title: Intrinsic disorder in PTEN and its interactome confers structural plasticity and functional versatility.
abstract: IDPs, while structurally poor, are functionally rich by virtue of their flexibility and modularity. However, how mutations in IDPs elicit diseases, remain elusive. Herein, we have identified tumor suppressor PTEN as an intrinsically disordered protein (IDP) and elucidated the molecular principles by which its intrinsically disordered region (IDR) at the carboxyl-terminus (C-tail) executes its functions. Post-translational modifications, conserved eukaryotic linear motifs and molecular recognition features present in the C-tail IDR enhance PTEN's protein-protein interactions that are required for its myriad cellular functions. PTEN primary and secondary interactomes are also enriched in IDPs, most being cancer related, revealing that PTEN functions emanate from and are nucleated by the C-tail IDR, which form pliable network-hubs. Together, PTEN higher order functional networks operate via multiple IDP-IDP interactions facilitated by its C-tail IDR. Targeting PTEN IDR and its interaction hubs emerges as a new paradigm for treatment of PTEN related pathologies.
authors.affiliation: Morsani College of Medicine, Department of Pathology and Cell Biology, University of South Florida, Tampa, FL 33612, USA
authors.forename: Prerna
authors.initials: P
authors.lastname: Malaney
authors.forename: Ravi Ramesh
authors.initials: RR
authors.lastname: Pathak
authors.forename: Bin
authors.initials: B
authors.lastname: Xue
authors.forename: Vladimir N
authors.initials: VN
authors.lastname: Uversky
authors.forename: Vrushank
authors.initials: V
authors.lastname: Davé
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D053263:Gene Regulatory Networks; D006801:Humans; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D060066:Protein Interaction Maps; D011499:Protein Processing, Post-Translational; D016415:Sequence Alignment; D015398:Signal Transduction
chemical_list: D051059:PTEN Phosphohydrolase