Von Willebrand factor type D domain (vWD) is an evolutionarily-conserved protein domain found in, among others, the von Willebrand factor (vWF). vWF is a large multimeric glycoprotein and it is synthesized by a type of bone marrow cell called megakaryocytes. The vWD domain allows vWF to perform its blood-clotting function by carrying factor VIII around.
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Platelet Adhesion and Aggregation
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Structure
The D8 domain (amino acids 6-102 in vWF) is a highly structured region containing 24 paired cysteine residues. Secondary structure prediction from 75 aligned vWF sequences has revealed a largely alternating sequence of alpha-helices and beta-strands in the larger vWF protein.[1]
vWD is visible as lobes in cryo-EM images of the vWF. In a "D" domain of the vWF it is associated with a few other cysteine-rich domains named C8 (Pfam PF08742), TIL (Pfam PF01826) and vWE.[2] A crystal structure for the "D" domains in vWF (D' and D3) was solved in 2018 (PDB: 6N29). The VWD domain proper and the vWE domain are composed mostly of antiparallel beta sheets. C8 folds into a few helices. TIL is mostly loops with a triad of beta sheets. VWD also contains a calcium binding site. All these domains are disulfide rich.[3]
Function
The vWD domain D'/D3 of the von Willebrand factor (vWF) serves as a carrier of clotting factor VIII (FVIII). The native conformation of the D' domain of vWF is not only required for factor VIII (FVIII) binding but also for normal multimerisation and optimal secretion. 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 disulphide bridge with the second conserved one. The other D domains in the protein are necessary for multimerisation.[4]
This domain is found in mucins, in zonadhesin, in otogelin, and in vitellogenin. Many of these proteins are extracellular glycoproteins. It is also found in a Cypridina-luciferin 2-monooxygenase P17554. Its actual functions in these proteins are unknown.
References
- ^ Perkins SJ, Smith KF, Williams SC, Haris PI, Chapman D, Sim RB (April 1994). "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 (1): 104–19. doi:10.1006/jmbi.1994.1271. PMID 8145250.
- ^ Zhou YF, Eng ET, Zhu J, Lu C, Walz T, Springer TA (12 July 2012). "Sequence and structure relationships within von Willebrand factor". Blood. 120 (2): 449–58. doi:10.1182/blood-2012-01-405134. PMC 3398765. PMID 22490677.
- ^ Dong X, Leksa NC, Chhabra ES, Arndt JW, Lu Q, Knockenhauer KE, Peters RT, Springer TA (4 April 2019). "The von Willebrand factor D'D3 assembly and structural principles for factor VIII binding and concatemer biogenesis". Blood. 133 (14): 1523–1533. doi:10.1182/blood-2018-10-876300. PMC 6450429. PMID 30642920.
- ^ Jorieux S, Fressinaud E, Goudemand J, Gaucher C, Meyer D, Mazurier C (May 2000). "Conformational changes in the D' domain of von Willebrand factor induced by CYS 25 and CYS 95 mutations lead to factor VIII binding defect and multimeric impairment". Blood. 95 (10): 3139–45. doi:10.1182/blood.V95.10.3139. PMID 10807780.
This page was last edited on 14 May 2021, at 14:41