title: Interactions of human fibrinogens with factor XIII: roles of calcium and the gamma' peptide.
abstract: Plasma factor XIII is the zymogen of the transglutaminase factor XIIIa. This enzyme catalyzes the formation of isopeptide cross-links between fibrin molecules in nascent blood clots that greatly increase the mechanical stability of clots and their resistance to thrombolytic enzymes. We have characterized the solution interactions of factor XIII with two variants of fibrinogen, the soluble precursor of fibrin. Both the predominant fibrinogen gamma(A)/gamma(A) and the major variant gamma(A)/gamma' form complexes with a 2 fibrinogen:1 factor XIII ratio. The absence of detectable concentrations of 1:1 complexes in equilibrium mixtures containing free factor XIII and 2:1 complexes suggests that this interaction is cooperative. Factor XIII binds fibrinogen gamma(A)/gamma' approximately 20-fold more tightly than fibrinogen gamma(A)/gamma(A), and the interaction with fibrinogen gamma(A)/gamma' (but not fibrinogen gamma(A)/gamma(A)) is accompanied by a significant release of Ca(2+). Taken together, these results suggest that the strikingly anionic gamma' C-terminal sequence contains features that are important for factor XIII binding. Consistent with this notion, a synthetic 20-residue polypeptide containing the gamma' sequence was found to associate with factor XIII in a 2:1 molar ratio and act as an efficient competitor for fibrinogen gamma(A)/gamma' binding.
authors.affiliation: Department of Biochemistry and Molecular Biology, Penn State University College of Medicine, 500 University Drive, Hershey, Pennsylvania 17033, USA.
authors.forename: M
authors.initials: M
authors.lastname: Moaddel
authors.forename: D H
authors.initials: DH
authors.lastname: Farrell
authors.forename: M A
authors.initials: MA
authors.lastname: Daugherty
authors.forename: M G
authors.initials: MG
authors.lastname: Fried
mesh_terms: D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism*; D004492:Edetic Acid; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation; D005176:Factor XIII / Q000737:chemistry*; D005340:Fibrinogen / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D010446:Peptide Fragments / Q000378:metabolism; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics; D014461:Ultracentrifugation
chemical_list: D010446:Peptide Fragments; D020033:Protein Isoforms; D005340:Fibrinogen; D005176:Factor XIII; D004492:Edetic Acid; D002118:Calcium