title: Structural basis for hemophilia A caused by mutations in the C domains of blood coagulation factor VIII.
abstract: Three dimensional homology models for the C1 and C2 domains of factor VIII (FVIII) were generated. Each C domain formed a beta-sandwich, and C1 was covalently connected to C2 in a head-to-head orientation. Of the >250 missense mutations that cause FVIII deficiency and hemophilia A, 34 are in the C domains. We used the FVIII C1-C2 model to infer the structural basis for the pathologic effects of these mutations. The mutated residues were divided into four categories: 15 conserved buried residues that affect normal packing of the hydrophobic side chains, 2 non-conserved buried residues that affect structure, 11 conserved exposed residues and 6 non-conserved exposed residues. The effects of all 34 missense mutations can be rationalized by predictable disruptions of FVIII structure while at most four mutations (S2069F, T2154I, R2209Q/G/L and E2181D) may affect residues directly involved in intermolecular interactions of FVIII/VIIIa with other coagulation factors or vWF.
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Gale
authors.forename: J L
authors.initials: JL
authors.lastname: Pellequer
authors.forename: E D
authors.initials: ED
authors.lastname: Getzoff
authors.forename: J H
authors.initials: JH
authors.lastname: Griffin
mesh_terms: D000595:Amino Acid Sequence; D005169:Factor VIII / Q000737:chemistry / Q000235:genetics*; D006467:Hemophilia A / Q000097:blood / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D011487:Protein Conformation; D016415:Sequence Alignment; D013329:Structure-Activity Relationship
chemical_list: D005169:Factor VIII