title: The intrinsically disordered tails of PTEN and PTEN-L have distinct roles in regulating substrate specificity and membrane activity.
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 pThr(366)/pSer(370) 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.
authors.affiliation: Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, U.K.
authors.forename: Glenn R
authors.initials: GR
authors.lastname: Masson
authors.affiliation: Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, U.K.
authors.forename: Olga
authors.initials: O
authors.lastname: Perisic
authors.affiliation: Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, U.K.
authors.forename: John E
authors.initials: JE
authors.lastname: Burke
authors.affiliation: Medical Research Council, Laboratory of Molecular Biology, Cambridge CB2 0QH, U.K. rlw@mrc-lmb.cam.ac.uk.
authors.forename: Roger L
authors.initials: RL
authors.lastname: Williams
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002462:Cell Membrane / Q000235:genetics* / Q000378:metabolism*; D007313:Insecta; D008969:Molecular Sequence Data; D051059:PTEN Phosphohydrolase / Q000737:chemistry* / Q000502:physiology*; D017433:Protein Structure, Secondary; D018411:Spodoptera; D013379:Substrate Specificity / Q000502:physiology
chemical_list: D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: (PTEN-L); hydrogen/deuterium exchange mass spectrometry (HDX–MS); interfacial catalysis; intrinsically disordered protein regions; phosphatase and tensin homologue deleted on chromosome 10 (PTEN)