The structural basis of PTEN regulation by multi-site phosphorylation

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 provided by: National Institute of General Medical SciencesCrossref Funder Registry ID: http://dx.doi.org/10.13039/100000057Award Number: NIH K99GM130961Funding provided by: National Institute of General Medical SciencesCrossref Funder Registry ID: http://dx.doi.org/10.13039/100000057Award Number: NIH F32GM120855Funding provided by: National Cancer InstituteCrossref Funder Registry ID: http://dx.doi.org/10.13039/100000054Award Number: NIH R01CA74305Funding provided by: National Institute of General Medical SciencesCrossref Funder Registry ID: http://dx.doi.org/10.13039/100000057Award Number: NIH R01GM136859Funding provided by: National Institutes of HealthCrossref Funder Registry ID: http://dx.doi.org/10.13039/100000002Award Number: NIH P50 CA06292