶2A的去甲基化功能和负向调控功能受PP2A特异的甲基化酶PME-1介导,PME-1酶是一种保守的酶,从人类到酵母该酶都很相似。
然而,PME-1酶作用的机制依旧不明。本篇文章中,将解析PME-1酶的晶体结构,以及人工合成的PP2A二聚体核心酶的结构。研究结果表明,PME-1可直接与PP2A的活性位点结合,二者结合在一起后会激活PME-1进行结构构象重排,挥发催化作用。令人惊讶的是,PP2A与PME-1相互作用后会促使PP2A锰离子丢失,导致PP2A失去酶活性(锰离子是维持PP2A酶活性的金属离子)。这些结构的分析,解析了PME-1酶在PP2A酶活性,甲基化以及整个酶在细胞中活性的影响。
原文摘要:Structural mechanism of demethylation and inactivation of protein phosphatase 2A
Cell, Vol 133, 154-163, 04 April 2008
【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.
(生物通 张欢)