Schematic diagram of a mechanism for regulating FXII activation. The image at the upper left proposes a model for FXII in a closed conformation (in solution) in which the KNG domain binds to lysine/arginine residues elsewhere in the heavy chain through an Asp-X-Asp/Glu lysine-binding motif (represented by the white triangle). In the diagram, the interaction is with residues in the N-terminal FN2 domain; however, the binding site(s) could reside elsewhere in the heavy chain. In the closed conformation, access to the FXII activation cleavage site (the Arg³⁵³-Val³⁵⁴ peptide bond, represented by the black circle) is limited, probably through steric interference by an unknown part of the heavy chain. The model was created after consideration of similarities between properties of FXII and the fibrinolytic protease plasminogen. The image at the upper right is a model for Glu-plasminogen based on reported crystal structures.^39,40  In unbound Glu-plasminogen, lysine and arginine residues in the N-terminal PAN domain bind to lysine-binding motifs on KNG (K) 4 and K-5. The lysine-binding site on K-2 interacts with the protease domain, while the site on K-1 is unbound. In this closed conformation, the activation cleavage site (Arg⁵⁶¹-Val⁵⁶² peptide bond) is masked by the linker between K-3 and K-4 (highlighted in red), rendering the protein relatively resistant to activation by tissue plasminogen activator and urokinase. Plasminogen binding to fibrin (center) is initiated by docking of K-1 to lysine residues on fibrin. Ultimately, lysine-binding sites on K-2, K-4, and K-5 also engage basic residues on fibrin, resulting in an open conformation with an accessible activation cleavage site (indicated by scissors). The lysine-binding interactions between the PAN domain and K-4 and K-5 in the closed conformation are disrupted by binding to fibrin. A similar process may occur when FXII binds to a negatively charged surface. Here, surface binding is through EGF1 and possibly the FN1 domain. The lysine-binding interaction involving KNG is disrupted, exposing the activation cleavage site (indicated by scissors).