| Literature DB >> 34625746 |
Daniel R Dempsey1,2, Thibault Viennet2,3, Reina Iwase1,2, Eunyoung Park2,3, Stephanie Henriquez4, Zan Chen4, Jeliazko R Jeliazkov5, Brad A Palanski1,2, Kim L Phan6, Paul Coote2,3, Jeffrey J Gray5, Michael J Eck2,3, Sandra B Gabelli7, Haribabu Arthanari8,9, Philip A Cole10,11.
Abstract
Phosphatase and tensin homolog (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 (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.Entities:
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Year: 2021 PMID： 34625746 PMCID： PMC8549118 DOI： 10.1038/s41594-021-00668-5
Source DB: PubMed Journal: Nat Struct Mol Biol ISSN： 1545-9985 Impact factor: 18.361