Sandbox Reserved 1482: Difference between revisions

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== Structure ==

====Primary Structure====

In humans, factor VIII is encoded by the F8 gene <ref name="Ngo" /> <ref name="~~pdb~~">UniProtKB – P00451 (FA8_HUMAN) (https://www.uniprot.org/uniprot/P00451)</ref> [1,2,9]. 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" /> [4].

In humans, factor VIII is encoded by the F8 gene <ref name="Ngo" /> <ref name="uni">UniProtKB – P00451 (FA8_HUMAN) (https://www.uniprot.org/uniprot/P00451)</ref> <ref name="pdb">Protein Database: 3CDZ. 2008 (http://www.rcsb.org/structure/3CDZ) </ref> [1,2,9]. 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" /> [4].

====Secondary Structure====

Factor VIII protein is composed of six globular domains: A1-A2-B-A3-C1-C2 and contains one Ca2+ and two Cu2+ ions. It has a molecular weight of 330 kDa <ref name="Ngo" /><ref name="El" /><ref name"~~pdb~~" /> [1,9,14].

Factor VIII protein is composed of six globular domains: A1-A2-B-A3-C1-C2 and contains one Ca2+ and two Cu2+ ions. It has a molecular weight of 330 kDa <ref name="Ngo" /><ref name="El" /><ref name="uni" /> [1,9,14].

The three A domains are homologous to the A domains of the copper-binding protein ceruloplasmin <ref name="wikipedia" /><ref name="El" /> [8,14]. Together, they form a triangular heterotrimer where the A1 and A3 domains interact with the C2 and C1 domains, respectively <ref name="Ngo" /> [9].

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Factor VIIIa is obtained by cleavage and release of the B domain <ref name="wikipedia" /><ref name="Ngo" /> [8,9,11]. 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" /> [9].

Factor VIIIa is obtained by cleavage and release of the B domain <ref name="wikipedia" /><ref name="Ngo" /><ref name="toole">Toole, J. J., Pittman, D. D., Orr, E. C., Murtha, P., Wasley, L. C., & Kaufman, R. J. (1986). A large region (approximately equal to 95 kDa) of human factor VIII is dispensable for in vitro procoagulant activity. Proceedings of the National Academy of Sciences, 83(16), 5939-5942.</ref> [8,9,11]. 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" /> [9].

The two chain that result are a heavy and a light chains <ref name="Ngo" /><ref name="El" /> [2,9,14].

The two chain that result are a heavy and a light chains <ref name="Ngo" /><ref name="El" /><ref name="pdb" /> [2,9,14].

The <scene name='80/802656/Heavy_chain/4'>heavy chain</scene> has a various size (90 or 120 kDa) <ref name="wikipedia" /> [3,8]. It consists of the A1-A2 domains <ref name="wikipedia" /><ref name="El" /> [3,8,14]. Both A1 and A2 domains are built up of two connected β barrels <ref name="Ngo" /> [9].

The <scene name='80/802656/Heavy_chain/4'>heavy chain</scene> has a various size (90 or 120 kDa) <ref name="wikipedia" /><ref name="Binhoreau">PMID: 1445279</ref> [3,8]. It consists of the A1-A2 domains <ref name="wikipedia" /><ref name="El" /><ref name="Binhoreau" /> [3,8,14]. Both A1 and A2 domains are built up of two connected β barrels <ref name="Ngo" /> [9].

The <scene name='80/802656/Light_chain/2'>light chain</scene> has a molecular weight of 80 kDa and is composed of 684 amino acids [3]. It contains two domains: a unique A domain of 371 amino acids and a duplicated C domain of 153 amino acids and 160 amino acids, respectively [3]. These domains are ranked in the following order A3-C1-C2 <ref name="wikipedia" /> [3,8]. It is composed of 42 % irregular structure, 36 % β-strands, and 22 % α-helices [3]. The C1 and C2 domains are defined by a distorted β barrel, while A3, as well as A1 and A2, is composed of two connected β barrels <ref name="Ngo" /> [9]. This chain also contains of the major binding site of von Willebrand Factor at its N-terminus [3].

The <scene name='80/802656/Light_chain/2'>light chain</scene> has a molecular weight of 80 kDa and is composed of 684 amino acids <ref name="Binhoreau" />[3]. It contains two domains: a unique A domain of 371 amino acids and a duplicated C domain of 153 amino acids and 160 amino acids, respectively <ref name="Binhoreau" />[3]. These domains are ranked in the following order A3-C1-C2 <ref name="wikipedia" /><ref name="Binhoreau" /> [3,8]. It is composed of 42 % irregular structure, 36 % β-strands, and 22 % α-helices <ref name="Binhoreau" />[3]. The C1 and C2 domains are defined by a distorted β barrel, while A3, as well as A1 and A2, is composed of two connected β barrels <ref name="Ngo" /> [9]. This chain also contains of the major binding site of von Willebrand Factor at its N-terminus <ref name="Binhoreau" />[3].

Both chains are no covalently associated through to a calcium ion to form the active heterodimers <ref name="Ngo" /> [3,9]. This complex is the pro-coagulant factor VIIIa <ref name="wikipedia" /> [8].

Both chains are no covalently associated through to a calcium ion to form the active heterodimers <ref name="Ngo" /><ref name="Binhoreau" /> [3,9]. This complex is the pro-coagulant factor VIIIa <ref name="wikipedia" /> [8].

Such an association is essentialfor the functioning of the factor VIII [3].

Such an association is essentialfor the functioning of the factor VIII <ref name="Binhoreau" />[3].

====Ligands====

Alpha-D-mannose, calcium ion (Ca2+), copper ion (Cu2+) and N-acetl-D-glucosamine are the four ligands the factor VIII is able to bind to [2].

Alpha-D-mannose, calcium ion (Ca2+), copper ion (Cu2+) and N-acetl-D-glucosamine are the four ligands the factor VIII is able to bind to <ref name="pdb" /> [2].

In factor VIII there are two copper ions and their binding sites are located internally within the <scene name='80/802656/A3cu/1'>A3</scene> and the <scene name='80/802656/A1/1'> A1 </scene> domain. In the latter, there is another ligand, a <scene name='80/802656/A1ca/1'>single calcium ion</scene>, bound to its binding site <ref name="Ngo" /> [9].

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The main medication to treat hemophilia A is concentrated factor VIII protein, called “clotting factor”. Getting this “clotting factor” is therefore a major concern for hemophilia-affected people [7].

Nowadays, recombinant coagulation factor VIII products, which are developed in a lab through the use of DNA technology <ref name="El" /> [11,14]. For instance, Toole and colleagues have created a biologically fully active factor with improved heterologous expression efficiency by deleting the B-domain from the native human factor VIII [11].

Nowadays, recombinant coagulation factor VIII products, which are developed in a lab through the use of DNA technology <ref name="El" /> <ref name="toole" /> [11,14]. For instance, Toole and colleagues have created a biologically fully active factor with improved heterologous expression efficiency by deleting the B-domain from the native human factor VIII <ref name="toole" /> [11].

@@ Line 42: / Line 42: @@
 == Structure ==
 ====Primary Structure====
-In humans, factor VIII is encoded by the F8 gene <ref name="Ngo" /> <ref name="pdb">UniProtKB – P00451 (FA8_HUMAN) (https://www.uniprot.org/uniprot/P00451)</ref> <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" /> <ref name="uni">UniProtKB – P00451 (FA8_HUMAN) (https://www.uniprot.org/uniprot/P00451)</ref> <ref name="pdb">Protein Database: 3CDZ. 2008 (http://www.rcsb.org/structure/3CDZ) </ref> <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====
-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" /><ref name="El" /><ref name"pdb" /> [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" /><ref name="El" /><ref name="uni" /> [1,9,14].
 The three A domains are homologous to the A domains of the copper-binding protein ceruloplasmin <ref name="wikipedia" /><ref name="El" /> <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" /><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>.
+Factor VIIIa is obtained by cleavage and release of the B domain <ref name="wikipedia" /><ref name="Ngo" /><ref name="toole">Toole, J. J., Pittman, D. D., Orr, E. C., Murtha, P., Wasley, L. C., & Kaufman, R. J. (1986). A large region (approximately equal to 95 kDa) of human factor VIII is dispensable for in vitro procoagulant activity. Proceedings of the National Academy of Sciences, 83(16), 5939-5942.</ref> <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 <ref name="Ngo" /><ref name="El" /> <sup>[2,9,14]</sup>.
+The two chain that result are a heavy and a light chains <ref name="Ngo" /><ref name="El" /><ref name="pdb" /> <sup>[2,9,14]</sup>.
-The <scene name='80/802656/Heavy_chain/4'>heavy chain</scene> has a various size (90 or 120 kDa) <ref name="wikipedia" /> <sup>[3,8]</sup>. It consists of the A<sub>1</sub>-A<sub>2</sub> domains <ref name="wikipedia" /><ref name="El" /> <sup>[3,8,14]</sup>. Both A<sub>1</sub> and A<sub>2</sub> domains are built up of two connected β barrels <ref name="Ngo" /> <sup>[9]</sup>.
+The <scene name='80/802656/Heavy_chain/4'>heavy chain</scene> has a various size (90 or 120 kDa) <ref name="wikipedia" /><ref name="Binhoreau">PMID: 1445279</ref> <sup>[3,8]</sup>. It consists of the A<sub>1</sub>-A<sub>2</sub> domains <ref name="wikipedia" /><ref name="El" /><ref name="Binhoreau" /> <sup>[3,8,14]</sup>. Both A<sub>1</sub> and A<sub>2</sub> domains are built up of two connected β barrels <ref name="Ngo" /> <sup>[9]</sup>.
-The <scene name='80/802656/Light_chain/2'>light chain</scene> has a molecular weight of 80 kDa and is composed of 684 amino acids <sup>[3]</sup>. It contains two domains: a unique A domain of 371 amino acids and a duplicated C domain of 153 amino acids and 160 amino acids, respectively <sup>[3]</sup>. These domains are ranked in the following order A<sub>3</sub>-C<sub>1</sub>-C<sub>2</sub> <ref name="wikipedia" /> <sup>[3,8]</sup>. It is composed of 42 % irregular structure, 36 % β-strands, and 22 % α-helices <sup>[3]</sup>. The C<sub>1</sub> and C<sub>2</sub> domains are defined by a distorted β barrel, while A<sub>3</sub>, as well as A<sub>1</sub> and A<sub>2</sub>, is composed of two connected β barrels <ref name="Ngo" /> <sup>[9]</sup>. This chain also contains of the major binding site of von Willebrand Factor at its N-terminus <sup>[3]</sup>.
+The <scene name='80/802656/Light_chain/2'>light chain</scene> has a molecular weight of 80 kDa and is composed of 684 amino acids <ref name="Binhoreau" /><sup>[3]</sup>. It contains two domains: a unique A domain of 371 amino acids and a duplicated C domain of 153 amino acids and 160 amino acids, respectively <ref name="Binhoreau" /><sup>[3]</sup>. These domains are ranked in the following order A<sub>3</sub>-C<sub>1</sub>-C<sub>2</sub> <ref name="wikipedia" /><ref name="Binhoreau" /> <sup>[3,8]</sup>. It is composed of 42 % irregular structure, 36 % β-strands, and 22 % α-helices <ref name="Binhoreau" /><sup>[3]</sup>. The C<sub>1</sub> and C<sub>2</sub> domains are defined by a distorted β barrel, while A<sub>3</sub>, as well as A<sub>1</sub> and A<sub>2</sub>, is composed of two connected β barrels <ref name="Ngo" /> <sup>[9]</sup>. This chain also contains of the major binding site of von Willebrand Factor at its N-terminus <ref name="Binhoreau" /><sup>[3]</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>.
+Both chains are no covalently associated through to a calcium ion to form the active heterodimers <ref name="Ngo" /><ref name="Binhoreau" /> <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 <ref name="Binhoreau" /><sup>[3]</sup>.
 ====Ligands====
-Alpha-D-mannose, calcium ion (Ca<sup>2+</sup>), copper ion (Cu<sup>2+</sup>) and N-acetl-D-glucosamine are the four ligands the factor VIII is able to bind to <sup>[2]</sup>.
+Alpha-D-mannose, calcium ion (Ca<sup>2+</sup>), copper ion (Cu<sup>2+</sup>) and N-acetl-D-glucosamine are the four ligands the factor VIII is able to bind to <ref name="pdb" /> <sup>[2]</sup>.
 In factor VIII there are two copper ions and their binding sites are located internally within the <scene name='80/802656/A3cu/1'>A3</scene> and the <scene name='80/802656/A1/1'> A1 </scene> domain. In the latter, there is another ligand, a <scene name='80/802656/A1ca/1'>single calcium ion</scene>, bound to its binding site <ref name="Ngo" /> <sup>[9]</sup>.
@@ Line 105: / Line 105: @@
 The main medication to treat hemophilia A is concentrated factor VIII protein, called “clotting factor”. Getting this “clotting factor” is therefore a major concern for hemophilia-affected people <sup>[7]</sup>.
-Nowadays, recombinant coagulation factor VIII products, which are developed in a lab through the use of DNA technology <ref name="El" /> <sup>[11,14]</sup>. For instance, Toole and colleagues have created a biologically fully active factor with improved heterologous expression efficiency by deleting the B-domain from the native human factor VIII <sup>[11]</sup>.
+Nowadays, recombinant coagulation factor VIII products, which are developed in a lab through the use of DNA technology <ref name="El" /> <ref name="toole" /> <sup>[11,14]</sup>. For instance, Toole and colleagues have created a biologically fully active factor with improved heterologous expression efficiency by deleting the B-domain from the native human factor VIII <ref name="toole" /> <sup>[11]</sup>.

Sandbox Reserved 1482: Difference between revisions

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