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 PKM2Y105E (phosphorylation mimic of Y105) decreases pyruvate kinase activity by inhibiting FBP (fructose 1,6-bisphosphate)-induced R-state formation, and PKM2K305Q (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.Electronic supplementary materialThe online version of this article (doi:10.1007/s13238-015-0132-x) contains supplementary material, which is available to authorized users.
Highlights
Most somatic cells produce energy predominantly through oxidative phosphorylation, whereas cancer cells produce energy mainly through the less efficient glycolytic pathway, followed by lactic acid production under aerobic conditions (Warburg, 1956)
Pyruvate kinase isoform M2 (PKM2) exists in a mixed population of monomer, dimer and tetramer, and prefers a T-state conformation if the tetramer forms in the absence of FBP
Upon FBP association, PKM2 undergoes a change from the T-state to the R-state conformation, which favors the recognition of PEP in the active site and enhances its pyruvate kinase activity
Summary
Most somatic cells produce energy predominantly through oxidative phosphorylation, whereas cancer cells produce energy mainly through the less efficient glycolytic pathway, followed by lactic acid production under aerobic conditions (Warburg, 1956) This aerobic glycolysis ( known as the Warburg effect) plays an important role in tumorigenesis (Vander Heiden et al, 2009; Koppenol et al, 2011; Chaneton and Gottlieb, 2012; Yang and Lu, 2013; Wong et al, 2015). The regulation of PKM2 pyruvate kinase activity plays an essential role in cancer metabolism and is crucial for the growth and survival of cancer cells (Chaneton and Gottlieb, 2012; Yang and Lu, 2013; Wong et al, 2015). PKM2 has been reported to function as a nuclear protein kinase to regulate gene transcription and promote tumorigenesis (Gao et al, 2012; Yang et al, 2012a, b; Gao et al, 2013; Lv et al, 2013; Keller et al, 2014)
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