Activated protein C performs these operations primarily by proteolytically inactivating proteins Factor Va and Factor VIIIa. APC is classified as a serine protease as it contains a residue of serine in its active site, in humans, protein C is encoded by the PROC gene, which is found on chromosome 2. The zymogenic form of protein C is a vitamin K-dependent glycoprotein that circulates in blood plasma and its structure is that of a two-chain polypeptide consisting of a light chain and a heavy chain connected by a disulfide bond. Because of EPCRs role, activated protein C is found primarily near endothelial cells, research into the clinical use of a recombinant form of human Activated Protein C known as Drotrecogin alfa-activated, branded Xigris by Eli Lilly and Company, has been surrounded by controversy. Eli Lilly ran a marketing campaign to promote its use for people with severe sepsis and septic shock. However, a 2011 Cochrane review found that its use cannot be recommended as it does not improve survival, in October 2011 Xigris was withdrawn from the market by Eli Lilly due to a higher mortality in a trial among adults. Protein Cs anticoagulant role in the body was first noted by Seegers et al. in 1960. Protein C was first isolated by Johan Stenflo from bovine plasma in 1976 and he named it protein C because it was the third protein that eluted from a DEAE-Sepharose ion-exchange chromotograph. Seegers was, at the time, searching for vitamin K-dependent coagulation factors undetected by clotting assays, soon after this, Seegers recognised Stenflos discovery was identical with his own. Activated protein C was discovered later that year, and in 1977 it was first recognised that APC inactivates Factor Va, in 1980, Vehar and Davie discovered that APC also inactivates Factor VIIIa, and soon after, Protein S was recognised as a cofactor by Walker. In 1982, a study by Griffin et al. First associated protein C deficiency with symptoms of venous thrombosis, homozygous protein C deficiency and the consequent serious health effects were described in 1984 by several scientists. CDNA cloning of protein C was first performed in 1984 by Beckmann et al. which produced a map of the responsible for producing protein C in the liver. In 1987 a seminal experiment was performed whereby it was demonstrated that activated protein C prevented coagulopathy, in 1993, a heritable resistance to APC was detected by Dahlbäck et al. and associated with familial thrombophilia. In 1994, the common genetic mutation that produces Factor VLeiden was noted. Two years later, Gla-domainless APC was imaged at a resolution of 2.8 Ångströms, near the end of that year, Drotrecogin alfa, a recombinant human activated protein C, became the first drug approved by the U. S. FDA for treating severe sepsis. In 2002, Science published an article that first showed protein C activates protease-activated receptor-1, the biologic instructions for synthesising protein C in humans are encoded in the gene officially named protein C. The genes symbol approved by the HUGO Gene Nomenclature Committee is PROC from protein C and it is located on the second chromosome and comprises nine exons
Domain structure of preproprotein C (top) and the mature heterodimer (bottom).
Blood coagulation and the protein C anticoagulation pathway