H2O2-induced Intermolecular Disulfide Bond Formation between Receptor Protein-tyrosine Phosphatases

Wijk, Thea van der; Overvoorde, John; Hertog, Jeroen den

doi:10.1074/jbc.m407483200

Cited by 72 publications

(51 citation statements)

References 29 publications

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“…Perhaps certain physiologic modifications such as phosphorylation or oxidation induce conformational changes that restore flexibility to the molecule and overcome the steric hindrance. Supporting this, RPTP␣ dimers are stabilized because of an oxidation-induced conformational change in the D2 domain (36). For all panels, data are representative of 3 independent experiments, each using 2-3 mice/genotype.…”

Section: Discussionmentioning

confidence: 98%

Differential impact of the CD45 juxtamembrane wedge on central and peripheral T cell receptor responses

Hermiston¹,

Zikherman²,

Tan

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The cooperative activity of protein tyrosine kinases and phosphatases plays a central role in regulation of T cell receptor (TCR) signal strength. Perturbing this balance, and thus the threshold for TCR signals, has profound impacts on T cell development and function. We previously generated mice containing a point mutation in the juxtamembrane wedge of the receptor-like protein tyrosine phosphatase CD45. Demonstrating the critical negative regulatory function of the wedge, the CD45 E613R (WEDGE) mutation led to a lymphoproliferative disorder (LPD) and a lupus-like autoimmune syndrome. Using genetic, cellular, and biochemical approaches, we now demonstrate that the CD45 wedge influences T cell development and function. Consistent with increased TCR signal strength, WEDGE mice have augmented positive selection and enhanced sensitivity to the CD4-mediated disease experimental autoimmune encephalitis (EAE). These correspond with hyperresponsive calcium and pERK responses to TCR stimulation in thymocytes, but surprisingly, not in peripheral T cells, where these responses are actually depressed. Together, the data support a role for the CD45 wedge in regulation of T cell responses in vivo and suggest that its effects depend on cellular context. autoimmunity ͉ tyrosine phosphatase ͉ tyrosine kinase ͉ thymocyte development T cell receptor (TCR) signal strength is influenced by the integration of multiple inputs including affinity for antigen, presence and activity of costimulatory molecules, and duration of the interaction with antigen-presenting cells (APCs) (1). Alterations in TCR signal strength impact many aspects of T cell biology including CD4 versus CD8 lineage commitment (1), effector and memory cell generation (2), and autoimmunity (3, 4). Currently, the factors defining signal strength and its functional outcome are incompletely understood.CD45, a receptor-like protein tyrosine phosphatase (RPTP) expressed on all nucleated hematopoietic cells, plays a critical positive regulatory role in antigen receptor signaling. Its absence in both mice and humans results in severe combined immunodeficiency (5, 6). CD45 mediates its effects, at least in part, by modulating the activation state of Src family protein tyrosine kinases (SFKs) (5, 7). Phosphorylation of the SFK C-terminal tyrosine by Csk inhibits the kinase while autophosphorylation of the catalytic domain tyrosine results in full activity. CD45 opposes Csk by dephosphorylating the negative regulatory tyrosine, generating a pool of primed SFKs capable of rapid activation upon receptor stimulation. In some cell types, CD45 can also dephosphorylate the catalytic tyrosine and negatively regulate SFKs.Regulation of CD45 itself is complex. Alternative splicing of the extracellular domain, regulated in a cell-and activation-specific manner, generates multiple isoforms differing in size and charge (5). Interestingly, CD45 polymorphisms influencing its alternative splicing, and thus isoform expression, are associated with several human autoimmune diseases (8). We initi...

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Section: Discussionmentioning

confidence: 98%

Differential impact of the CD45 juxtamembrane wedge on central and peripheral T cell receptor responses

Hermiston¹,

Zikherman²,

Tan

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Oxidation of Cys723 (presumably by causing conformational changes of the PTP loop altering the protein's molecular surface) promotes D2-D2 associations (39) affecting the overall quaternary structure of RPTPR. The oxidation-induced association of D2 domains could be triggered by changes in the surface properties of D2 resulting from generation of the cyclic sulfenamide and opening of the PTP loop or, as suggested by van der Wijk et al (57), be mediated by intermolecular disulfides involving Cys723.…”

Section: Discussionmentioning

confidence: 99%

Reversible Oxidation of the Membrane Distal Domain of Receptor PTPα Is Mediated by a Cyclic Sulfenamide

et al. 2006

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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 RPTPR may function as a redox sensor that mediates regulation of D1 via reactive oxygen species. Oxidation of Cys723 of RPTPR D2 (equivalent to PTP catalytic Cys residues) stabilizes RPTPR dimers, induces rotational coupling, and is required for inactivation of D1 phosphatase activity. Here, we investigated the structural consequences of RPTPR D2 oxidation. Exposure of RPTPR 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 RPTPR D2 oxidation have implications for RPTPR quaternary structure and allosteric regulation of D1 phosphatase activity.The reversible tyrosine phosphorylation of proteins, reciprocally controlled by tyrosine kinases and phosphatases, is crucial to the regulation of diverse cellular processes, including growth, proliferation, and differentiation (1). Redox reactions, mediated by reactive oxygen species (ROS), 1 control PTP activity in response to a variety of hormones and growth factors (2-6). Generation of ROS accompanies PTK activation (7,8), with oxidation-induced inhibition of PTP activity amplifying PTK-dependent signaling (9-11).PTP-catalyzed protein dephosphorylation proceeds via a nucleophilic displacement reaction utilizing an essential cysteine residue conserved within the PTP signature motif Cys(X) 5 Arg (12-15). The low pK a of the catalytic cysteine necessary for its function (16) renders PTPs susceptible to inactivation by ROS-induced cysteine oxidation. However, the reversibility of redox-mediated inactivation of PTPs requires that a reversibly oxidized state of the cysteine residue be stabilized at the PTP catalytic site and that formation of SO 2 and SO 3 , two irreversibly oxidized species of cysteine, be suppressed (17). Crystallographic studies of the tyrosine specific cytosolic PTP1B revealed that the reversibly oxidized form of the enzyme was not the expected sulfenic acid or disulfide bond, but an oxidation state of cysteine termed a cyclic sulfenamide, a species not previously observed in proteins (18,19). Generation of the cyclic sulfenamide inhibits catalytic activity by blocking the nucleophilic cysteine residue through a covalent bond of its thiol group with the neighboring main chain amide, a linkage that is accompanied by profound conformational transitions of the catalytic site PTP and pTyr loops. The oxidation properties of the catalyt...

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“…How RPTP␣-D2 changes conformation in response to H 2 O 2 remains elusive and will require elucidation of the crystal structure of oxidized RPTP␣-D2. The catalytic Cys 723 is required for the conformational change (8), and recently we found evidence that none of the other cysteines in RPTP␣ is involved in H 2 O 2 -induced stable dimer formation (39), ruling out the possibility of intramolecular disulfide bond formation, which has been observed in nonclassical Cys-based PTPs, including LMW-PTP (40), PTEN (41), and CDC25 (42). It is likely that the conformational FIG.…”

Section: Discussionmentioning

confidence: 99%

Differential Oxidation of Protein-tyrosine Phosphatases

Groen

Lemeer

Wijk

et al. 2005

Journal of Biological Chemistry

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122

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Oxidation is emerging as an important regulatory mechanism of protein-tyrosine phosphatases (PTPs).Here we report that PTPs are differentially oxidized, and we provide evidence for the underlying mechanism. The membrane-proximal RPTP␣-D1 was catalytically active but not readily oxidized as assessed by immunoprobing with an antibody that recognized oxidized catalytic site cysteines in PTPs (oxPTPs). In contrast, the membrane-distal RPTP␣-D2, a poor PTP, was readily oxidized. Oxidized catalytic site cysteines in PTP immunoprobing and mass spectrometry demonstrated that mutation of two residues in the Tyr(P) loop and the WPD loop that reverse catalytic activity of RPTP␣-D1 and RPTP␣-D2 also reversed oxidizability, suggesting that oxidizability and catalytic activity are coupled. However, catalytically active PTP1B and LAR-D1 were readily oxidized. Oxidizability was strongly dependent on pH, indicating that the microenvironment of the catalytic cysteine has an important role. Crystal structures of PTP domains demonstrated that the orientation of the absolutely conserved PTP loop arginine correlates with oxidizability of PTPs, and consistently, RPTP-D1, with a similar conformation as RPTP␣-D1, was not readily oxidized. In conclusion, PTPs are differentially oxidized at physiological pH and H 2 O 2 concentrations, and the PTP loop arginine is an important determinant for susceptibility to oxidation.

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H2O2-induced Intermolecular Disulfide Bond Formation between Receptor Protein-tyrosine Phosphatases

Cited by 72 publications

References 29 publications

Differential impact of the CD45 juxtamembrane wedge on central and peripheral T cell receptor responses

Differential impact of the CD45 juxtamembrane wedge on central and peripheral T cell receptor responses

Reversible Oxidation of the Membrane Distal Domain of Receptor PTPα Is Mediated by a Cyclic Sulfenamide

Differential Oxidation of Protein-tyrosine Phosphatases

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