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20-September-2008 09:55:55 - Von Willebrand factor Von Willebrand factor PDB rendering based on 1ao3. Available structures: 1ao3, 1atz, 1auq, 1fe8, 1fns, 1ijb, 1ijk, 1m10, 1oak, 1sq0, 1u0n, 1uex, 2adf Identifiers Symbols VWF; F8VWF; VWD External IDs OMIM: 193400 MGI: 98941 HomoloGene: 466 Gene ontology Molecular function: protease binding protein binding Cellular component: extracellular region proteinaceous extracellular matrix Biological process: cell adhesion response to wounding platelet activation RNA expression pattern More reference expression data Orthologs Human Mouse Entrez 7450 22371 Ensembl ENSG00000110799 ENSMUSG00000001930 Uniprot P04275 Q2I0J7 Refseq NM_000552 mRNA NP_000543 protein NM_011708 mRNA NP_035838 protein Location Chr 12: 5.93 - 6.1 Mb Chr 6: 125.51 - 125.65 Mb Pubmed search 1 2 Von Willebrand factor vWF is a blood glycoprotein involved in hemostasis. It is deficient or defective in von Willebrand disease and is involved in a large number of other diseases, including thrombotic thrombocytopenic purpura, Heyde's syndrome, and possibly hemolytic-uremic syndrome.1 Contents 1 Biochemistry 1.1 Synthesis 1.2 Structure 1.3 Function 1.4 Catabolism 2 Role in disease 3 History 4 References 5 See also Biochemistry Synthesis vWF is a large multimeric glycoprotein present in blood plasma and produced constitutively in endothelium in the Weibel-Palade bodies, megakaryocytes α-granules of platelets, and subendothelial connective tissue.1 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:1 the D'/D3 domain, which binds to Factor VIII the A1 domain, which binds to: platelet GPIb-receptor heparin possibly collagen the A3 domain, which binds to collagen the C1 domain, in which the RGD domain binds to platelet integrin αIIbβ3 when this is activated the cysteine 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. Monomers are subsequently N-glycosylated, arranged into dimers in the endoplasmic reticulum and into multimers in the Golgi apparatus by crosslinking of cysteine residues via disulfide bonds. With respect to the glycosylation, vWF is one of the few proteins that carry ABO blood group system antigens.1 Multimers of vWF can be extremely large, 20,000 kDa, and consist of over 80 subunits of 250 kDa each. Only the large multimers are functional. Some cleavage products that result from vWF production are also secreted but probably serve no function.1 VWF monomer and multimers VWF monomer and multimers Function Von Willebrand factor is not an enzyme and therefore has no catalytic activity. Its primary function is binding to other proteins, particularly Factor VIII and it is important in platelet adhesion to wound sites.1 vWF binds to a number of cells and molecules. The most important ones are:1 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. vWF binds to collagen, e.g., when it is exposed in endothelial cells due to damage occurring to the blood vessel. vWF binds to platelet gpIb when it forms a complex with 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 appears to play a major role in blood coagulation. vWF deficiency or dysfunction von Willebrand disease therefore leads to a bleeding tendency, which is most apparent in tissues having high blood flow shear in narrow vessels. From studies it appears that vWF uncoils under these circumstances, decelerating passing platelets.1 Catabolism The biological breakdown catabolism of vWF is largely mediated by a protein cryptically termed ADAMTS13 acronym of a disintegrin-like and metalloprotease with thrombospondin type 1 motif no. 13. It is a metalloproteinase which cleaves vWF between tyrosine at position 842 and methionine at position 843 or 1605-1606 of the gene in the A2 domain. This breaks down the multimers into smaller units, which are degraded by other peptidases.2 Role in disease Main article: Von Willebrand disease Herary or acquired defects of vWF lead to von Willebrand disease vWD, a bleeding diathesis of the skin and mucous membranes, causing nosebleeds, menorrhagia, and gastrointestinal bleeding. The point at which the mutation occurs determines the severity of the bleeding diathesis. There are three types I, II and III, and type II is further divided in several subtypes. Treatment depends on the nature of the abnormality and the severity of the symptoms.3 Most cases of vWD are herary, but abnormalities to vWF may be acquired; aortic valve stenosis, for instance, has been linked to vWD type IIA, causing gastrointestinal bleeding - an association known as Heyde's syndrome.4 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.5 Higher levels of vWF are more common among people that have had ischaemic stroke from blood-clotting for the first time. Occurrence is not affected by ADAMTS13, and the only significant genetic factor is the person's blood group.6 History vWF is named after Dr. Erik von Willebrand 1870-1949, a Finnish doctor who in 1924 first described a herary bleeding disorder in families from the Åland islands, who had a tendency for cutaneous and mucosal bleeding, including menorrhagia. Although von Willebrand could not identify the definite cause, he distinguished von Willebrand disease vWD from haemophilia and other forms of bleeding diathesis.7 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.1 References ^ a b c d e f g h i Sadler JE 1998. Biochemistry and genetics of von Willebrand factor. Annu. Rev. Biochem. 67: 395-424. doi:10.1146/annurev.biochem.67.1.395. PMID 9759493. ^ Levy GG, Motto DG, Ginsburg D 2005. ADAMTS13 turns 3. Blood 106 1: 11-7. doi:10.1182/blood-2004-10-4097. PMID 15774620. ^ Sadler JE, Budde U, Eikenboom JC, et al 2006. Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. J. Thromb. Haemost. 4 10: 2103-14. doi:10.1111/j.1538-7836.2006.02146.x. PMID 16889557. ^ Vincentelli A, Susen S, Le Tourneau T, et al 2003. Acquired von Willebrand syndrome in aortic stenosis. N. Engl. J. Med. 349 4: 343-9. doi:10.1056/NEJMoa022831. PMID 12878741. ^ Moake JL 2004. von Willebrand factor, ADAMTS-13, and thrombotic thrombocytopenic purpura. Semin. Hematol. 41 1: 4-14. doi:10.1053/j.seminhematol.2003.10.003. PMID 14727254. ^ Bongers T, de Maat M, van Goor M, et. al 2006. High von Willebrand factor levels increase the risk of first ischemic stroke: influence of ADAMTS13, inflammation, and genetic variability. Stroke 37 11: 2672-7. doi:10.1161/01.STR.0000244767.39962.f7. PMID 16990571. ^ von Willebrand EA 1926. Herär pseudohemofili. Fin Läkaresällsk Handl 68: 87-112. Reproduced in Von Willebrand EA 1999. Herary pseudohaemophilia. Haemophilia 5 3: 223-31; discussion 222. doi:10.1046/j.1365-2516.1999.00302.x. PMID 10444294. See also von Willebrand disease Bernard-Soulier syndrome v d e Proteins: coagulation Coagulation factors primary hemostasis: vWF intrinsic pathway: HMWK/Bradykinin - Kallikrein - Hageman / FXII - FXI - FIX - FVIII extrinsic pathway: Tissue factor / FIII - FVII common pathway: FX - FV - Prothrombin / FII, Fibrin / FI - FXIII Coagulation inhibitors Antithrombin inhibits II, IX, X, XI, XII - Protein C inhibits V, VIII/Protein S cofactor for protein C - Protein Z inhibits X - ZPI inhibits X, XI - TFPI inhibits III Fibrinolysis Plasmin - tPA/urokinase - PAI-1/2 - α2-AP - α2-macroglobulin - TAFI Retrieved from http://en..org/wiki/Von_Willebrand_factor Categories: Genes on chromosome 12 | Human proteins | Hematology | Coagulation system Views Article Discussion this page History Personal tools Log in / create account Navigation Main page Contents Featured content Current events Random article Search Go Search Interaction Community portal Recent changes Contact Donate to Help Toolbox What links here Related changes Upload file Special pages Printable version Permanent link Cite this page Languages العربية Deutsch Español Français Italiano Polski Português Svenska This page was last modified on 10 July 2008, at 20:38
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