Structural insight into mechanisms for dynamic regulation of PKM2
Protein & Cell
;
(12): 275-287, 2015.
Article
in English
| WPRIM
| ID: wpr-757603
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.
Full text:
Available
Index:
WPRIM (Western Pacific)
Main subject:
Pathology
/
Phosphorylation
/
Acetylation
/
Protein Conformation
/
Thyroid Hormones
/
Tumor Cells, Cultured
/
Kinetics
/
Carrier Proteins
/
Models, Molecular
/
Gene Expression
Limits:
Humans
Language:
English
Journal:
Protein & Cell
Year:
2015
Type:
Article
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