Sandbox Reserved 1482: Difference between revisions
From Proteopedia
Jump to navigationJump to search
No edit summary |
No edit summary |
||
| Line 31: | Line 31: | ||
====The coagulation process==== | ====The coagulation process==== | ||
In response to an injury, the coagulation factor VIII is separated from von Willebrand factor. The active form is called “Factor VIIIa” and is obtained by a proteolytic cleavage of the B-domain of Factor VIII by thrombin <ref name="wikipedia" /> <sup>[8,9]</sup>. Then the two remaining chains are linked together thanks to a metal link (probably calcium ion) <ref name="Ngo" /> <sup>[9]</sup>. | In response to an injury, the coagulation factor VIII is separated from von Willebrand factor. The active form is called “Factor VIIIa” and is obtained by a proteolytic cleavage of the B-domain of Factor VIII by thrombin <ref name="wikipedia" /><ref name="Ngo" /> <sup>[8,9]</sup>. Then the two remaining chains are linked together thanks to a metal link (probably calcium ion) <ref name="Ngo" /> <sup>[9]</sup>. | ||
Thus the factor VIIIa is a non-covalent dimer <ref name="Ngo" /> <sup>[9]</sup>. | Thus the factor VIIIa is a non-covalent dimer <ref name="Ngo" /> <sup>[9]</sup>. | ||
It is the catalyst for the activation reaction of the factor X (to [[Factor Xa]]) by activated [[Factor IX]]a in the presence of calcium ion and phospholipids. | It is the catalyst for the activation reaction of the factor X (to [[Factor Xa]]) by activated [[Factor IX]]a in the presence of calcium ion and phospholipids. | ||
The factor X activation reaction by factor IXa is accelerated approximately 200,000 times when factor VIII interacts with factor IXa. <ref name="wikipedia" /> <sup>[8,9,14]</sup> | The factor X activation reaction by factor IXa is accelerated approximately 200,000 times when factor VIII interacts with factor IXa. <ref name="wikipedia" /><ref name="Ngo" /> <sup>[8,9,14]</sup> | ||
Then, no longer protected by the von Willebrand factor, the factor VIIIa is proteolytically inactivated and quickly cleared from the blood stream, whereas, factor Xa becomes able (with the help of other factors) to stop the bleeding by forming a blood clot. <ref name="wikipedia" /> <sup>[8,14]</sup> | Then, no longer protected by the von Willebrand factor, the factor VIIIa is proteolytically inactivated and quickly cleared from the blood stream, whereas, factor Xa becomes able (with the help of other factors) to stop the bleeding by forming a blood clot. <ref name="wikipedia" /> <sup>[8,14]</sup> | ||
| Line 42: | Line 42: | ||
== Structure == | == Structure == | ||
====Primary Structure==== | ====Primary Structure==== | ||
In humans, factor VIII is encoded by the F8 gene <sup>[1,2,9]</sup>. This gene maps on the most distant band of the long arm of the X-chromosome (region Xq28). It is 186 kb in size (0.1 % of the whole size of the chromosome) and contains 26 exons <ref name="Antonarakis" /> <sup>[4]</sup>. | In humans, factor VIII is encoded by the F8 gene <ref name="Ngo" /> <sup>[1,2,9]</sup>. This gene maps on the most distant band of the long arm of the X-chromosome (region Xq28). It is 186 kb in size (0.1 % of the whole size of the chromosome) and contains 26 exons <ref name="Antonarakis" /> <sup>[4]</sup>. | ||
====Secondary Structure==== | ====Secondary Structure==== | ||
Factor VIII protein is composed of six globular domains: A<sub>1</sub>-A<sub>2</sub>-B-A<sub>3</sub>-C<sub>1</sub>-C<sub>2</sub> and contains one Ca<sup>2+</sup> and two Cu<sup>2+</sup> ions. It has a molecular weight of 330 kDa [1,9,14]. | Factor VIII protein is composed of six globular domains: A<sub>1</sub>-A<sub>2</sub>-B-A<sub>3</sub>-C<sub>1</sub>-C<sub>2</sub> and contains one Ca<sup>2+</sup> and two Cu<sup>2+</sup> ions. It has a molecular weight of 330 kDa <ref name="Ngo" /> [1,9,14]. | ||
The three A domains are homologous to the A domains of the copper-binding protein ceruloplasmin <ref name="wikipedia" /> <sup>[8,14]</sup>. Together, they form a triangular heterotrimer where the A<sub>1</sub> and A<sub>3</sub> domains interact with the C<sub>2</sub> and C<sub>1</sub> domains, respectively <ref name="Ngo" /> <sup>[9]</sup>. | The three A domains are homologous to the A domains of the copper-binding protein ceruloplasmin <ref name="wikipedia" /> <sup>[8,14]</sup>. Together, they form a triangular heterotrimer where the A<sub>1</sub> and A<sub>3</sub> domains interact with the C<sub>2</sub> and C<sub>1</sub> domains, respectively <ref name="Ngo" /> <sup>[9]</sup>. | ||
| Line 53: | Line 53: | ||
Factor VIIIa is obtained by cleavage and release of the B domain <ref name="wikipedia" /> <sup>[8,9,11]</sup>. Although factor VIIIa can be formed from at least two cleavages involving Arg372 and Arg1689, fully factor VIIIa is obtained by a third cleavage at Arg740 <ref name="Ngo" /> <sup>[9]</sup>. | Factor VIIIa is obtained by cleavage and release of the B domain <ref name="wikipedia" /><ref name="Ngo" /> <sup>[8,9,11]</sup>. Although factor VIIIa can be formed from at least two cleavages involving Arg372 and Arg1689, fully factor VIIIa is obtained by a third cleavage at Arg740 <ref name="Ngo" /> <sup>[9]</sup>. | ||
The two chain that result are a heavy and a light chains <sup>[2,9,14]</sup>. | The two chain that result are a heavy and a light chains <ref name="Ngo" /> <sup>[2,9,14]</sup>. | ||
| Line 63: | Line 63: | ||
Both chains are no covalently associated through to a calcium ion to form the active heterodimers <sup>[3,9]</sup>. This complex is the pro-coagulant factor VIIIa <ref name="wikipedia" /> <sup>[8]</sup>. | Both chains are no covalently associated through to a calcium ion to form the active heterodimers <ref name="Ngo" /> <sup>[3,9]</sup>. This complex is the pro-coagulant factor VIIIa <ref name="wikipedia" /> <sup>[8]</sup>. | ||
Such an association is essentialfor the functioning of the factor VIII <sup>[3]</sup>. | Such an association is essentialfor the functioning of the factor VIII <sup>[3]</sup>. | ||
