Fibrin(ogen) as a cofactor for the thrombin-catalyzed activation of FXIII-A2B2. (A) Thrombin (violet) binds (red star) through exosite 1 to the central domain of one fibrin molecule (blue) and FXIII-A2B2 (gray) binds (orange star) through the B subunit to the γ′ chain (yellow) of a second fibrin molecule.9 When fibrin polymerizes, enzyme and substrate are brought together to enhance the rate of activation. (B) FXIII-A2B2 binds through the B subunit to the γ′ chains of 2 fibrinogen molecules.7 When fibrin polymerizes, thrombin binds through exosite 2 to the γ′ chain to enhance the rate of substrate cleavage. In this model, the γ′ chain also enhances the calcium-dependent activation step. (C) Thrombin binds through exosite 1 to the central domain of fibrinogen and FXIII-A2B2 binds through the B subunit to α chain residues 371-425. Either fibrinogen or fibrin monomer could serve as the cofactor in this configuration where enzyme and substrate are in close proximity on one molecule. Because kinetic analyses indicate FXIII-A2B2 activation occurs subsequent to thrombin-catalyzed cleavage of fibrinopeptide A from fibrinogen, this model suggests that substrate specificity determines the sequential appearance of fibrin and FXIIIa. Illustration by Oleg V. Gorkun, PhD.
