Factor VIIIa dissociates

Stable Identifier
R-HSA-9670014
Type
Reaction [dissociation]
Species
Homo sapiens
Compartment
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Factor 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.

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