3omh

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{{STRUCTURE_3omh| PDB=3omh | SCENE= }}
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==Crystal structure of PTPN22 in complex with SKAP-HOM pTyr75 peptide==
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===Crystal structure of PTPN22 in complex with SKAP-HOM pTyr75 peptide===
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<StructureSection load='3omh' size='340' side='right' caption='[[3omh]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
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{{ABSTRACT_PUBMED_21719704}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3omh]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3OMH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3OMH FirstGlance]. <br>
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</td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2qct|2qct]], [[2qcj|2qcj]]</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PTPN22, PTPN8 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Protein-tyrosine-phosphatase Protein-tyrosine-phosphatase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.3.48 3.1.3.48] </span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3omh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3omh OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3omh RCSB], [http://www.ebi.ac.uk/pdbsum/3omh PDBsum]</span></td></tr>
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</table>
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== Disease ==
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[[http://www.uniprot.org/uniprot/PTN22_HUMAN PTN22_HUMAN]] Defects in PTPN22 are a cause of susceptibility to systemic lupus erythematosus (SLE) [MIM:[http://omim.org/entry/152700 152700]]. SLE is a chronic, inflammatory and often febrile multisystemic disorder of connective tissue. It affects principally the skin, joints, kidneys and serosal membranes. It is thought to represent a failure of the regulatory mechanisms of the autoimmune system.<ref>PMID:15273934</ref>
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== Function ==
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[[http://www.uniprot.org/uniprot/PTN22_HUMAN PTN22_HUMAN]] Acts as negative regulator of T-cell receptor (TCR) signaling by direct dephosphorylation of the Src family kinases LCK and FYN, ITAMs of the TCRz/CD3 complex, as well as ZAP70, VAV, VCP and other key signaling molecules. Associates with and probably dephosphorylates CBL. Dephosphorylates LCK at its activating 'Tyr-394' residue. Dephosphorylates ZAP70 at its activating 'Tyr-493' residue. Dephosphorylates the immune system activator SKAP2.<ref>PMID:16461343</ref> <ref>PMID:18056643</ref> <ref>PMID:19167335</ref> <ref>PMID:21719704</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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A missense single-nucleotide polymorphism in the gene encoding the lymphoid-specific tyrosine phosphatase (Lyp) has been identified as a causal factor in a wide spectrum of autoimmune diseases. Interestingly, the autoimmune-predisposing variant of Lyp appears to represent a gain-of-function mutation, implicating Lyp as an attractive target for the development of effective strategies for the treatment of many autoimmune disorders. Unfortunately, the precise biological functions of Lyp in signaling cascades and cellular physiology are poorly understood. Identification and characterization of Lyp substrates will help define the chain of molecular events coupling Lyp dysfunction to diseases. In the current study, we identified consensus sequence motifs for Lyp substrate recognition using an "inverse alanine scanning" combinatorial library approach. The intrinsic sequence specificity data led to the discovery and characterization of SKAP-HOM, a cytosolic adaptor protein required for proper activation of the immune system, as a bona fide Lyp substrate. To determine the molecular basis for Lyp substrate recognition, we solved crystal structures of Lyp in complex with the consensus peptide as well as the phosphopeptide derived from SKAP-HOM. Together with the biochemical data, the structures define the molecular determinants for Lyp substrate specificity and provide a solid foundation upon which novel therapeutics targeting Lyp can be developed for multiple autoimmune diseases.
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==Disease==
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Substrate Specificity of Lymphoid-specific Tyrosine Phosphatase (Lyp) and Identification of Src Kinase-associated Protein of 55 kDa Homolog (SKAP-HOM) as a Lyp Substrate.,Yu X, Chen M, Zhang S, Yu ZH, Sun JP, Wang L, Liu S, Imasaki T, Takagi Y, Zhang ZY J Biol Chem. 2011 Sep 2;286(35):30526-34. Epub 2011 Jun 30. PMID:21719704<ref>PMID:21719704</ref>
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[[http://www.uniprot.org/uniprot/PTN22_HUMAN PTN22_HUMAN]] Defects in PTPN22 are a cause of susceptibility to systemic lupus erythematosus (SLE) [MIM:[http://omim.org/entry/152700 152700]]. SLE is a chronic, inflammatory and often febrile multisystemic disorder of connective tissue. It affects principally the skin, joints, kidneys and serosal membranes. It is thought to represent a failure of the regulatory mechanisms of the autoimmune system.<ref>PMID:15273934</ref>
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==Function==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[http://www.uniprot.org/uniprot/PTN22_HUMAN PTN22_HUMAN]] Acts as negative regulator of T-cell receptor (TCR) signaling by direct dephosphorylation of the Src family kinases LCK and FYN, ITAMs of the TCRz/CD3 complex, as well as ZAP70, VAV, VCP and other key signaling molecules. Associates with and probably dephosphorylates CBL. Dephosphorylates LCK at its activating 'Tyr-394' residue. Dephosphorylates ZAP70 at its activating 'Tyr-493' residue. Dephosphorylates the immune system activator SKAP2.<ref>PMID:16461343</ref><ref>PMID:18056643</ref><ref>PMID:19167335</ref><ref>PMID:21719704</ref>
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</div>
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==About this Structure==
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[[3omh]] is a 8 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3OMH OCA].
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==See Also==
==See Also==
*[[Tyrosine phosphatase|Tyrosine phosphatase]]
*[[Tyrosine phosphatase|Tyrosine phosphatase]]
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== References ==
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==Reference==
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<references/>
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<ref group="xtra">PMID:021719704</ref><references group="xtra"/><references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Protein-tyrosine-phosphatase]]
[[Category: Protein-tyrosine-phosphatase]]
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[[Category: Sun, J P.]]
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[[Category: Sun, J P]]
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[[Category: Yu, X.]]
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[[Category: Yu, X]]
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[[Category: Zhang, S.]]
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[[Category: Zhang, S]]
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[[Category: Zhang, Z Y.]]
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[[Category: Zhang, Z Y]]
[[Category: Hydrolase]]
[[Category: Hydrolase]]
[[Category: Tyrosine phosphatase]]
[[Category: Tyrosine phosphatase]]

Revision as of 07:18, 19 December 2014

Crystal structure of PTPN22 in complex with SKAP-HOM pTyr75 peptide

3omh, resolution 2.90Å

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