Aj. Gale et al., Structural basis for hemophilia A caused by mutations in the C domains of blood coagulation factor VIII, THROMB HAEM, 83(1), 2000, pp. 78-85
Three dimensional homology models for the C1 and C2 domains of factor VIII
(FVIII) were generated. Each C domain formed a P-sandwich. and C1 was coval
ently connected to C2 in a head-to-head orientation. Of the >250 missense m
utations that cause FVIII deficiency and hemophilia A, 34 are in the C doma
ins. We used the FVIII C1-C2 model to infer the structural basis for the pa
thologic effects of these mutations. The mutated residues were divided into
four categories: 15 conserved buried residues that affect normal packing o
f the hydrophobic side chains, 2 non-conserved buried residues that affect
structure, 11 conserved exposed residues and 6 non-conserved exposed residu
es. The effects of all 34 missense mutations can be rationalized by predict
able disruptions of FVIII structure while at most four mutations (S2069F, T
2154I, R2209Q/G/L, and E2181D) may, affect residues directly involved in in
termolecular interactions of FVIII/VIIIa with other coagulation factors or
vWF.