2v76
From Proteopedia
Crystal structure of the human dok1 PTB domain
Structural highlights
FunctionDOK1_HUMAN DOK proteins are enzymatically inert adaptor or scaffolding proteins. They provide a docking platform for the assembly of multimolecular signaling complexes. DOK1 appears to be a negative regulator of the insulin signaling pathway. Modulates integrin activation by competing with talin for the same binding site on ITGB3.[1] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedIntegrins play a fundamental role in cell migration and adhesion; knowledge of how they are regulated and controlled is vital for understanding these processes. Recent work showed that Dok1 negatively regulates integrin activation, presumably by competition with talin. To understand how this occurs, we used NMR spectroscopy and x-ray crystallography to investigate the molecular details of interactions with integrins. The binding affinities of beta3 integrin tails for the Dok1 and talin phosphotyrosine binding domains were quantified using 15N-1H hetero-nuclear single quantum correlation titrations, revealing that the unphosphorylated integrin tail binds more strongly to talin than Dok1. Chemical shift mapping showed that unlike talin, Dok1 exclusively interacts with the canonical NPXY motif of the beta3 integrin tail. Upon phosphorylation of Tyr 747 in the beta3 integrin tail, however, Dok1 then binds much more strongly than talin. Thus, we show that phosphorylation of Tyr 747 provides a switch for integrin ligand binding. This switch may represent an in vivo mechanism for control of integrin receptor activation. These results have implications for the control of integrin signaling by proteins containing phosphotyrosine binding domains. An integrin phosphorylation switch: the effect of beta3 integrin tail phosphorylation on Dok1 and talin binding.,Oxley CL, Anthis NJ, Lowe ED, Vakonakis I, Campbell ID, Wegener KL J Biol Chem. 2008 Feb 29;283(9):5420-6. Epub 2007 Dec 21. PMID:18156175[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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