Sandbox Reserved 1482: Difference between revisions
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====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 <ref name="Ngo" /><ref name="El" /><ref name="uni" />. | 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" />. | ||
In the following, the structure of an engineered protein is further described. This protein has no B domain to mimic the active factor VIIIa. In addition, it is more amenable to structural studies because it shows higher stability expression levels and structural homogenity <ref name="Ngo" /><ref name="toole">Toole JJ, Pittman DD, Orr EC, Murtha P, Wasley LC & Kaufman RJ. 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. 1986 Aug; 83(16): 5939-5942. PMID: 3016730 doi https://doi.org/10.1073/pnas.83.16.5939</ref>. | |||
The three A domains are homologous to the A domains of the copper-binding protein [[Ceruloplasmin]] <ref name="wikipedia" /><ref name="El" />. 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" />. | The three A domains are homologous to the A domains of the copper-binding protein [[Ceruloplasmin]] <ref name="wikipedia" /><ref name="El" />. 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" />. | ||
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The C domains belong to the phospholipid-binding discoidin domain family <ref name="wikipedia" />. They are adjacent at the base of the triangular heterotrimer. Moreover, C<sub>1</sub> and C<sub>2</sub> domains are structurally homologous and they have the ability to bind the membrane. Indeed, both C domain protrude three β-hairpin loops with hydrophobic and basic residues in the same direction. Thanks to these loops the factor VIII might interact with the phospholipid bilayer. <ref name="Ngo" /> | The C domains belong to the phospholipid-binding discoidin domain family <ref name="wikipedia" />. They are adjacent at the base of the triangular heterotrimer. Moreover, C<sub>1</sub> and C<sub>2</sub> domains are structurally homologous and they have the ability to bind the membrane. Indeed, both C domain protrude three β-hairpin loops with hydrophobic and basic residues in the same direction. Thanks to these loops the factor VIII might interact with the phospholipid bilayer. <ref name="Ngo" /> | ||
Factor VIIIa is obtained by cleavage and release of the B domain <ref name="wikipedia" /><ref name="Ngo" /><ref name="toole" | Factor VIIIa is obtained by cleavage and release of the B domain <ref name="wikipedia" /><ref name="Ngo" /><ref name="toole" />. Although factor VIIIa can be formed from at least two cleavages involving Arg372 and Arg1689, fully active factor VIIIa is obtained only after a third cleavage at Arg740 <ref name="Ngo" />. | ||
