Structural investigation of the A domains of human blood coagulation factor V by molecular modeling.
Factor V (FV) is a large (2,196 amino acids) nonenzymatic cofactor in the coagulation cascade with a domain organization (A1-A2-B-A3-C1-C2) similar to the one of factor VIII (FVIII). FV is activated to factor Va (FVa) by thrombin, which cleaves away the B domain leaving a heterodimeric structure composed of a heavy chain (A1-A2) and a light chain (A3-C1-C2). Activated protein C (APC), together with its cofactor protein S (PS), inhibits the coagulation cascade via limited proteolysis of FVa and FVIIIa (APC cleaves FVa at residues R306, R506, and R679). The A domains of FV and FVIII share important sequence identity with the plasma copper-binding protein ceruloplasmin (CP). The X-ray structure of CP and theoretical models for FVIII have been recently reported. This information allowed us to build a theoretical model (994 residues) for the A domains of human FV/FVa (residues 1-656 and 1546-1883). Structural analysis of the FV model indicates that: (a) the three A domains are arranged in a triangular fashion as in the case of CP and the organization of these domains should remain essentially the same before and after activation; (b) a Type II copper ion is located at the A1-A3 interface; (c) residues R306 and R506 (cleavage sites for APC) are both solvent exposed; (d) residues 1667-1765 within the A3 domain, expected to interact with the membrane, are essentially buried; (e) APC does not bind to FVa residues 1865-1874. Several other features of factor V/Va, like the R506Q and A221V mutations; factor Xa (FXa) and human neutrophil elastase (HNE) cleavages; protein S, prothrombin and FXa binding, are also investigated.
Villoutreix
B O
BO
Lund University, The Wallenberg Laboratory, Department of Clinical Chemistry, University Hospital, Malmö, Sweden. bruno.villoutreix@klkemi.mas.lu.se
Dahlbäck
B
B
D000595:Amino Acid Sequence; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002570:Ceruloplasmin / Q000737:chemistry; D003300:Copper / Q000378:metabolism; D019281:Dimerization; D005165:Factor V / Q000737:chemistry* / Q000378:metabolism; D005169:Factor VIII / Q000737:chemistry; D015951:Factor Xa / Q000378:metabolism; D006801:Humans; D019272:Leukocyte Elastase / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011486:Protein C / Q000378:metabolism; D011487:Protein Conformation; D017293:Protein S / Q000378:metabolism; D017385:Sequence Homology; D013917:Thrombin / Q000378:metabolism
D011486:Protein C; D017293:Protein S; D003300:Copper; D005165:Factor V; D005169:Factor VIII; D002570:Ceruloplasmin; D019272:Leukocyte Elastase; D013917:Thrombin; D015951:Factor Xa; D002118:Calcium