1fe8
From Proteopedia
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CRYSTAL STRUCTURE OF THE VON WILLEBRAND FACTOR A3 DOMAIN IN COMPLEX WITH A FAB FRAGMENT OF IGG RU5 THAT INHIBITS COLLAGEN BINDING
Contents |
Overview
Von Willebrand factor (vWF) is a multimeric glycoprotein that mediates, platelet adhesion and thrombus formation at sites of vascular injury. vWF, functions as a molecular bridge between collagen and platelet receptor, glycoprotein Ib. The major collagen-binding site of vWF is contained, within the A3 domain, but its precise location is unknown. To localize the, collagen-binding site, we determined the crystal structure of A3 in, complex with an Fab fragment of antibody RU5 that inhibits collagen, binding. The structure shows that RU5 recognizes a nonlinear epitope, consisting of residues 962-966, 981-997, and 1022-1026. Alanine mutants, were constructed of residues Arg(963), Glu(987), His(990), Arg(1016), and, His(1023), located in or close to the epitope. Mutants were expressed as, fully processed multimeric vWF. Mutation of His(1023) abolished collagen, binding, whereas mutation of Arg(963) and Arg(1016) reduced collagen, binding by 25-35%. These residues are part of loops alpha3beta4 and, alpha1beta2 and alpha-helix 3, respectively, and lie near the bottom face, of the domain. His(1023) and flanking residues display multiple, conformations in available A3-crystal structures, suggesting that binding, of A3 to collagen involves an induced-fit mechanism. The collagen-binding, site of A3 is located distant from the top face of the domain where, collagen-binding sites are found in homologous integrin I domains.
Disease
Known diseases associated with this structure: von Willebrand disease OMIM:[193400]
About this Structure
1FE8 is a Single protein structure of sequence from Homo sapiens and Mus musculus with NAG and CAC as ligands. Full crystallographic information is available from OCA.
Reference
Identification of the collagen-binding site of the von Willebrand factor A3-domain., Romijn RA, Bouma B, Wuyster W, Gros P, Kroon J, Sixma JJ, Huizinga EG, J Biol Chem. 2001 Mar 30;276(13):9985-91. Epub 2000 Nov 29. PMID:11098050
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