Von Willebrand factor (VWF) is a multimeric adhesive protein involved in the initiation and progression of thrombus formation at sites of vascular injury []. VWF allows platelets to adhere to sites of vascular injury, forming a bridge between the sub-endothelial collagen matrix and the platelet-surface receptor complex GPIb-IX-V []. VWF is also a chaperone for coagulation factor VIII, delivering it to the injury site and protecting it from clearance from the plasma []. The protein is multidomain with four VWFD domains, four TIL domains, three VWFA domains, three VWFC domains and a C-terminal CTCK domain []. VWF is cleaved to release von Willebrand antigen 2 by a furin-like endopeptidase []. Von Willebrand diseases 1, 2 and 3 are deficiencies of VWF, resulting in impaired platelet aggregation and prolonged bleeding after trauma []. Von Willebrand disease 3 results in haemophilia.
The von Willebrand factor is a large multimeric glycoprotein found in blood plasma. Mutant forms are involved in the aetiology of bleeding disorders []. In von Willebrand factor, the type A domain (vWF) is the prototype for a 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 [, , ]. 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. Proteins that incorporate vWF domains participate in numerous biological events (e.g. cell adhesion, migration, homing, pattern formation, and signal transduction), involving interaction with a large array of ligands []. 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 α-helices and β-strands []. The vWF domain fold is predicted to be a doubly-wound, open, twisted β-sheet flanked by α-helices []. 3D structures have been determined for the I-domains of integrins alpha-M (CD11b; with bound magnesium) []and alpha-L (CD11a; with bound manganese) []. 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 site represents a general metal ion-dependent adhesion site (MIDAS) for binding protein ligands []. 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 [].
Members of this subgroup are bacterial in origin. They are typified by the presence of a MIDAS motif [, ].The von Willebrand factor is a large multimeric glycoprotein found in blood plasma. Mutant forms are involved in the aetiology of bleeding disorders []. In von Willebrand factor, the type A domain (vWF) is the prototype for a 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 [, , ]. 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. Proteins that incorporate vWF domains participate in numerous biological events (e.g. cell adhesion, migration, homing, pattern formation, and signal transduction), involving interaction with a large array of ligands []. 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 α-helices and β-strands []. The vWF domain fold is predicted to be a doubly-wound, open, twisted β-sheet flanked by α-helices []. 3D structures have been determined for the I-domains of integrins alpha-M (CD11b; with bound magnesium) []and alpha-L (CD11a; with bound manganese) []. 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 site represents a general metal ion-dependent adhesion site (MIDAS) for binding protein ligands []. 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 [].
The von Willebrand factor is a large multimeric glycoprotein found in blood plasma. Mutant forms are involved in the aetiology of bleeding disorders []. In von Willebrand factor, the type A domain (vWF) is the prototype for a 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 [, , ]. 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. Proteins that incorporate vWF domains participate in numerous biological events (e.g. cell adhesion, migration, homing, pattern formation, and signal transduction), involving interaction with a large array of ligands []. 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 α-helices and β-strands []. The vWF domain fold is predicted to be a doubly-wound, open, twisted β-sheet flanked by α-helices []. 3D structures have been determined for the I-domains of integrins alpha-M (CD11b; with bound magnesium) []and alpha-L (CD11a; with bound manganese) []. 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 site represents a general metal ion-dependent adhesion site (MIDAS) for binding protein ligands []. 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 [].
Von Willebrand factor (VWF) is a large, multimeric blood glycoproteinsynthesized in endothelial cells and megakaryocytes, that is required fornormal hemostasis. Mutant forms are involved in the most common inheritedbleeding disorder (von Willebrand disease: VWD). VWF mediates the adhesion ofplatelets to sites of vascular damage by binding to specific platelet membraneglycoproteins and to constituents of exposed connective tissue. It is alsoessential for the transport of the blood clotting factor VIII [, ].VWF is a large multidomain protein. The type D domain (VWFD) is not onlyrequired for blood clotting factor VIII binding but also for normalmultimerization of VWF [, ]. The interaction between blood clotting factorVIII and VWF is necessary for normal survival of blood clotting factor VIII inblood circulation. The VWFD domain is a highly structured region, in which thefirst conserved Cys has been found to form a disulfide bridge with the secondconserved one [, ].The VWFD domain can occur in association with a lot of different domains likevitellogenin, VWFC, VWFA, and ZP.Proteins with a VWFD domain are listed below:Mammalian von Willebrand factor (VWF), a multifunctional protein involvedin maintaining homeostasis. It consists of 4 VWFD domains (D1-4), 3 VWFA domains,3 VWFB domains, 2 VWFC domains, an X domain and a C-terminal cystine knot [].There might be a third VWFC domain within the type B domain region []. The structure of the VWF D3 domain has been revealed []. Mammalian zonadhesin, which binds in a species-specific manner to the zonapellucida of the egg.Mammalian bone morphogenetic protein-binding (BMP-binding) endothelialregulator protein.Mammalian alpha-tectorin, which is one of the major non-collagenouscomponents of the tectorial membrane.Mammalian mucins, glycoproteins that are major constituents of theglycocalyx that covers mucosal epithelium.Mammalian vitellogenin, a major lipoprotein in many oviparous animals,which is a precursor of a lipid-binding product named as lipovitellin.This entry represents the VWFD domain.
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 [, , ]. 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 []. 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 α-helices and β-strands []. The domain is named after the von Willebrand factor (VWF) type C repeat which is found in multidomain protein/multifunctional proteins involved in maintaining homeostasis [, ]. For the von Willebrand factor the duplicated VWFC domain is thought to participate in oligomerisation, but not in the initial dimerisation step []. The presence of this region in a number of other complex-forming proteins points to the possible involvement of the VWFC domain in complex formation.
Members of this family usually are small proteins (PatC, TenC, TruC) of unknown function in cyanobactin (prenylated cyclic peptide) biosynthesis clusters, where a different small protein is a known cyanobactin precursor (patellamide, anacyclamide, piricyclamide, etc). They may instead be the C-terminal domain of a longer protein that otherwise consists mostly of lectin-like or VWF type A domains, in similar context. Similar to the cyanobactin precursors, members of this family have two very strongly conserved regions separated by a hypervariable region, suggesting these proteins may undergo a similar maturation [].
These proteins belong to MEROPS peptidase family S1 (chymotrypsin family, clan PA(S)), subfamily S1A.This family contains two mammalian proteins, complement C2 and complement factor B, which, respectively, have analogous roles in the classical and alternative pathways of complement activation. These proteins are composed of three regions, an N-terminal three-module complement control protein domain, a von Willebrand factor A domain, and a C-terminal serine protease domain. Briefly, they are activated by cleavage and function as the serine protease components of the C3/C5 convertases, which play similar roles in these pathways although composed of different proteins. Homologs in non-mammalian species are often more or less equally related to mammalian C2 and B and may be designated as complement B/C2. Strongylocentrotus purpuratus (Purple sea urchin) has an atypical factor B with a five-module complement control protein domain.The structures of the von Willebrand factor A and serine protease domains from human complement factor B () have been analysed [, ]. The A domain forms the classical vWF A domain fold, which consists of a central β-sheet flanked on both sides by amphipathic alpha helices. It contains an integrin-like MIDAS (metal ion-dependent adhesion site) motif that adopts the open conformation typical of integrin-ligand complexes, with an acidic residue from another A domain (provided by a fortuitous crystal contact) completing the coordination of the metal ion. Although a closed conformation was not observed, modelling studies suggest that the A domain could adopt this conformation, implying that as with integrins, ligand-binding may induce conformational changes which transduce a signal to other domains in the protein []. The serine protease domain forms a chymotrypsin fold with several novel features []. Like other serine proteases it forms two β-sheets, composed of six β-strands each, surrounded by surface helices and loops. However, several novel deletions and insertions occur within these surface helices and loops, and differences in active site conformation also exist.
