FXIII-A₂B₂ binding to fibrinogen residues γ390-396 promotes FXIII-A₂ B₂ activation and activity. (A) Fibrinogen is composed of 2 Aα- (purple), 2 Bβ- (teal), and 2 γ-chains (green) arranged in a trinodular structure with 2 distal D domains and a central E domain. The Aα-chains have a C-terminal domain (αC) that extends beyond the D domain. FXIII-A₂B₂ circulates bound to fibrinogen γ-chain residues 390-396 via the FXIII-B subunits. (B) Once coagulation is initiated, thrombin interacts with the fibrinogen E domain and cleaves fibrinopeptides A from the Aα-chains. As fibrin monomers polymerize, FXIII-A₂B₂ associated with γ390-396 is brought into contact with thrombin at the D:E:D interface to form a ternary complex.⁴⁰  This complex facilitates thrombin-mediated activation peptide cleavage from the FXIII-A subunits.^22-28,40  (C) Following activation peptide cleavage, fibrin promotes the calcium-mediated FXIII-B subunit dissociation from the FXIII-A subunits to yield FXIIIa.^12,22  FXIIIa then crosslinks (black line) the nearby γ-chains yielding γ-γ dimers.²⁰  This γ-chain crosslinking also promotes dissociation of FXIII-B₂ from the fibrin clot.¹²  (D) FXIIIa translocates from the γ-chain to the αC region, binding at or near α-chain residue E396,^11,44,45  and catalyzes the formation of crosslinks between fibrin α-chains and between fibrin and other plasma proteins.