von Willebrand factor
VWF | |||
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Gene ontology | |||
Molecular function | |||
Cellular component | |||
Biological process | |||
Sources:Amigo / QuickGO |
Ensembl | |||||||||
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UniProt | |||||||||
RefSeq (mRNA) | |||||||||
RefSeq (protein) | |||||||||
Location (UCSC) | Chr 12: 5.95 – 6.12 Mb | Chr 6: 125.52 – 125.66 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
Von Willebrand factor (VWF) (German: [fɔn ˈvɪləbʁant]) is a blood glycoprotein that promotes hemostasis, specifically, platelet adhesion. It is deficient and/or defective in von Willebrand disease and is involved in many other diseases, including thrombotic thrombocytopenic purpura, Heyde's syndrome, and possibly hemolytic–uremic syndrome.[5] Increased plasma levels in many cardiovascular, neoplastic, metabolic (e.g. diabetes), and connective tissue diseases are presumed to arise from adverse changes to the endothelium, and may predict an increased risk of thrombosis.[6]
Biochemistry
Synthesis
VWF is a large multimeric glycoprotein present in blood plasma and produced constitutively as ultra-large VWF in endothelium (in the Weibel–Palade bodies), megakaryocytes (α-granules of platelets), and subendothelial connective tissue.[5]
Structure
The basic VWF monomer is a 2050-amino acid protein. Every monomer contains a number of specific domains with a specific function; elements of note are:[5]
- the D'/D3 domain, which binds to factor VIII (von Willebrand factor type D domain).[7]
- the A1 domain, which binds to:
- the A2 domain, which must partially unfold to expose the buried cleavage site for the specific ADAMTS13 protease that inactivates VWF by making much smaller multimers. The partial unfolding is affected by shear flow in the blood, by calcium binding, and by the lump of a sequence-adjacent "vicinal disulfide" at the A2-domain C-terminus.[8][9]
- the A3 domain, which binds to collagen (von Willebrand factor type A domain)
- the C4 domain, in which the integrin αIIbβ3 when this is activated (von Willebrand factor type C domain)
- the other C domains, which may interact in ER dimers: the larger protein show six beads of (C and C-like) domains under cryo-EM.[7]
- the "cystine knot" domain (at the C-terminal end of the protein), which VWF shares with platelet-derived growth factor (PDGF), transforming growth factor-β (TGFβ) and β-human chorionic gonadotropin (βHCG, of pregnancy test fame). (von Willebrand factor type C domain)
Monomers are subsequently
Multimers of VWF can be extremely large, >20,000
Function
Von Willebrand Factor's primary function is binding to other proteins, in particular factor VIII, and it is important in platelet adhesion to wound sites.[5] It is not an enzyme and, thus, has no catalytic activity.
VWF binds to a number of cells and molecules. The most important ones are:[5]
- Factor VIII is bound to VWF while inactive in circulation; factor VIII degrades rapidly when not bound to VWF. Factor VIII is released from VWF by the action of thrombin. In the absence of VWF, factor VIII has a half-life of 1–2 hours; when carried by intact VWF, factor VIII has a half-life of 8–12 hours.
- VWF binds to collagen, e.g., when collagen is exposed beneath endothelial cells due to damage occurring to the blood vessel. Endothelium also releases VWF which forms additional links between the platelets' glycoprotein Ib/IX/V and the collagen fibrils
- VWF binds to platelet gpIX and gpV; this binding occurs under all circumstances, but is most efficient under high shear stress(i.e., rapid blood flow in narrow blood vessels, see below).
- VWF binds to other platelet receptors when they are activated, e.g., by thrombin (i.e., when coagulation has been stimulated).
VWF plays a major role in blood coagulation. Therefore, VWF deficiency or dysfunction (von Willebrand disease) leads to a bleeding tendency, which is most apparent in tissues having high blood flow
Catabolism
The biological breakdown (
The half-life of vWF in human plasma is around 16 hours; glycosylation variation on vWF molecules from different individuals result in a larger range of 4.2 to 26 hours. Liver cells as well as macrophages take up vWF for clearance via ASGPRs and LRP1. SIGLEC5 and CLEC4M also recognize vWF.[10]
Role in disease
In thrombotic thrombocytopenic purpura (TTP) and hemolytic–uremic syndrome (HUS), ADAMTS13 either is deficient or has been inhibited by antibodies directed at the enzyme. This leads to decreased breakdown of the ultra-large multimers of VWF and microangiopathic hemolytic anemia with deposition of fibrin and platelets in small vessels, and capillary necrosis. In TTP, the organ most obviously affected is the brain; in HUS, the kidney.[15]
Higher levels of VWF are more common among people that have had
History
VWF is named after
In the 1950s, vWD was shown to be caused by a plasma factor deficiency (instead of being caused by platelet disorders), and, in the 1970s, the VWF protein was purified.[5] Harvey J. Weiss[19] and coworkers developed a quantitative assay for VWF function that remains a mainstay of laboratory evaluation for VWD to this day.[20]
Interactions
Von Willebrand Factor has been shown to
Recently, It has been reported that the cooperation and interactions within the von Willebrand Factors enhances the adsorption probability in the primary haemostasis. Such cooperation is proven by calculating the adsorption probability of flowing VWF once it crosses another adsorbed one. Such cooperation is held within a wide range of shear rates.[22]
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000110799 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000001930 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ PMID 9759493.
- PMID 27628010.
- ^ PMID 22490677.
- PMID 21750539.
- PMID 20354169.
- ^ S2CID 27785232.
- S2CID 3490036.
- S2CID 25645477.
- S2CID 23875096.
- PMID 12878741.
- PMID 14727254.
- S2CID 4964177.
- PMID 21497043.
- S2CID 221750622.
- S2CID 41340436.
- PMID 4201262.
- PMID 3490481.
- PMID 26179989.
External links
- GeneReviews/NCBI/NIH/UW entry on von Willebrand Factor Deficiency. Includes: Type 1 von Willebrand Disease, Type 2A von Willebrand Disease, Type 2B von Willebrand Disease, Type 2M von Willebrand Disease, Type 2N von Willebrand Disease, Type 3 von Willebrand Disease
- Overview of all the structural information available in the PDB for UniProt: P04275 (von Willebrand factor) at the PDBe-KB.