Protein C

1AUT, 1LQV, 3F6U, 3JTC, 4DT7562419123ENSG00000115718ENSMUSG00000024386P04070P33587NM_000312NM_001042767NM_001042768NM_008934NM_001313938NP_000303NP_001036232NP_001036233NP_001300867NP_032960Protein C, also known as autoprothrombin IIA and blood coagulation factor XIV,:6822 is a zymogen, the activated form of which plays an important role in regulating anticoagulation, inflammation, cell death, and maintaining the permeability of blood vessel walls in humans and other animals. Activated protein C (APC) 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.:35 In humans, protein C is encoded by the PROC gene, which is found on chromosome 2.1aut: Human activated protein C1lqv: Crystal structure of the Endothelial protein C receptor with phospholipid in the groove in complex with Gla domain of protein C. Protein C, also known as autoprothrombin IIA and blood coagulation factor XIV,:6822 is a zymogen, the activated form of which plays an important role in regulating anticoagulation, inflammation, cell death, and maintaining the permeability of blood vessel walls in humans and other animals. Activated protein C (APC) 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.:35 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. Its structure is that of a two-chain polypeptide consisting of a light chain and a heavy chain connected by a disulfide bond.:4673 The protein C zymogen is activated when it binds to thrombin, another protein heavily involved in coagulation, and protein C's activation is greatly promoted by the presence of thrombomodulin and endothelial protein C receptors (EPCRs). Because of EPCR's role, activated protein C is found primarily near endothelial cells (i.e., those that make up the walls of blood vessels), and it is these cells and leukocytes (white blood cells) that APC affects.:34:3162 Because of the crucial role that protein C plays as an anticoagulant, those with deficiencies in protein C, or some kind of resistance to APC, suffer from a significantly increased risk of forming dangerous blood clots (thrombosis). Research into the clinical use of a recombinant form of human Activated Protein C (rhAPC) known as Drotrecogin alfa-activated, branded Xigris by Eli Lilly and Company, has been surrounded by controversy. Eli Lilly ran an aggressive marketing campaign to promote its use for people with severe sepsis and septic shock, and sponsored the 2004Surviving Sepsis Campaign Guidelines. However, a 2012 Cochrane review found that its use cannot be recommended as it does not improve survival and increases bleeding risk. In October 2011 Xigris was withdrawn from the market by Eli Lilly due to a higher mortality in a trial among adults. Protein C's anticoagulant role in the human body was first noted by Seegers et al. in 1960, who gave protein C its original name, autoprothrombin II-a.:6822 Protein C was first isolated by Johan Stenflo from bovine plasma in 1976, and Stenflo determined it to be a vitamin K-dependent protein. He named it protein C because it was the third protein ('peak C') 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, which measure global clotting function. Soon after this, Seegers recognised Stenflo's discovery was identical with his own.:6822 Activated protein C was discovered later that year, and in 1977 it was first recognised that APC inactivates Factor Va.:2382 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 family 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.:1214 cDNA cloning of protein C was first performed in 1984 by Beckmann et al. which produced a map of the gene responsible for producing protein C in the liver. In 1987 a seminal experiment was performed (Taylor et al.) whereby it was demonstrated that activated protein C prevented coagulopathy and death in baboons infused with lethal concentrations of E. coli.:2382 In 1993, a heritable resistance to APC was detected by Dahlbäck et al. and associated with familial thrombophilia. In 1994, the relatively common genetic mutation that produces Factor VLeiden was noted (Bertina et al.). Two years later, Gla-domainless APC was imaged at a resolution of 2.8 Ångströms.α Beginning with the PROWESS clinical trial of 2001, it was recognised that many of the symptoms of sepsis may be ameliorated by infusion of APC, and mortality rates of septic patients may be significantly decreased.:3161,6 Near the end of that year, Drotrecogin alfa (activated), 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 (PAR-1) and this process accounts for the protein's modulation of the immune system.:2382 The biologic instructions for synthesising protein C in humans are encoded in the gene officially named 'protein C (inactivator of coagulation factors Va and VIIIa)'. The gene's symbol approved by the HUGO Gene Nomenclature Committee is 'PROC' from 'protein C'. It is located on the second chromosome (2q13-q14) and comprises nine exons.:2383 The nucleotide sequence that codes for human protein C is approximately 11,000 bases long.:4675 Human protein C is a vitamin K-dependent glycoprotein structurally similar to other vitamin K-dependent proteins affecting blood clotting, such as prothrombin, Factor VII, Factor IX and Factor X.:1215 Protein C synthesis occurs in the liver and begins with a single-chain precursor molecule: a 32 amino acid N-terminus signal peptide preceding a propeptide.:S11 Protein C is formed when a dipeptide of Lys198 and Arg199 is removed; this causes the transformation into a heterodimer with N-linked carbohydrates on each chain. The protein has one light chain (21 kDa) and one heavy chain (41 kDa) connected by a disulfide bond between Cys183 and Cys319. Inactive protein C comprises 419 amino acids in multiple domains::2383 one Gla domain (residues 43–88); a helical aromatic segment (89–96); two epidermal growth factor (EGF)-like domains (97–132 and 136–176); an activation peptide (200–211); and a trypsin-like serine protease domain (212–450). The light chain contains the Gla- and EGF-like domains and the aromatic segment. The heavy chain contains the protease domain and the activation petide. It is in this form that 85–90% of protein C circulates in the plasma as a zymogen, waiting to be activated.:6822 The remaining protein C zymogen comprises slightly modified forms of the protein. Activation of the enzyme occurs when a thrombin molecule cleaves away the activation peptide from the N-terminus of the heavy chain.:4673:S11 The active site contains a catalytic triad typical of serine proteases (His253, Asp299 and Ser402).:2833 The Gla domain is particularly useful for binding to negatively charged phospholipids for anticoagulation and to EPCR for cytoprotection. One particular exosite augments protein C's ability to inactivate Factor Va efficiently. Another is necessary for interacting with thrombomodulin.:2833