Project 16581 on FAH (GPU, OpenMM 8.1)

[msoconnor2]

Protein phosphatase 2A (PP2A) mutations have been linked to intellectual disability and cancer, potentially disrupting the protein’s autoinhibition mechanism and phosphorylation-induced activation. The mutations are located distant from the active and substrate sites, their impact on the mechanism remains unclear. Allosteric pathway analysis, integrated with biochemical experiments, probes PP2A autoinhibition. In the wild-type (WT) system, regulatory subunit B56δ's C-arm impedes active and substrate sites, enacting dual autoinhibition. The disease mutant, E198K, markedly weakens the WT's allosteric pathways by taking a different route, favoring substrate site exposure. A novel path clustering algorithm, introduced in this work, streamlines the allosteric pathway analysis. E198K and phosphorylated WT share strikingly similar allosteric channels, suggesting a conserved autoinhibition alleviation between these variants. Folding at home will be used to study the conformational change involved in the opening of this N/C-arm interface in order to determine why the E198K mutant is more active than the WT.

Project details:
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