title: Structural insight into mechanisms for dynamic regulation of PKM2.
abstract: 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.
authors: Fudan University Shanghai Cancer Center and Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, 200032 China.
authors: Ping
authors: P
authors: Wang
authors: Fudan University Shanghai Cancer Center and Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, 200032 China.
authors: Chang
authors: C
authors: Sun
authors: Fudan University Shanghai Cancer Center and Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, 200032 China.
authors: Tingting
authors: T
authors: Zhu
authors: Fudan University Shanghai Cancer Center and Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, 200032 China.|State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200433 China.
authors: Yanhui
authors: Y
authors: Xu
mesh_terms: D000107:Acetylation; D000494:Allosteric Regulation; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018360:Crystallography, X-Ray; D005635:Fructosediphosphates / Q000737:chemistry / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007700:Kinetics; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D009154:Mutation; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation; D011487:Protein Conformation; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D021122:Protein Subunits / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D013963:Thyroid Hormones / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D002352:Carrier Proteins; D005635:Fructosediphosphates; D008565:Membrane Proteins; D021122:Protein Subunits; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins; C029063:fructose-1,6-diphosphate
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