Interactions of Human Fibrinogens with Factor XIII: Roles of Calcium and the γ‘ Peptide

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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 γA/γA and the major variant γA/γ‘ 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 γA/γ‘ ∼20-fold more tightly than fibrinogen γA/γA, and the interaction with fibrinogen γA/γ‘ (but not fibrinogen γA/γA) is accompanied by a significant release of Ca2+. Taken together, these results suggest that the strikingly anionic γ‘ C-terminal sequence contains features that are important for factor XIII binding. Consistent with this notion, a synthetic 20-residue polypeptide containing the γ‘ sequence was found to associate with factor XIII in a 2:1 molar ratio and act as an efficient competitor for fibrinogen γA/γ‘ binding.

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