| text | Coagulation factor XII (FXII) is secreted as an inactive zymogen. During contact activation, surface-bound FXII is cleaved at the R372-V373 peptide bond, converting FXII into its active form, FXIIa (also known as αFXIIa) (Jukema BN et al., 2016; de Maat S et al., 2019). FXIIa is a heterodimer consisting of N-terminal heavy chain, FXII(20–372), and C-terminal light chain, FXII(373–615). These two chains are held together via a disulfide bond (McMullen BA & Fujikawa K, 1985; Cool DE et al., 1985). Further cleavage of FXIIa at R353 and R362 produces β-factor XII (βFXIIa), which comprises the C-terminal light chain FXII(373–615) and nine residues from the heavy chain (FXII(354–362)) (Fujikawa K & McMullen BA, 1983; Cool DE et al., 1985; Ivanov I et al., 2017). The cleavage at R353 separates the C-terminal catalytic domain from the noncatalytic surface-binding domains, thereby impairing the surface-dependent activity of FXIIa (Revak SD & Cochrane CG, 1976; Cochrane CG & Griffin JH, 1979; de Maat S et al., 2019). Despite losing surface-binding properties, βFXIIa retains enzymatic activity in solution (so-called “fluid phase"), including the ability to activate FXII, plasminogen, prekallikrein and C1 (Revak SD et al., 1977; Goldsmith GH et al., 1978; Cochrane CG & Griffin JH, 1979; Jukema BN et al., 2016; de Maat S et al., 2019). Structural studies have demonstrated that the catalytic domain of βFXIIa adopts the characteristic fold of active serine proteases (Dementiev A et al., 2018) and identified a potential exosite, which may play a critical role in mediating interactions with cofactors, substrates, and inhibitors (Dementiev A et al., 2018; Pathak M et al., 2019). |
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