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Exploring Structural Perturbations Caused by Cancer-Related Mutations in Pyruvate Kinase M2: A Comparison with the Wild-Type Enzyme
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DOI：10.1021/acs.jpcb.5c08286.png)
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Abstract
En 中文
One of the key glycolytic enzymes, pyruvate kinase (PKM2), is frequently found in mutated forms in cancer cells. While many have investigated the impact of the mutations on tumor size and progressions, their structural effects on the architecture of PKM2 have not been thoroughly studied. We examined 11 mutants using MD simulations and assessed their effects on structural dynamics, domain flexibility, and interaction networks. Among them, six mutants displayed significant perturbations compared to the WT, while five others retained WT-like behavior. RMSF and PCA demonstrated that mutations lead to destabilization of the B domain by disrupting its natural inward closure toward the A domain. Instead, they exhibited an outward or rotational movement, resulting in increased interdomain distances and a weakening of the native contacts between the A and B domains. Further analysis revealed that in the crucial region responsible for domain closure, there was a disruption of hydrogen bonds and salt bridges that are essential for stabilization. For the highly fluctuating mutants, R246S weakens the helical contacts to the hinge region, while K367 M and R399E compromise beta-sheet pathways linked to the active and allosteric sites, P117L affects the anchor points in the hinge region, and R455Q and H464A destabilize the allosteric pockets by disrupting the connectivity between the helix, beta-sheet, and the hinge. Collectively, these mutations impair communication with the domain closure region and suggest potential avenues for understanding cancer-related mutants.
Keywords:
MOLECULAR-DYNAMICS
ALLOSTERIC REGULATION
TUMOR
METABOLISM
ISOFORM
PROTEIN
GENE
DESTABILIZATION
GLYCOLYSIS
MECHANISM
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