期刊
PROTEIN & CELL
卷 6, 期 4, 页码 275-287出版社
SPRINGEROPEN
DOI: 10.1007/s13238-015-0132-x
关键词
pyruvate kinase M2; crystal structure; allosteric regulation; Warburg effect; post-translational modifications
类别
资金
- National Natural Science Foundation of China [31270779, 31425008]
- Basic Research Project of Shanghai Science and Technology Commission [12JC1402700]
- Program of Shanghai Subject Chief Scientist [14XD1400500]
- ShuGuang project [11SG06]
- Shanghai Municipal Education Commission
- Shanghai Education Development Foundation
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 PKM2(Y105E) (phosphorylation mimic of Y105) decreases pyruvate kinase activity by inhibiting FBP (fructose 1,6-bisphosphate)-induced R-state formation, and PKM2(K305Q) (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.
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