Structural insight into mechanisms for dynamic regulation of PKM2

作     者：Ping Wang Chang Sun Tingting Zhu Yanhui Xu1 

作者机构：Fudan University Shanghai Cancer Center and Institute of Biomedical Sciences Shanghai Medical College of Fudano University Shanghai 200032 China State Key Laboratory of Genetic Engineering School of Life Sciences Fudan University Shanghai 200433 China 

出 版 物：《Protein & Cell》 (蛋白质与细胞（英文版）)

年 卷 期：2015年第6卷第4期

页      面：275-287页

核心收录：

学科分类：0710[理学-生物学] 071010[理学-生物化学与分子生物学] 081704[工学-应用化学] 07[理学] 08[工学] 0817[工学-化学工程与技术] 081402[工学-结构工程] 081304[工学-建筑技术科学] 0813[工学-建筑学] 0814[工学-土木工程] 

基　　金：国家自然科学基金 the Basic Research Project of Shanghai Science and Technology Commission the Program of Shanghai Subject Chief Scientist "ShuGuang" project supported by Shanghai Municipal Education Commission and Shanghai Education Development Foundation 

主　　题：pyruvate kinase M2 crystal structureallosteric regulation Warburg effect post-translational modifications 

摘      要：Pyruvate kinase isoform M2 （PKM2） converts phospho- enolpyruvate （PEP） to pyruvate and plays an important role in cancer metabolism. Here, we show that post- translational modifications and a patient-derived muta- tion 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 confor- mational changes between an inactive T-state and an active R-state tetramers of PKM2. Biochemical and structural analyses demonstrate that PKM2^Y105E （phos- phorylation mimic of Y105） decreases pyruvate kinase activity by inhibiting FBP （fructose 1,6-bisphosphate）- induced R-state formation, and PKM2K^3305Q （acetylation mimic of K305） abolishes the activity by hindering tet- ramer 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 muta- tion and provides a structural basis for further investi- gation of other modifications and mutations of PKM2 yet to be discovered.