title: Homology models of the C domains of blood coagulation factors V and VIII: a proposed membrane binding mode for FV and FVIII C2 domains.
abstract: We present homology models of the C domains of coagulation factors V (FV) and VIII (FVIII). Using a threading approach, we identified the binding domain of galactose oxidase as an appropriate template for each C domain. The C1 and C2 domains of FV associate to form an elongated cylinder of 80A long and 30A diameter. The folding unit is a beta-sandwich with a long axis of 40A and a diameter of 30A. The current model allows us to propose a membrane binding mode for the C2 domains of FV and FVIII with three major characteristics: 1) solvent-exposed hydrophobic side chains from three loops at one end of the beta-sandwich are buried in the hydrophobic layer of the outer phospholipid leaflet; 2) a crown of positively charged residues is located in the polar zone of the phospholipid head groups; and 3) the long axis of the beta-sandwich of the C2 domain is perpendicular to the plane of the membrane. This proposal satisfies experimentally observed characteristics of membrane binding for the C2 domain and the light chain of FVa.
authors.affiliation: Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Pellequer
authors.forename: A J
authors.initials: AJ
authors.lastname: Gale
authors.forename: J H
authors.initials: JH
authors.lastname: Griffin
authors.forename: E D
authors.initials: ED
authors.lastname: Getzoff
mesh_terms: D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000378:metabolism; D005165:Factor V / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005169:Factor VIII / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
chemical_list: D005165:Factor V; D005169:Factor VIII