title: The KIM-family protein-tyrosine phosphatases use distinct reversible oxidation intermediates: Intramolecular or intermolecular disulfide bond formation.
abstract: The kinase interaction motif (KIM) family of protein-tyrosine phosphatases (PTPs) includes hematopoietic protein-tyrosine phosphatase (HePTP), striatal-enriched protein-tyrosine phosphatase (STEP), and protein-tyrosine phosphatase receptor type R (PTPRR). KIM-PTPs bind and dephosphorylate mitogen-activated protein kinases (MAPKs) and thereby critically modulate cell proliferation and differentiation. PTP activity can readily be diminished by reactive oxygen species (ROS),e.g.H2O2, which oxidize the catalytically indispensable active-site cysteine. This initial oxidation generates an unstable sulfenic acid intermediate that is quickly converted into either a sulfinic/sulfonic acid (catalytically dead and irreversible inactivation) or a stable sulfenamide or disulfide bond intermediate (reversible inactivation). Critically, our understanding of ROS-mediated PTP oxidation is not yet sufficient to predict the molecular responses of PTPs to oxidative stress. However, identifying distinct responses will enable novel routes for PTP-selective drug design, important for managing diseases such as cancer and Alzheimer's disease. Therefore, we performed a detailed biochemical and molecular study of all KIM-PTP family members to determine their H2O2oxidation profiles and identify their reversible inactivation mechanism(s). We show that despite having nearly identical 3D structures and sequences, each KIM-PTP family member has a unique oxidation profile. Furthermore, we also show that whereas STEP and PTPRR stabilize their reversibly oxidized state by forming an intramolecular disulfide bond, HePTP uses an unexpected mechanism, namely, formation of a reversible intermolecular disulfide bond. In summary, despite being closely related, KIM-PTPs significantly differ in oxidation profiles. These findings highlight that oxidation protection is critical when analyzing PTPs, for example, in drug screening.
authors.affiliation: From the Departments of Molecular Pharmacology, Physiology and Biotechnology.
authors.forename: Luciana E S F
authors.initials: LESF
authors.lastname: Machado
authors.affiliation: Chemistry, and.
authors.forename: Tun-Li
authors.initials: TL
authors.lastname: Shen
authors.affiliation: Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island 02912.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Page
authors.affiliation: From the Departments of Molecular Pharmacology, Physiology and Biotechnology, wolfgangpeti@email.arizona.edu.|Chemistry, and.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Peti
mesh_terms: D000470:Alkaloids; D010084:Oxidation-Reduction; D010880:Piperidines; D000072417:Protein Domains; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D000470:Alkaloids; D010880:Piperidines; C438970:himandravine; D017027:Protein Tyrosine Phosphatases
keywords: biophysics; enzyme inactivation; nuclear magnetic resonance (NMR); oxidation-reduction (redox); tyrosine-protein phosphatase (tyrosine phosphatase)