HOMOLOGY MODELS OF THE C-DOMAINS OF BLOOD-COAGULATION FACTOR-V AND FACTOR-VIII - A PROPOSED MEMBRANE-BINDING MODE FOR FV AND FVIII C2-DOMAINS

We present homology models of the C domains of coagulation factors V ( EV) and VIII (FVIII). Using a threading approach, we identified the bi nding domain of galactose oxidase as an appropriate template for each C domain. The C1 and C2 domains of FV associate to form an elongated c ylinder of 80 Angstrom long and 30 Angstrom diameter. The folding unit is a beta-sandwich with a long axis of 40 Angstrom and a diameter of 30 Angstrom. The current model allows us to propose a membrane binding mode for the C2 domains of FV and FVIII with three major characterist ics: 1) solvent-exposed hydrophobic side chains from three loops at on e 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) t he long axis of the beta-sandwich of the C2 domain is perpendicular to the plane of the membrane. This proposal satisfies experimentally obs erved characteristics of membrane binding for the C2 domain and the li ght chain of FVa. (C) 1998 Academic Press.