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Details on Person Factor VIII (FVIII) circulates in plasma as a heterodimer (d...

Class:IdSummation:9670020
_displayNameFactor VIII (FVIII) circulates in plasma as a heterodimer (d...
_timestamp2019-12-04 03:00:00
created[InstanceEdit:9670022] Shamovsky, Veronica, 2019-12-04
literatureReference[LiteratureReference:9661682] Biosynthesis, assembly and secretion of coagulation factor VIII
[LiteratureReference:9670024] Characterization of the interaction between the A2 subunit and A1/A3-C1-C2 dimer in human factor VIIIa
[LiteratureReference:5607045] Human factor VIIIa subunit structure. Reconstruction of factor VIIIa from the isolated A1/A3-C1-C2 dimer and A2 subunit
[LiteratureReference:9670009] Factor VIII structure and function
[LiteratureReference:9670015] Contribution of A1 subunit residue Q316 in thrombin-activated factor VIII to A2 subunit dissociation
[LiteratureReference:9670016] A1 subunit-mediated regulation of thrombin-activated factor VIII A2 subunit dissociation
[LiteratureReference:9670011] Identification of residues contributing to A2 domain-dependent structural stability in factor VIII and factor VIIIa
[LiteratureReference:9670018] Generation of enhanced stability factor VIII variants by replacement of charged residues at the A2 domain interface
[LiteratureReference:9670012] Stabilizing interactions between D666-S1787 and T657-Y1792 at the A2-A3 interface support factor VIIIa stability in the blood clotting pathway
[LiteratureReference:9670010] Modification of interdomain interfaces within the A3C1C2 subunit of factor VIII affects its stability and activity
textFactor VIII (FVIII) circulates in plasma as a heterodimer (domain structure A1-A2-B:A3-C1-C2) that requires thrombin cleavage to elicit procoagulant activity (Kaufman RJ et al. 1997). Upon activation by thrombin FVIII is converted to the labile FVIIIa, a heterotrimer of A1, A2 and A3C1C2 subunits, which serves as a cofactor for FIXa (Fay PJ 2006). At physiological concentrations, FVIIIa decays as a result of A2 subunit dissociation, which is weakly associated with the A1:A3-C1-C2 dimer by primarily electrostatic interactions (Fay PJet al. 1991; Fay PJ & Smudzin TM 1992; Parker ET et al 2006). Site-directed mutagenesis, functional and structural studies suggest that multiple residues at the A1-A2 and A2-A3 domain interfaces contribute to non-covalent interactions in stabilizing the protein (Parker ET & Lollar P 2007; Wakabayashi H & Fay PJ 2008, 2013; Wakabayashi H et al. 2008; Monaghan M et al. 2016). Retention of A2 polypeptide is required for normal stability of FVIIIa and dissociation of A2 correlates with FVIIIa inactivation and consequent loss of FXase activity.
(summation)[Reaction:9670014] Factor VIIIa dissociates [Homo sapiens]
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