Structural insight into mechanisms for dynamic regulation of PKM2.
10.1007/s13238-015-0132-x
- Author:
Ping WANG
1
;
Chang SUN
1
;
Tingting ZHU
1
;
Yanhui XU
1
Author Information
1. Fudan University Shanghai Cancer Center and Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, 200032 China.
- Publication Type:Journal Article
- MeSH:
Acetylation;
Allosteric Regulation;
Carrier Proteins;
chemistry;
genetics;
metabolism;
Crystallography, X-Ray;
Fructosediphosphates;
chemistry;
metabolism;
Gene Expression;
Humans;
Kinetics;
Membrane Proteins;
chemistry;
genetics;
metabolism;
Models, Molecular;
Mutation;
Neoplasms;
enzymology;
genetics;
pathology;
Phosphorylation;
Protein Conformation;
Protein Multimerization;
Protein Processing, Post-Translational;
Protein Subunits;
chemistry;
genetics;
metabolism;
Thyroid Hormones;
chemistry;
genetics;
metabolism;
Tumor Cells, Cultured
- From:
Protein & Cell
2015;6(4):275-287
- CountryChina
- Language:English
-
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.
