title: Reversible oxidation of the membrane distal domain of receptor PTPalpha is mediated by a cyclic sulfenamide.
abstract: Protein tyrosine phosphatases (PTPs) are fundamental to the regulation of cellular signalling cascades triggered by protein tyrosine kinases. Most receptor-like PTPs (RPTPs) comprise two tandem PTP domains, with only the membrane proximal domains (D1) having significant phosphatase activity; the membrane distal domains (D2) display little to no catalytic activity. Intriguingly, however, many RPTP D2s share the catalytically essential Cys and Arg residues of D1s. D2 of RPTPalpha may function as a redox sensor that mediates regulation of D1 via reactive oxygen species. Oxidation of Cys723 of RPTPalpha D2 (equivalent to PTP catalytic Cys residues) stabilizes RPTPalpha dimers, induces rotational coupling, and is required for inactivation of D1 phosphatase activity. Here, we investigated the structural consequences of RPTPalpha D2 oxidation. Exposure of RPTPalpha D2 to oxidants promotes formation of a cyclic sulfenamide species, a reversibly oxidized state of Cys723, accompanied by conformational changes of the D2 catalytic site. The cyclic sulfenamide is highly resistant to terminal oxidation to sulfinic and sulfonic acids. Conformational changes associated with RPTPalpha D2 oxidation have implications for RPTPalpha quaternary structure and allosteric regulation of D1 phosphatase activity.
authors.affiliation: Section of Structural Biology, Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, United Kingdom.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Arnoud
authors.initials: A
authors.lastname: Groen
authors.forename: Simone
authors.initials: S
authors.lastname: Lemeer
authors.forename: Anne
authors.initials: A
authors.lastname: Jans
authors.forename: Monique
authors.initials: M
authors.lastname: Slijper
authors.forename: S Mark
authors.initials: SM
authors.lastname: Roe
authors.forename: Jeroen
authors.initials: J
authors.lastname: den Hertog
authors.forename: David
authors.initials: D
authors.lastname: Barford
mesh_terms: D000577:Amides / Q000737:chemistry*; D000595:Amino Acid Sequence; D000818:Animals; D002850:Chromatography, Gel; D018360:Crystallography, X-Ray; D003545:Cysteine / Q000737:chemistry; D019281:Dimerization; D006861:Hydrogen Peroxide / Q000737:chemistry; D051379:Mice; D008958:Models, Molecular; D010084:Oxidation-Reduction; D011487:Protein Conformation / Q000187:drug effects; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry* / Q000276:immunology; D017382:Reactive Oxygen Species / Q000737:chemistry; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000276:immunology; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013434:Sulfenic Acids / Q000737:chemistry*
chemical_list: D000577:Amides; D017382:Reactive Oxygen Species; D011956:Receptors, Cell Surface; D013434:Sulfenic Acids; D006861:Hydrogen Peroxide; D017027:Protein Tyrosine Phosphatases; C516843:Ptpra protein, mouse; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4; D003545:Cysteine