Von Willebrand factor contains several type D domains: D1 and D2 are present within the N-terminal propeptide whereas the remaining D domains are required for multimerisation.
Von Willebrand factor (VWF) is a large, multimeric blood glycoprotein synthesized in endothelial cells and megakaryocytes, that is required for normal hemostasis. Mutant forms are involved in the most common inherited bleeding disorder (von Willebrand disease: VWD). VWF mediates the adhesion of platelets to sites of vascular damage by binding to specific platelet membrane glycoproteins and to constituents of exposed connective tissue. It is also essential for the transport of the blood clotting factor VIII [ (PUBMED:9759493) (PUBMED:2311582) ].
VWF is a large multidomain protein. The type D domain (VWFD) is not only required for blood clotting factor VIII binding but also for normal multimerization of VWF [ (PUBMED:10807780) (PUBMED:2311582) ]. The interaction between blood clotting factor VIII and VWF is necessary for normal survival of blood clotting factor VIII in blood circulation. The VWFD domain is a highly structured region, in which the first conserved Cys has been found to form a disulfide bridge with the second conserved one [ (PUBMED:10807780) (PUBMED:2311582) ].
The VWFD domain can occur in association with a lot of different domains like vitellogenin, VWFC, VWFA, and ZP.
Proteins with a VWFD domain are listed below:
Mammalian von Willebrand factor (VWF), a multifunctional protein involved in 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 [ (PUBMED:22490677) ]. There might be a third VWFC domain within the type B domain region [ (PUBMED:2311582) ]. The structure of the VWF D3 domain has been revealed [ (PUBMED:30642920) ].
Mammalian zonadhesin, which binds in a species-specific manner to the zona pellucida of the egg.
Mammalian bone morphogenetic protein-binding (BMP-binding) endothelial regulator protein.
Mammalian alpha-tectorin, which is one of the major non-collagenous components of the tectorial membrane.
Mammalian mucins, glycoproteins that are major constituents of the glycocalyx 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.
Family alignment:
There are 25698 VWD domains in 12416 proteins in SMART's nrdb database.
Click on the following links for more information.
Evolution (species in which this domain is found)
Taxonomic distribution of proteins containing VWD domain.
This tree includes only several representative species. The complete taxonomic breakdown of all proteins with VWD domain is also avaliable.
Click on the protein counts, or double click on taxonomic names to display all proteins containing VWD domain in the selected taxonomic class.
Literature (relevant references for this domain)
Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.
Species diversity in the structure of zonadhesin, a sperm-specific membrane protein containing multiple cell adhesion molecule-like domains.
J Biol Chem. 1998; 273: 3415-21
Display abstract
A hallmark of gamete interactions at fertilization is relative or absolute species specificity. A pig sperm protein that binds to the extracellular matrix of the egg in a species-specific manner was recently identified and named zonadhesin (Hardy, D. M., and Garbers, D. L. (1995) J. Biol. Chem. 270, 26025-26028). We have now cloned a cDNA for mouse zonadhesin (16.4 kb), and it demonstrates a large species variation in the numbers and arrangements of domains. Expression of mouse zonadhesin mRNA is evident only within the testis, and the protein is found exclusively on the apical region of the sperm head. There are 20 partial D-domains, found as tandem repeats, inserted between two of the four full D-domains and an additional partial D-domain. These domains are homologous to the D-domains of von Willebrand factor and alpha-tectorin. A region at the N terminus of the mouse cDNA contains three tandem repeats homologous to MAM domains. These are domains comprised of about 160 amino acids that are present in transmembrane proteins such as the meprins and receptor protein-tyrosine phosphatases, where they appear to function in cell/cell interactions. Additionally, mouse zonadhesin contains a mucin-like domain and a domain homologous to epidermal growth factor (EGF). A putative single transmembrane segment separates a short carboxyl tail from the extracellular region. The existence of MAM, mucin, D-, and EGF domains suggest that mouse zonadhesin functions in multiple cell adhesion processes, where binding to the extracellular matrix of the egg is but one of the functions of this sperm-specific membrane protein.
Biochemistry and genetics of von Willebrand factor.
Annu Rev Biochem. 1998; 67: 395-424
Display abstract
Von Willebrand factor (VWF) is a blood glycoprotein that is required for normal hemostasis, and deficiency of VWF, or von Willebrand disease (VWD), is the most common inherited bleeding disorder. VWF mediates the adhesion of platelets to sites of vascular damage by binding to specific platelet membrane glycoproteins and to constituents of exposed connective tissue. These activities appear to be regulated by allosteric mechanisms and possibly by hydrodynamic shear forces. VWF also is a carrier protein for blood clotting factor VIII, and this interaction is required for normal factor VIII survival in the circulation. VWF is assembled from identical approximately 250 kDa subunits into disulfide-linked multimers that may be > 20,000 kDa. Mutations in VWD can disrupt this complex biosynthetic process at several steps to impair the assembly, intracellular targeting, or secretion of VWF multimers. Other VWD mutations impair the survival of VWF in plasma or the function of specific ligand binding sites. This growing body of information about VWF synthesis, structure, and function has allowed the reclassification of VWD based upon distinct pathophysiologic mechanisms that appear to correlate with clinical symptoms and the response to therapy.
The modular architecture of a new family of growth regulators related to connective tissue growth factor.
FEBS Lett. 1993; 327: 125-30
Display abstract
Recently, several groups have characterized and sequenced members of a new family of growth regulators (originally called cef10, connective tissue growth factor, fisp-12, cyr61, or, alternatively, beta IG-M1 and beta IG-M2), all of which belong to immediate-early genes expressed after induction by growth factors or certain oncogenes. Sequence analysis of this family revealed the presence of four distinct modules. Each module has homologues in other extracellular mosaic proteins such as Von Willebrand factor, slit, thrombospondins, fibrillar collagens, IGF-binding proteins and mucins. Classification and analysis of these modules suggests the location of binding regions and, by analogy to better characterized modules in other proteins, sheds some light onto the structure of this new family.
Collagens are typical mosaic proteins containing a number of shuffled domains. These domains have been classified by sequence similarity in order to characterize their structural and functional relationships to other proteins. This analysis provides an overview of homologies of collagen domains. It also reveals two new relationships: (i) a module common to type V, IX, XI, and XII collagens was found to be homologous to the heparin binding domain of thrombospondin; (ii) the modular architecture of a human type VII collagen fragment was identified. Its N-terminal globular domain contains fibronectin type III repeats located adjacent to a Von Willebrand factor type A module. The proposed structural similarities point to analogous subfunctions of the respective domains in otherwise distinct proteins.
An integumentary mucin (FIM-B.1) from Xenopus laevis homologous with von Willebrand factor.
Biochemistry. 1990; 29: 6240-4
Display abstract
We present a new protein from X. laevis skin termed "frog integumentary mucin B.1" (FIM-B.1) with a general structure similar to FIM-A.1 (formerly "spasmolysin"). The central region consisting of tandem repeats of 11 amino acid residues is probably a target for extensive O-glycosylation, whereas the C-terminal cysteine-rich domain shows pronounced homology with the C1-C2 domains and the C-terminal end of von Willebrand factor. Furthermore, we describe homology with antistasin, an anticoagulant peptide from a leech. We also discuss some implications concerning the evolutionary origin of von Willebrand factor. In situ hybridization studies revealed the expression of FIM-B.1 exclusively in mucous glands of the skin. This is comparable with FIM-A.1 but is in contrast to all other physiologically active peptides, which are synthesized in granular glands.
Domains involved in multimer assembly of von willebrand factor (vWF): multimerization is independent of dimerization.
EMBO J. 1990; 9: 797-803
Display abstract
The precursor protein of von Willebrand factor (pro-vWF) consist of four repeated domains, denoted D1-D2-D'-D3-A1-A2-A3-D4-B1-B2-B3-C1-C2. The domains D1 and D2 constitute the amino-terminal pro-polypeptide and the remaining domains mature vWF, generated upon proteolytic processing. We have shown previously that the pro-polypeptide of pro-vWF is obligatory for assembly of pro-vWF dimers into multimers, a process vital for efficient adhesion of platelets to an injured vessel wall. Here, we have employed full length vWF cDNA to construct a series of deletion mutants, based on the homology between the various domains. Specifically, the domains D', D3 or both were deleted and the multimeric pattern of the mutant vWF proteins was analysed after transient expression in COS-1 cells. It is demonstrated that in addition to the pro-polypeptide, both the D' and the D3 domain are required for multimer assembly. Furthermore, by analysing a construct containing only the domains D' and D3 next to the pro-polypeptide it is shown that this is the only part of the vWF protein involved in multimer assembly. Since, the formation of pro-vWF dimers relies on the carboxy-terminal area of mature vWF, it is concluded that multimer assembly is a process independent of dimerization.
cDNA sequences for human von Willebrand factor reveal five types of repeated domains and five possible protein sequence polymorphisms.
Biochemistry. 1986; 25: 3164-71
Display abstract
A human umbilical vein endothelial cell cDNA library in lambda gt11 was screened with two previously described cDNA inserts for human von Willebrand factor. Among 16 positive isolates, two that hybridized with a probe corresponding to the amino terminus of von Willebrand factor were sequenced. Together, these four cDNA inserts span 6.5 kilobases of the von Willebrand factor mRNA sequence, completely specifying the 2050 amino acids of the subunit of mature, secreted von Willebrand factor and 24 residues of a precursor peptide. Approximately 77% of the sequence is contained in five types of repeated domains. Domain A consists of 193-220 amino acids and is present in three tandem copies between residues 497 and 1111. Domain B contains 25-35 amino acids and is present in three copies between residues 1533 and 1636. Domain C consists of 116-119 amino acids and is duplicated between residues 1637 and 1899. In contrast to the essentially contiguous repetition of domains A-C, the two copies of domains D and E are each separated by 804 and 1383 amino acids, respectively. Domain D1 contains 289 amino acids between residues 79 and 367, while domain D2 consists of 270 amino acids between residues 1171 and 1440. Domain E1 consists of 46 amino acids between residues 25 and 70, and domain E2 consists of 46 amino acids between residues 1453 and 1498. The triplicated A domains are notably poor in Cys content, while the remaining domains are Cys-rich. The A domains appear to be homologous to a 225-residue segment of complement factor B.(ABSTRACT TRUNCATED AT 250 WORDS)
Full-length von Willebrand factor (vWF) cDNA encodes a highly repetitive protein considerably larger than the mature vWF subunit.
EMBO J. 1986; 5: 1839-47
Display abstract
Full-length human von Willebrand factor (vWF) cDNA was assembled from partial, overlapping vWF cDNAs. This cDNA construct includes a coding sequence of 8439 nucleotides which encode a single-chain precursor of 2813 amino-acid residues, representing a putative signal peptide, a prosequence and mature vWF of 22, 741 and 2050 amino acids, respectively. This represents the longest coding sequence determined to date. In-vitro expression of full-length vWF cDNA revealed the synthesis of a polypeptide with a mol. wt corresponding with that of the unglycosylated precursor. The precursor is a highly repetitive protein which consists of two duplicated (B, C), a triplicated (A), a quadruplicated (D) and a partly duplicated domain (D'), in the following order: H-D1-D2-D'-D3-A1-A2-A3-D4-B1-B2-C1-C2-OH. Both the prosequence, composed of two D domains (D1, D2), and mature vWF harbor an arg-gly-asp ('R-G-D') sequence which has been implicated in cell-attachment functions. It is argued that the pro-sequence is equivalent to von Willebrand Antigen II (vW AgII).
Disease (disease genes where sequence variants are found in this domain)
SwissProt sequences and OMIM curated human diseases associated with missense mutations within the VWD domain.
This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with VWD domain which could be assigned to a KEGG orthologous group, and not all proteins containing VWD domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.
Links (links to other resources describing this domain)
