User:Manon Raiffort/Sandbox: Difference between revisions

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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.

In the plasma it is cleaved by the processing metalloprotease [[ADAM|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

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 ~~diferent~~ phenomenon :

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.

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*''' 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.

* 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<ref>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.</ref>.

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

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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 : 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.

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<ref>Federation mondiale de l'Hémophilie, https://www.wfh.org/fr/page.aspx?pid=1134.</ref> : 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.

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== Structural highlights ==

===~~Generality~~ ===

===Generalities ===

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

Each monomer is composed of 11 domains : D’-D3-A1-A2-A3-D4-B1-B2-B3-C1-C2<ref>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.</ref>.

* D'/D3 : Links to factor VIII

* A1 : Links to GPIb Receptor of platelet and collagen

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=== A3 domain ===

A3 domain is a domain of 20kDa between the residues 920 to 1111 of the von willebrand factor.

It has a dinucleotide-binding fold. This is a structure in which a central β sheet is encompassed by 7 α-helix (named α1 to α7) connected by loops. The β sheet is composed by 6 strands (named respectively β1 to β6) and are all parallel except the β3 which is on the sheet’s edge.

It has <scene name='75/750301/Secondary_structure/1'> a dinucleotide-binding fold </scene>. This is a structure in which a central β sheet is encompassed by <scene name='75/750301/Alpha_helix/1'>7 α-helix</scene> (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.

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

== References ==

http://www.bloodjournal.org/content/98/6/~~1662~~.~~long~~?sso-checked=true

~~Purification~~ of ~~human~~ von Willebrand ~~factor–cleaving protease~~ and its ~~identification as a new member of the metalloproteinase family~~.

* Hans Deckmyn and Karen Vanhoorelbeke, (2006) When collagen meets VWF. Blood [[http://www.bloodjournal.org/content/bloodjournal/108/12/3628.full.pdf?sso-checked=true]]

~~Kazuo Fujikawa, Hiroshi Suzuki, Brad McMullen and Dominic Chung<references/>~~

*Zaverio M. Ruggeri (2001) Structure of von Willebrand factor and its function in platelet adhesion and thrombus formation. Best Practice & Research Clinical Haematology

@@ Line 19: / Line 19: @@
 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.
+In the plasma it is cleaved by the processing metalloprotease [[ADAM|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
+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 diferent phenomenon :
+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.
@@ Line 31: / Line 31: @@
 *''' 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.
+* 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<ref>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.</ref>.
 * Interaction with receptor of '''platelet integrins αIIb/β3 ''' by the C1 domain which contains the RGD pattern : Arg-Gly-Asp
@@ Line 40: / Line 40: @@
 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 : 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.
+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<ref>Federation mondiale de l'Hémophilie, https://www.wfh.org/fr/page.aspx?pid=1134.</ref> : 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.
@@ Line 56: / Line 56: @@
 == Structural highlights ==
-===Generality ===
+===Generalities ===
-Each monomer is composed of 11 domains : D’-D3-A1-A2-A3-D4-B1-B2-B3-C1-C2
+Each monomer is composed of 11 domains : D’-D3-A1-A2-A3-D4-B1-B2-B3-C1-C2<ref>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.</ref>.
 * D'/D3 : Links to factor VIII
 * A1 : Links to GPIb Receptor of platelet and collagen
@@ Line 66: / Line 66: @@
 === A3 domain ===
 A3 domain is a domain of 20kDa between the residues 920 to 1111 of the von willebrand factor.
-It has a dinucleotide-binding fold. This is a structure in which a central β sheet is encompassed by 7 α-helix (named α1 to α7) connected by loops. The β sheet is composed by 6 strands (named respectively β1 to β6) and are all parallel except the β3 which is on the sheet’s edge.
+It has <scene name='75/750301/Secondary_structure/1'> a dinucleotide-binding fold </scene>. This is a structure in which a central β sheet is encompassed by <scene name='75/750301/Alpha_helix/1'>7 α-helix</scene>  (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.
-This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.
 == References ==
-http://www.bloodjournal.org/content/98/6/1662.long?sso-checked=true
+<references />
-Purification of human von Willebrand factor–cleaving protease and its identification as a new member of the metalloproteinase family.
+* Hans Deckmyn and Karen Vanhoorelbeke, (2006) When collagen meets VWF. Blood [[http://www.bloodjournal.org/content/bloodjournal/108/12/3628.full.pdf?sso-checked=true]]
-Kazuo Fujikawa, Hiroshi Suzuki, Brad McMullen and Dominic Chung<references/>
+*Zaverio M. Ruggeri (2001) Structure of von Willebrand factor and its function in platelet adhesion and thrombus formation. Best Practice & Research Clinical Haematology