title: Molecular reconstruction and homology modelling of the catalytic domain of the common ancestor of the haemostatic vitamin-K-dependent serine proteinases.
abstract: The vitamin-K-dependent serine proteinases of coagulation have evolved by a process of gene duplication and divergence, acquiring along the way a considerable degree of functional diversity that has equipped them for their different roles in haemostasis. The cDNA sequences encoding the catalytic domains of the early mammalian ancestors of five vitamin-K-dependent factors (factors VII, IX and X, protein C and prothrombin) were reconstructed by employing cDNA sequence data from a range of extant mammals and by using established phylogenies. The cDNA sequence of the putative common ancestor of these early mammalian proteins was then reconstructed from the five sequences by using a deduced phylogeny that was different in a number of respects from those previously proposed. Factor IX is proposed to have branched off early on, followed by protein C and prothrombin and finally factors VII and X. Significant differences in mutation rates were observed between proteins within a species; factor IX exhibited a lower mutation rate than the other proteins, consistent with its early emergence. Differences in mutation rates were also observed between species for a given protein and these exhibited an inverse correlation with generation time. A biophysically plausible structure for the ancestral vitamin-K-dependent factor protein was constructed by comparative methods. Studies of the functional architecture of this model provide new insights into the evolution of protein-binding specificity in this family of proteins.
authors.affiliation: Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff, UK. krawczak@cardiff.ac.uk
authors.forename: M
authors.initials: M
authors.lastname: Krawczak
authors.forename: A
authors.initials: A
authors.lastname: Wacey
authors.forename: D N
authors.initials: DN
authors.lastname: Cooper
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002384:Catalysis; D018076:DNA, Complementary; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010802:Phylogeny; D012689:Sequence Homology, Nucleic Acid; D012697:Serine Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014812:Vitamin K / Q000378:metabolism*
chemical_list: D018076:DNA, Complementary; D014812:Vitamin K; D012697:Serine Endopeptidases