The structural basis of PTEN regulation by multi-site phosphorylation.
Publication Type:Journal Article
Source:Nat Struct Mol Biol, Volume 28, Issue 10, p.858-868 (2021)
Keywords:Animals, Ciona intestinalis, Crystallography, X-Ray, Fluorescence Polarization, Humans, Magnetic Resonance Spectroscopy, Molecular Docking Simulation, Phosphorylation, PTEN Phosphohydrolase
<p>Phosphatase and tensin homolog (PTEN) is a phosphatidylinositol-3,4,5-triphosphate (PIP) 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 (phospho-C-tail) events on Ser380, Thr382, Thr383 and Ser385, but the molecular details of this multi-faceted 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 forms a belt around the C2 and phosphatase domains of PTEN. We also visualize a previously proposed dynamic N-terminal α-helix and show that 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.</p>