Factor XIII: novel structural and functional aspects

Abstract

Summary. Factor (F)XIII is a protransglutaminase that, in addition to maintaining hemostasis, has multiple plasmatic and intracellular functions. Its plasmatic form (pFXIII) is a tetramer of two potentially active A (FXIII-A) and two inhibitory/carrier B (FXIII-B) subunits, whereas its cellular form (cFXIII) is a dimer of FXIII-A. FXIII-A belongs to the family of transglutaminases (TGs), which show modest similarity in the primary structure, but a high degree of conservatism in their domain and sub-domain secondary structure. FXIII-A consists of an activation peptide, a bsandwich, a catalytic and two b-barrel domains. FXIII-B is a glycoprotein consisting of 10 repetitive sushi domains each held together by two internal disulfide bonds. The structural elements of FXIII-A involved in the interaction with FXIII-B have not been elucidated; in FXIII-B the first sushi domain seems important for complex formation. In the circulation pFXIII is bound to the fibrinogen cÕ-chain through its B subunit. In the process of pFXIII activation first thrombin cleaves off the activation peptide from FXIII-A, then in the presence of Ca 2+ FXIII-B dissociates and FXIII-A becomes transformed into an active transglutaminase (FXIIIa). The activation is highly accelerated by the presence of fibrin(ogen). cFXIII does not require proteolysis for intracellular activation. The three-dimensional structure of FXIIIa has not been resolved. Based on analogies with transglutaminase-2, a three-dimensional structure of FXIIIa was developed by molecular modeling, which shows good agreement with the drastic structural changes demonstrated by biochemical studies. The structural requirements for enzyme-substrate interaction and for transglutaminase activity are also reviewed.

Factor XIII and inflammatory cells

“…The two subunits form a tight tetrameric complex (FXIII-A 2 B 2 ) in the plasma; practically all FXIII-A is in complex, while about 50% of FXIII-B circulates in free form. A cellular dimeric form of FXIII-A (cFXIII) is also present in the cytoplasm of platelets and monocytes/macrophages [1,2].…”

“…Then, in the presence of Ca 2 + , FXIII-B dissociates and the remaining FXIII-A dimer assumes an enzymatically active configuration (FXIIIa). The activation of pFXIII occurs rapidly on the surface of fibrin, which accelerates the activation process 80-100-folds [1,2]. The activation of cFXIII in the cytoplasm occurs through a nonproteolytic mechanism and the rise of intracellular Ca 2 + concentration seems sufficient to bring about the active configuration [3][4][5].…”

“…FXIIIa, a transglutaminase (TG), catalyzes an acyl transfer reaction, resulting in ε(γ-glutamyl)lysyl cross-links between peptide chains [1,2]. The main hemostatic function of FXIIIa is to cross-link fibrin chains and covalently attach the main inhibitor of plasmin, α 2 -plasmin inhibitor (α 2 PI), to fibrin.…”

“…The activation of pFXIII occurs rapidly on the surface of fibrin, which accelerates the activation process 80-100-folds [1,2]. The activation of cFXIII in the cytoplasm occurs through a nonproteolytic mechanism and the rise of intracellular Ca 2 + concentration seems sufficient to bring about the active configuration [3][4][5].FXIIIa, a transglutaminase (TG), catalyzes an acyl transfer reaction, resulting in ε(γ-glutamyl)lysyl cross-links between peptide chains [1,2]. The main hemostatic function of FXIIIa is to cross-link fibrin chains and covalently attach the main inhibitor of plasmin, α 2 -plasmin inhibitor (α 2 PI), to fibrin.…”

(±) cis-bisamido epoxides: A novel series of potent FXIII-A inhibitors

“…Gratifyingly, all compounds showed negligible inhibition of cathepsin S at concentrations as high as 100 µM, which equates to around 10,000 fold selectivity for FXIII-A. Having established that the inhibitors show a level of selectivity for the active site of FXIII-A, we wished to determine the extent of this selectivity via comparison of the FXIII-A inhibitory activity with that shown with transglutaminase II (TGII), which is a transglutaminase with a remarkably close structural similarity to FXIII-A [17]. However, as shown in Table 1, the inhibitors also displayed similar levels of potency to TGII, in keeping with the very high structural similarities between the two enzymes.…”