Structural insight into mechanisms for dynamic regulation of PKM2
Structural insight into mechanisms for dynamic regulation of PKM2
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PKM2 动态调节机制的结构洞察
DOI：
10.1007/s13238-015-0132-x
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发表时间：
2015-04-01
期刊：
影响因子：
21.1
通讯作者：
Xu, Yanhui
中科院分区：
文献类型：
--
作者：
Wang, Ping;Sun, Chang;Xu, Yanhui
丙酮酸激酶亚型M2(PKM2)将磷酸烯醇式丙酮酸(PEP)转化为丙酮酸，在肿瘤代谢中起重要作用。在这里，我们证明了翻译后修饰和患者来源的突变通过调节PKM2四聚体的构象来调节PKM2的丙酮酸激酶活性。我们测定了人PKM2突变体的晶体结构，并提出了一个“跷跷板”模型来解释PKM2的非活性T态和活性R态四聚体之间的构象变化。生化和结构分析表明，PKM2Y105E(Y105的磷酸化模拟物)通过抑制1，6-二磷酸果糖(FBP)诱导的R-态的形成而降低丙酮酸激酶的活性，而PKM2K305Q(K305的乙酰化模拟物)通过阻碍四聚体的形成而取消该活性。K422R是一种患者来源的PKM2突变，由于分子间强烈的相互作用，它有利于稳定的、不活跃的T状态四聚体。我们的研究揭示了翻译后修饰和患者来源的突变对PKM2的动态调节机制，并为进一步研究PKM2的其他尚未发现的修饰和突变提供了结构基础。
Pyruvate kinase isoform M2 (PKM2) converts phosphoenolpyruvate (PEP) to pyruvate and plays an important role in cancer metabolism. Here, we show that post-translational modifications and a patient-derived mutation regulate pyruvate kinase activity of PKM2 through modulating the conformation of the PKM2 tetramer. We determined crystal structures of human PKM2 mutants and proposed a “seesaw” model to illustrate conformational changes between an inactive T-state and an active R-state tetramers of PKM2. Biochemical and structural analyses demonstrate that PKM2Y105E(phosphorylation mimic of Y105) decreases pyruvate kinase activity by inhibiting FBP (fructose 1,6-bisphosphate)-induced R-state formation, and PKM2K305Q(acetylation mimic of K305) abolishes the activity by hindering tetramer formation. K422R, a patient-derived mutation of PKM2, favors a stable, inactive T-state tetramer because of strong intermolecular interactions. Our study reveals the mechanism for dynamic regulation of PKM2 by post-translational modifications and a patient-derived mutation and provides a structural basis for further investigation of other modifications and mutations of PKM2 yet to be discovered.