CPW Catalogue

Proteases and Zymogens

Proteases and Zymogens

All of the proteases involved in blood coagulation are trypsin-like members of the chymotrypsin family of serine proteases. They circulate as inactive zymogens, requiring cleavage of a conserved Arg15-Ile16 bond for activation of the protease domain. The new N-terminus at Ile16 becomes a tethered ligand, forming a salt-bridge with Asp 194 within a hydrophobic activation pocket. This event stabilises the substrate binding site and the oxyanion hole, conferring activity.

The zymogens and proteases in blood coagulation are mostly vitamin K factors, with N-terminal, membrane-anchoring gamma-carboxyglutamic acid (Gla) domains. These include: fVII, fIX, fX, prothrombin, protein C, and also the pseudo-protease cofactors, protein S and protein Z. With the exception of prothrombin, all of these factors are composed of an N-terminal Gla domain, two epidermal growth-factor-like (EGF) domains, and a C-terminal protease domain. Prothrombin has a Gla, two kringle domains, and a protease domain. Clotting proteases involved in contact activation (fIX, fXII, pre-kallikrein) are different with respect to domains and domain organisation, but these too possess a C-terminal chymotrypsin protease domain.

Factor X

Factor Xa

Factor IX

Factor IXa

Protein C

Factor XIa