Protein C is multidomain vitamin K-dependent plasma glycoprotein that belongs to the serine protease family, and it is evolutionarily derived from chymotrypsinogen . It has a modular structure, composed by an amino terminal Gla-domain (a region enriched in gamma-carboxyglutamic acid residues) shared by other vitamin K-dependent proteins, followed by a short connecting region, two discrete epidermal growth factor (EGF)-like modules, which constitute the light (L) chain, a stretch which contains the activation cleavage site, followed by the serine protease domain (heavy or H chain) with the active site amino acid triad Ser195, Asp102, His65. It is firstly secreted as a zymogen protein and furtherly activated to the mature form on the vascular endothelium. The zymogen also contains an amino-terminal leader sequence followed by a propeptide, which is cleaved upon secretion. The mature protein is composed by two chains (light
chains) linked by a disulfide bridge.
Figure 1 illustrates the domain organization of the protein:
The crystal structure of the activated Gla-domainless form of the protein C (APC) has been solved at 2.8 A resolution by Mather et al 1996
. See figure 2 below.
The light chain is constituted by two tandem EGF-like domains: of them, the N-terminal one, is modified to contain a Ca2+ binding consensus sequence and include 3 negatively charged or polar residues directly involved in calcium binding, a beta-hydroxylated (Asp113) and an aromatic residue (Phe118), which are thought to be important for calcium binding site stabilization.
The heavy chain contains a typical trypsin-like serine protease domain including two beta-barrel modules each formed by six antiparallel strands. The barrels provide a scaffold for two couples of facing loops forming the active site pocket where the triad residues are accomodated.