The intrinsically disordered tails of PTEN and PTEN-L have distinct roles in regulating substrate specificity and membrane activity

Glenn R. Masson, Olga Perisic, John E. Burke, Roger L. Williams (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

54 Citations (Scopus)

Abstract

Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a lipid and protein phosphatase, and both activities are necessary for its role as a tumour suppressor. PTEN activity is controlled by phosphorylation of its intrinsically disordered C-terminal tail. A recently discovered variant of PTEN, PTEN-long (PTEN-L), has a 173-residue N-terminal extension that causes PTEN-L to exhibit unique behaviour, such as movement from one cell to another. Using hydrogen/deuterium exchange mass spectrometry (HDX–MS) and biophysical assays, we show that both the N-terminal extension of PTEN-L and C-terminal tail of PTEN affect the phosphatase activity using unique mechanisms. Phosphorylation of six residues in the C-terminal tail of PTEN results in auto-inhibitory interactions with the phosphatase and C2 domains, effectively blocking both the active site and the membrane-binding interface of PTEN. Partially dephosphorylating PTEN on pThr366/pSer370 results in sufficient exposure of the active site to allow a selective activation for soluble substrates. Using HDX–MS, we identified a membrane-binding element in the N-terminal extension of PTEN-L, termed the membrane-binding helix (MBH). The MBH radically alters the membrane binding mechanism of PTEN-L compared with PTEN, switching PTEN-L to a ‘scooting’ mode of catalysis from the ‘hopping’ mode that is characteristic of PTEN.
Original languageEnglish
Pages (from-to)135-144
Number of pages10
JournalBiochemical Journal
Volume473
Issue number2
DOIs
Publication statusPublished - 5 Jan 2016

Fingerprint

Dive into the research topics of 'The intrinsically disordered tails of PTEN and PTEN-L have distinct roles in regulating substrate specificity and membrane activity'. Together they form a unique fingerprint.

Cite this