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The structural basis of PTEN regulation by multi-site phosphorylation

Citation

Dempsey, Daniel et al. (2022), The structural basis of PTEN regulation by multi-site phosphorylation, Dryad, Dataset, https://doi.org/10.5061/dryad.dfn2z34zh

Abstract

PTEN is a phosphatidylinositol-3,4,5-triphosphate (PIP3) phospholipid phosphatase that is commonly mutated or silenced in cancer. PTEN's catalytic activity, cellular membrane localization, and stability are orchestrated by a cluster of C-terminal phosphorylation events on Ser380, Thr382, Thr383, and Ser385, but the molecular details of this multifaceted regulation have remained uncertain. Here we use a combination of protein semisynthesis, biochemical analysis, NMR, X-ray crystallography, and computational simulations on human PTEN and its sea squirt homolog VSP to obtain a detailed picture of how the phospho-C-tail belts around PTEN's C2 and phosphatase domains. We also visualize a previously proposed dynamic N-terminal alpha-helix and show it is key for PTEN catalysis but disordered upon phospho-C-tail interaction. This structural model provides a comprehensive framework for how C-tail phosphorylation can impact PTEN's cellular functions.   

Funding

National Institute of General Medical Sciences, Award: NIH K99GM130961

National Institute of General Medical Sciences, Award: NIH F32GM120855

National Cancer Institute, Award: NIH R01CA74305

National Institute of General Medical Sciences, Award: NIH R01GM136859

National Institutes of Health, Award: NIH P50 CA062924