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From Proteopedia

Von Willebrand Factor is a blood multimeric glycoprotein which is synthetized by endothelials cells of the blood vessels and megakaryocytes of the bone marrow. It is found as big multimers in α-granules of platelet, in plasma, in endothelials and subendothelials cells. It is the biggest protein in the blood.

When a blood vessel is damaged , some mechanisms come into play in order to stop the bleeding. It is called hemostasis process and the Von Willebrand factor is involved into it.

Synthesis

The protein is encoded by a gene of 52 exons localized on the chromosome 12.

vWF precursor is synthetized as a very large protein in endothelium cells and megakaryocytes.

It undergoes post-translationnal events :

• Delete the signal peptide and a large propeptide
• Formation of intra and inter chains disulfide bonds
• Glycosylations

Dimers are formed in the endoplasmic reticulum (ER) thanks to disulfide bonds formation of C-terminal. These dimers create some multimers via formation N-terminal disulfide bridges between them in the Golgi apparatus.

The mature vWF is synthetized in endothelium cells. It can be immediately secreted (constitutive way) or stocked in the Weibel-Palade body (regulated way).

In the plasma it is cleaved by the processing metalloprotease ADAMTS-13 into smaller multimers. This mechanism cut the peptidyl bond between Y1,605 and M1,606 within the A2 domain of VWF. So, vWF exists as a mixture of disulfide bonded multimers with a size between 500 kDa and 10 000 kDa. This creates a size distribution.

Each multimer is composed of numerous dimers made of two identical subunits which contains several domains : D’-D3-A1-A2-A3-D4-B1-B2-B3-C1-C2.

Function

Von Willebrand factor has several functions in different phenomenon :

• Primary haemostasis : Afer a damaged of blood vessels, platelets will adhere to subendothelium which is a thrombogenic surface thanks to vWF. The platelet plug is formed thaks to the platelets aggregation. Domain A1 of vWF links to the receptor Gp-1b-IX-V, which is found on platelet.

• Coagulation = Secondary Haemostasis : The goal of this step is to create a thrombus. Numerous coagulated factors are involved during this process. The plasma procoagulant co-enzyme Factor VIII plays a central role in the coagulation : catalyses activation of factor X and stabilizes the thrombus which stop the bleeding. vWF acts as a carrier for this factor. The factor VIII is bound to two domains : D'/D3. Without vWF the factor VIII will be cleaved by serin proteases.

• Interaction with Collagen : On the one hand the A1 and A3 domains of vWF link to the collagen of the subepithelium and on the other hand it binds to the platelets thanks to Gp Ib receptor. The collagen have some residues positively charged. However some residues of the A3 domain of the vWF are negatively charged. Some studies suggests that the interaction between collagen and the A3 domains is possible thanks to these charges^[1].

• Interaction with receptor of platelet integrins αIIb/β3 by the C1 domain which contains the RGD pattern : Arg-Gly-Asp

Disease

Von Willebrand factor is directly or indirectly responsible of some diseases.

In the directly way, the von willebrand disease is caused by a mutation or by hereditary transmission. They are due to an anomaly qualitative or quantitative of the factor. There is 3 types of von Willebrand diseases^[2] : in the type I and II, the hereditary transmission is involved (there is 50% chance that the child got the defect gene). But in type III, the child receives the defect gene of the both parents. It is necessary to determine which type a patient has in order to give them the right treatment.

• Type I : It's a partial quantitative deficit. The factor works correctly but is present in insufficient quantity.
• Type II : It's a qualitative deficit. The factor is present in normal quantity but doesn’t work correctly, because of a structural anomaly. There are 4 sub-types in it:
  • IIA : The structure cann’t allow the interaction with the thrombocytes and the vessels. So the platelets are not kept together and the plugging can’t manage to stop the bleeding.
  • IIB : The fixation to the platelets is to strong so their aggregation occurs into the blood and not to the injury. The body tries to eliminate this heap and this can cause a deficiency of the platelets in the blood.
  • IIM :It's due to a weak affinity of the factor for the platelets/sub-endothelium. The anchor to the platelets is perturbed and this results in the non aggregation of platelet to the wound.
  • IIN : It's not a problem with the platelet but with the factor VIII. The von willebrand factor has a weak affinity to the factor VIII so he carries less the factor. Because of its responsibility into the stabilisation of the pre-plug, the bleeding can’t be stopped.
• Type III : It is a complete quantitative deficit. There is no synthesis of the proteine and this is accompanied with a plasma deficit in factor VIII.

In an indirectly way, the factor von willebrand serves as an intermediary. The Thrombotic Thrombocytopenic Purpura (TTP) is one example of this process. There are 2 forms of this disease : an autoimmune or medical cause. It is also found as the syndrome of Shulman-Upshaw (hereditary cause). The first is caused by an antibody which inactivates the ADAMTS13 protein. This lead to a non-cleavage of the von willebrand factor into smallest multimer. So in the blood is an unusual structure of the factor (biggest multimer) and this cause a non correct coagulation. Thrombi are formed into the circulation.

Structural highlights

Generalities

Each monomer is composed of 11 domains : D’-D3-A1-A2-A3-D4-B1-B2-B3-C1-C2^[3].

• D'/D3 : Links to factor VIII
• A1 : Links to GPIb Receptor of platelet and collagen
• A2 : Cleavage site for ADAMTS13
• A3 : Links to Collagen, type I or type III
• C1 : Links to Integrin αIIb/β3 by the RGD motif

A3 domain

A3 domain is a domain of 20kDa between the residues 920 to 1111 of the von willebrand factor. It has . This is a structure in which a central β sheet is encompassed by (named α1 to α7) connected by loops. The β sheet (yellow) is composed by 6 strands (named respectively β1 to β6) and are all parallel except the β3 which is on the sheet’s edge. In this domain, two cysteine residues (923 and 1109) put the N-terminal and C-terminal region together by a disulfide bond. The A3 domain is composed of negative charged and this allows the interaction with the collagen which has positive charged residues on it.

References

1. ↑ Huizinga et el. (1997)Crystal structure of the A3 domain of human von Willebrand factor: implications for collagen binding, http://www.cell.com/structure/fulltext/S0969-2126(97)00266-9.
2. ↑ Federation mondiale de l'Hémophilie, https://www.wfh.org/fr/page.aspx?pid=1134.
3. ↑ Purification of human von Willebrand factor–cleaving protease and its identification as a new member of the metalloproteinase family, http://www.bloodjournal.org/content/98/6/1662?sso-checked=true.

• Hans Deckmyn and Karen Vanhoorelbeke, (2006) When collagen meets VWF. Blood [[1]]
• Zaverio M. Ruggeri (2001) Structure of von Willebrand factor and its function in platelet adhesion and thrombus formation. Best Practice & Research Clinical Haematology