Structural basis for the function and regulation of the receptor protein tyrosine phosphatase CD45

Nam, Hyun Joo; Poy, Florence; Saito, Haruo; Frederick, Christin

doi:10.1084/jem.20041890

Cited by 97 publications

(93 citation statements)

References 58 publications

(74 reference statements)

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“…When we initially proposed that the wedge was the basis for the observed inhibition of phosphatase activity during receptor dimerization, it was a putative structure based on sequence homology and modeling studies derived from the crystal structures of RPTP␣. The recently solved crystal structure of CD45 confirms the presence of the wedge (35). However, because of steric hindrance between the D1 and D2 domains, the structure precludes wedge-mediated inhibition of the catalytic site during receptor dimerization.…”

Section: Discussionmentioning

confidence: 87%

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: 87%

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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“…Therefore, it is tempting to speculate that additional expression of CD45RA isoforms enhances the phosphatase activity of variant cells thereby generating a more active pool of p56 lck kinase molecules. However, alternative explanations for the enhancement of TCR signaling by variant CD45RA isoforms should also be considered in particular because recent crystal structure data show that the cytoplasmic CD45 domains probably cannot dimerize (27). The localization of molecules within lipid rafts is crucial for their effects on TCR signaling (28,29).…”

Section: Discussionmentioning

confidence: 99%

The 77C→G Mutation in the Human CD45 (PTPRC) Gene Leads to Increased Intensity of TCR Signaling in T Cell Lines from Healthy Individuals and Patients with Multiple Sclerosis

Do¹,

Baars²,

Borns³

et al. 2006

The Journal of Immunology

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The 77C→G mutation in exon A of the human CD45 gene occurs with low frequency in healthy individuals. An enhanced frequency of 77C→G individuals has been reported in cohorts of patients suffering from multiple sclerosis, systemic sclerosis, autoimmune hepatitis, and HIV-1. To investigate the mechanisms by which the variant allele may contribute to disease susceptibility, we compared T cell reactivity in heterozygous carriers of the mutation (healthy individuals and multiple sclerosis patients) and wild-type controls. In vitro-generated T cell lines and freshly isolated CD4+CD45R0+ primed/memory T cells from 77C→G individuals aberrantly expressed CD45RA isoforms and showed enhanced proliferation and IL-2 production when stimulated with anti-TCR/CD3 mAb or Ag. Mutant T cell lines contained a more active pool of p56lck tyrosine kinase and responded with increased phosphorylation of Zap70 and TCR-ζ and an enhanced Ca2+ flux to TCR/CD3 stimulation. These data suggest that 77C→G may act as a risk factor for certain diseases by increasing the intensity of TCR signaling.

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“…The D2 domain regulates the activity of the D1 domain positively and negatively (Felberg and Johnson, 1998), and can affect the signals downstream of the TCR (Kashio et al, 1998;Wang et al, 1999;Greer et al, 2001). D1 and D2 are connected by a "linker" domain that is unstructured but stabilizes a D1-D2 interface that forms a network of hydrogen bonds, hydrophobic interactions, and salt bridges (Nam et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Allosteric Noncompetitive Small Molecule Selective Inhibitors of CD45 Tyrosine Phosphatase Suppress T-Cell Receptor Signals and Inflammation In Vivo

et al. 2014

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CD45 is a receptor-like member of the protein tyrosine phosphatase (PTP) family. We screened in silico for small molecules binding at a predicted allosteric pocket unique to the CD45 intracellular domain, and validated inhibitors by in vitro phosphatase assays. Compound 211 exhibited a CD45 IC 50 value of 200 nM and had .100-fold selectivity over six related PTPs. The relevance of the allosteric pocket was verified through site-directed mutagenesis. Compound 211 has a noncompetitive mechanism of action, and it is extremely effective at preventing dephosphorylation of substrate Lck phosphotyrosine (pY)-505 versus preventing dephosphorylation of Lck pY-393. In cultured primary T cells, compound 211 prevents T-cell receptor-mediated activation of Lck, Zap-70, and mitogen-activated protein kinase, and interleukin-2 production. In a delayed-type hypersensitivity reaction in vivo, compound 211 abolished inflammation. This work demonstrates a novel approach to develop effective allosteric inhibitors that can be expanded to target the corresponding allosteric domains of other receptor PTPs.

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Structural basis for the function and regulation of the receptor protein tyrosine phosphatase CD45

Cited by 97 publications

References 58 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

The 77C→G Mutation in the Human CD45 (PTPRC) Gene Leads to Increased Intensity of TCR Signaling in T Cell Lines from Healthy Individuals and Patients with Multiple Sclerosis

Allosteric Noncompetitive Small Molecule Selective Inhibitors of CD45 Tyrosine Phosphatase Suppress T-Cell Receptor Signals and Inflammation In Vivo

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