Molecular features of phosphatase and tensin homolog (PTEN) Regulation by C-terminal phosphorylation

Zan Chen, Daniel R. Dempsey, Stefani N. Thomas, Dawn Hayward, David M. Bolduc, Philip A. Cole

Research output: Contribution to journalArticlepeer-review

38 Scopus citations


PTEN is a tumor suppressor that functions to negatively regulate the PI3K/AKT pathway as the lipid phosphatase for phosphatidylinositol 3,4,5-triphosphate. Phosphorylation of a cluster of Ser/Thr residues (amino acids 380-385) on the C-terminal tail serves to alter the conformational state of PTEN from an open active state to a closed inhibited state, resulting in a reduction of plasma membrane localization and inhibition of enzyme activity. The relative contribution of each phosphorylation site to PTEN autoinhibition and the structural basis for the conformational closure is still unclear. To further the structural understanding of PTEN regulation by C-terminal tail phosphorylation, we used protein semisynthesis to insert stoichiometric and site-specific phospho-Ser/Thr(s) in the C-terminal tail of PTEN. Additionally, we employed photo-cross-linking to map the intramolecular PTEN interactions of the phospho-tail. Systematic evaluation of the PTEN C-tail phospho-cluster showed autoinhibition, and conformational closure was influenced by the aggregate effect of multiple phospho-sites rather than dominated by a single phosphorylation site. Moreover, photo-crosslinking suggested a direct interaction between the PTEN C-tail and a segment in the N-terminal region of the catalytic domain. Mutagenesis experiments provided additional insights into how the PTEN phospho-tail interacts with both the C2 and catalytic domains.

Original languageEnglish (US)
Pages (from-to)14160-14169
Number of pages10
JournalJournal of Biological Chemistry
Issue number27
StatePublished - Jul 1 2016
Externally publishedYes

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© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.


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