1atz
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HUMAN VON WILLEBRAND FACTOR A3 DOMAIN
OverviewOverview
BACKGROUND: Bleeding from a damaged blood vessel is stopped by the, formation of a platelet plug. The multimeric plasma glycoprotein, von, Willebrand factor (vWF), plays an essential role in this process by, anchoring blood platelets to the damaged vessel wall under conditions of, high shear stress. This factor mediates platelet adhesion by binding both, to collagen of the damaged blood vessel and to glycoprotein Ib on the, platelet membrane. The A3 domain of vWF allows it to bind to collagen, types I and III present in the perivascular connective tissue of the, damaged vessel wall. To gain insight into the mechanism of collagen, binding by vWF, we have determined the crystal structure of the human vWF, A3 domain. RESULTS: The crystal structure of the 20 kDa A3 domain of human, vWF (residues 920-1111), determined by the method of multiwavelength, anomalous dispersion at 1.8 A resolution, exhibits a common, dinucleotide-binding fold. The putative collagen-binding site of the A3, domain is rather smooth and shows a markedly high concentration of, negatively charged residues. This region encompasses a potential, metal-binding site containing the motif DXSXS, which is required for, ligand interaction in the homologous I-type domains of integrins CR3 and, LFA-1. Although vWF A3 has considerable sequence and structural similarity, with CR3 and LFA-1 in this region, one loop of A3 adopts a conformation, which is incompatible with ion binding. CONCLUSIONS: The structure of the, A3 domain suggests that adhesion to collagen is primarily achieved through, interactions between negatively charged residues on A3 and positively, charged residues on collagen. The absence of a pronounced binding groove, precludes a large van der Waals surface interaction between A3 and, collagen and is consistent with the low affinity for collagen of a single, A3 domain and the requirement for multimeric vWF for tight association, with collagen. The absence of bound metal ions upon soaking the crystal in, MgCl2 and vWF A3's conformational incompatibility for metal binding is, consistent with the absence of a functional role for metal ion binding in, A3, which contrasts the metal ion activation required for ligand binding, by the homologous integrin I type domains.
DiseaseDisease
Known diseases associated with this structure: von Willebrand disease OMIM:[193400]
About this StructureAbout this Structure
1ATZ is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Crystal structure of the A3 domain of human von Willebrand factor: implications for collagen binding., Huizinga EG, Martijn van der Plas R, Kroon J, Sixma JJ, Gros P, Structure. 1997 Sep 15;5(9):1147-56. PMID:9331419
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