2mc1

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{{STRUCTURE_2mc1| PDB=2mc1 | SCENE= }}
 
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===Solution structure of the Vav1 SH2 domain complexed with a Syk-derived singly phosphorylated peptide===
 
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==Function==
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==Solution structure of the Vav1 SH2 domain complexed with a Syk-derived singly phosphorylated peptide==
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[[http://www.uniprot.org/uniprot/VAV_HUMAN VAV_HUMAN]] Couples tyrosine kinase signals with the activation of the Rho/Rac GTPases, thus leading to cell differentiation and/or proliferation. [[http://www.uniprot.org/uniprot/KSYK_MOUSE KSYK_MOUSE]] Non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immunoreceptors like the B-cell receptor (BCR). Regulates several biological processes including innate and adaptive immunity, cell adhesion, osteoclast maturation, platelet activation and vascular development. Assembles into signaling complexes with activated receptors at the plasma membrane via interaction between its SH2 domains and the receptor tyrosine-phosphorylated ITAM domains. The association with the receptor can also be indirect and mediated by adapter proteins containing ITAM or partial hemITAM domains. The phosphorylation of the ITAM domains is generally mediated by SRC subfamily kinases upon engagement of the receptor. More rarely signal transduction via SYK could be ITAM-independent. Direct downstream effectors phosphorylated by SYK include VAV1, PLCG1, PI-3-kinase, LCP2 and BLNK. Initially identified as essential in B-cell receptor (BCR) signaling, it is necessary for the maturation of B-cells most probably at the pro-B to pre-B transition. Activated upon BCR engagement, it phosphorylates and activates BLNK an adapter linking the activated BCR to downstream signaling adapters and effectors. It also phosphorylates and activates PLCG1 and the PKC signaling pathway. It also phosphorylates BTK and regulates its activity in B-cell antigen receptor (BCR)-coupled signaling. Beside its function downstream of BCR plays also a role in T-cell receptor signaling. Plays also a crucial role in the innate immune response to fungal, bacterial and viral pathogens. It is for instance activated by the membrane lectin CLEC7A. Upon stimulation by fungal proteins, CLEC7A together with SYK activates immune cells inducing the production of ROS. Also activates the inflammasome and NF-kappa-B-mediated transcription of chemokines and cytokines in presence of pathogens. Regulates neutrophil degranulation and phagocytosis through activation of the MAPK signaling cascade. Also mediates the activation of dendritic cells by cell necrosis stimuli. Also involved in mast cells activation. Also functions downstream of receptors mediating cell adhesion. Relays for instance, integrin-mediated neutrophils and macrophages activation and P-selectin receptor/SELPG-mediated recruitment of leukocytes to inflammatory loci. Plays also a role in non-immune processes. It is for instance involved in vascular development where it may regulate blood and lymphatic vascular separation. It is also required for osteoclast development and function. Functions in the activation of platelets by collagen, mediating PLCG2 phosphorylation and activation. May be coupled to the collagen receptor by the ITAM domain-containing FCER1G. Also activated by the membrane lectin CLEC1B that is required for activation of platelets by PDPN/podoplanin. Involved in platelet adhesion being activated by ITGB3 engaged by fibrinogen.<ref>PMID:9171347</ref> <ref>PMID:11672534</ref> <ref>PMID:11940607</ref> <ref>PMID:12522250</ref> <ref>PMID:15956283</ref> <ref>PMID:15845454</ref> <ref>PMID:16174766</ref> <ref>PMID:17086186</ref> <ref>PMID:17353363</ref> <ref>PMID:19797524</ref> <ref>PMID:19124738</ref> <ref>PMID:19339971</ref> <ref>PMID:19219027</ref>
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<StructureSection load='2mc1' size='340' side='right'caption='[[2mc1]]' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2mc1]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2MC1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2MC1 FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR, 20 models</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2mc1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2mc1 OCA], [https://pdbe.org/2mc1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2mc1 RCSB], [https://www.ebi.ac.uk/pdbsum/2mc1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2mc1 ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/VAV_HUMAN VAV_HUMAN] Couples tyrosine kinase signals with the activation of the Rho/Rac GTPases, thus leading to cell differentiation and/or proliferation.
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The association of Syk, a central tyrosine kinase in B cell signaling, with Vav SH2 domain is controlled by phosphorylation of two closely spaced tyrosines in Syk linker B: Y342 and Y346. Previous studies established both singly phosphorylated and doubly phosphorylated forms play a role in signaling. The structure of the doubly phosphorylated form identified a new recognition of phosphotyrosine whereby two phosphotyrosines bind simultaneously to the Vav SH2 domain, one in the canonical pTyr pocket and one in the specificity pocket on the opposite side of the central betasheet. It is unknown if the specificity pocket can bind phosphotyrosine independent of phosphotyrosine binding the pTyr pocket. To address this gap in knowledge, we determined the structure of the complex between Vav1 SH2 and a peptide (SykLBYpY) modeling the singly phosphorylatedY346 form of Syk with unphosphorylated Y342. The NMR data conclusively establish that recognition of phosphotyrosine is swapped between the two pockets; phosphorylated pY346 binds the specificity pocket of Vav1 SH2, and unphosphorylated Y342 occupies what is normally the pTyr binding pocket. Nearly identical changes in chemical shifts occurred upon binding all three forms of singly and doubly phosphorylated peptides; however somewhat smaller shift perturbations for SykLBYpY from residues in regions of high internal mobility suggest that internal motions are coupled to binding affinity. The differential recognition that includes this swapped binding of phosphotyrosine to the specificity pocket of Vav SH2 increases the repertoire of possible phosphotyrosine binding by SH2 domains in regulating proteinprotein interactions in cellular signaling.
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==About this Structure==
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Differential recognition of Syk-binding sites by each of the two phosphotyrosine-binding pockets of the Vav SH2 domain.,Chen CH, Piraner D, Gorenstein NM, Geahlen RL, Post CB Biopolymers. 2013 Aug 17. doi: 10.1002/bip.22371. PMID:23955592<ref>PMID:23955592</ref>
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[[2mc1]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2MC1 OCA].
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==Reference==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<references group="xtra"/><references/>
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</div>
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<div class="pdbe-citations 2mc1" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Chen, C.]]
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[[Category: Large Structures]]
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[[Category: Geahlen, R L.]]
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[[Category: Mus musculus]]
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[[Category: Gorenstein, N M.]]
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[[Category: Chen C]]
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[[Category: Piraner, D.]]
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[[Category: Geahlen RL]]
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[[Category: Post, C B.]]
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[[Category: Gorenstein NM]]
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[[Category: B cell signaling protein]]
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[[Category: Piraner D]]
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[[Category: Phosphorylated peptide]]
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[[Category: Post CB]]
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[[Category: Phosphotyrosine binding domain]]
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[[Category: Signaling protein-protein binding complex]]
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[[Category: Syk kinase]]
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[[Category: Tyrosine kinase]]
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Current revision

Solution structure of the Vav1 SH2 domain complexed with a Syk-derived singly phosphorylated peptide

PDB ID 2mc1

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