In normal tissues pkm2 protein alternates between high-activity tetramer form and low-activity dimer form. However, it has distinctive tendency to act as dimeric protein in tumor cells which has low enzymatic activity results in an increase in the anabolic synthesis of macromolecule from glycolysis and thus promotes cancer cell
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Alterations in cell metabolism are a characteristic of many cancers. Cancer cells are metabolically rewired to support their rapid growth (Kim and Dang, 2006; Vander Heiden et al., 2009). The best-characterized metabolic phenotype observed in tumor cells is aerobic glycolysis, also known as the Warburg effect, which is a shift of ATP generation from high efficient oxidation phosphorylation to low efficient glycolysis even under normal oxygen concentration (Gatenby and Gillies, 2004; Warburg, 1956). Pyruvate kinase catalyzes the final step in glycolysis by transferring the phosphate from phosphoenolpyruvate (PEP) to ADP, thereby generating pyruvate and ATP (Altenberg and Greulich, 2004; Corcoran et al., 1976). In mammals, pyruvate kinase is encoded by two genes, PKLR and PKM (Noguchi et al., 1987). PKM2 is one of the splicing variants from PKM gene, expressed in development and most cancers, and plays a central role in tumorigenesis (Chaneton and Gottlieb, 2012; Christofk et al., 2008; Yang and Lu, 2013; Yang et al., 2012a).
The activity of PKM2 can be regulated by numerous allosteric effectors and posttranslational modifications (PTMs) that could change its conformation. For example, binding to metabolites, such as fructose-1,6-bisphosphate (FBP), can forge PKM2 into more active tetramer (Dombrauckas et al., 2005). Phosphorylation of PKM2 at tyrosine 105 inhibits the tetramer formation and pyruvate kinase activity of PKM2 (Hitosugi et al., 2009). Moreover, acetylation of residue K305 inhibits pyruvate kinase activity of PKM2 (Lv et al., 2011). Interestingly, a patient-derived mutation K422R of PKM2 (PKM2 K422R) was shown to decrease its pyruvate kinase activity in Bloom Syndrome (BS) patients (Iqbal et al., 2014). However, the detailed mechanisms underlying the regulation of PKM2 activity by those PTMs and mutations remain unclear. In this issue, Wang et al. (2015) demonstrated a structure-based mechanism for dynamic regulation of PKM2 by PTMs and a patient-derived mutation (Wang et al., 2015).
As reported in previous studies, PKM2 switches between dimer and tetramer and tetramer formation is crucial for PKM2 activation (Dombrauckas et al., 2005; Gui et al., 2013). The gel-filtration analyses of in vitro purified PKM2 proteins by Wang et al. showed a mixed population of PKM2 in monomer, dimer and tetramer. PKM2 WT prefers dimer under normal condition and tends to form a more active tetramer in the presence of FBP. However, acetylation-mimic mutant, PKM2 K305Q, mainly exists as a monomer, and becomes a dimer upon FBP treatment. Either monomeric or dimeric PKM2 K305Q shows much lower glycolytic activity as determined by pyruvate kinase assay. Analyzing structure, they noticed that PKM2 K305Q loses the intermolecular interactions on the A-A′ interface, which leads to the failure to form tetramer. Y105E, a phosphorylation-mimic mutation, was previously reported to inhibit PKM2 activity. In this study, it was further confirmed to prevent the FBP-induced active tetramer formation by disrupting FBP association. Taken together, these results further highlight the importance of the tetramer formation in PKM2 activation and suggest that the regulation of PKM2 oligomerization may be a general mechanism to modulate PKM2 activity.
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