The von Willebrand factor is a large multimeric glycoprotein found in bloodplasma. Mutant forms are involved in the aetiology of bleeding disorders [1]. In von Willebrand factor, the type A domain (vWF) is the prototype fora protein superfamily. The vWF domain is found in various plasma proteins:complement factors B, C2, CR3 and CR4; the integrins (I-domains); collagen types VI, VII, XII and XIV; and other extracellular proteins [2, 3, 4]. Although the majority of VWA-containing proteins are extracellular, the most ancient ones present in all eukaryotes are all intracellular proteins involved in functions such as transcription, DNA repair, ribosomal and membrane transport and the proteasome. A common feature appears to be involvement in multiprotein complexes. Proteinsthat incorporate vWF domains participate in numerous biological events(e.g. cell adhesion, migration, homing, pattern formation, and signaltransduction), involving interaction with a large array of ligands [5]. A number of human diseases arise from mutations in VWA domains.

Secondary structure prediction from 75 aligned vWF sequences has revealed a largely alternating sequence of alpha-helices and beta-strands [5]. The vWF domain fold is predicted to be adoubly-wound, open, twisted beta-sheet flanked by alpha-helices [5]. 3D structures have been determined for the I-domains of integrins CD11b(with bound magnesium) [6] and CD11a (with bound manganese) [7]. The domain adopts a classic alpha/beta Rossmann fold and contains an unusual metal ion coordination site at its surface. It has been suggested that this siterepresents a general metal ion-dependent adhesion site (MIDAS) for binding protein ligands [8]. The residues constituting the MIDAS motif in the CD11band CD11a I-domains are completely conserved, but the manner in which the metal ion is coordinated differs slightly [8].

1. von Willebrand factor. FASEB J. 7, 308-16
2. Type A modules: interacting domains found in several non-fibrillar collagens and in other extracellular matrix proteins. Matrix 13, 297-306
3. The secondary structure of the von Willebrand factor type A domain in factor B of human complement by Fourier transform infrared spectroscopy. Its occurrence in collagen types VI, VII, XII and XIV, the integrins and other proteins by averaged structure predictions. J. Mol. Biol. 238, 104-19
4. Shuffled domains in extracellular proteins. FEBS Lett. 286, 47-54
5. The protein fold of the von Willebrand factor type A domain is predicted to be similar to the open twisted beta-sheet flanked by alpha-helices found in human ras-p21. FEBS Lett. 358, 283-6
6. Crystal structure of the A domain from the alpha subunit of integrin CR3 (CD11b/CD18). Cell 80, 631-8
7. Crystal structure of the I-domain from the CD11a/CD18 (LFA-1, alpha L beta 2) integrin. Proc. Natl. Acad. Sci. U.S.A. 92, 10277-81

The von Willebrand factor is a large multimeric glycoprotein found in bloodplasma. Mutant forms a
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