Protein C
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Protein C is a protein that in humans is encoded by the PROC gene.[2][3] Protein C is a major physiological anticoagulant. It is a vitamin K-dependent serine protease enzyme (EC 3.4.21.69) that is activated by thrombin into activated protein C (APC). The activated form (with protein S and phospholipid as a cofactor) degrades Factor Va and Factor VIIIa.
The protein C pathway’s key enzyme, activated protein C, provides physiologic antithrombotic activity and exhibits both anti-inflammatory and anti-apoptotic activities.[4][5] It also plays a role in the development of thrombosis and ischemic stroke.[citation needed]
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Role in disease
Protein C deficiency is a rare genetic disorder that predisposes to venous thrombosis and habitual abortion. If homozygous, this presents with a form of disseminated intravascular coagulation in newborns termed purpura fulminans; it is treated by replacing the defective protein C.
Activated protein C resistance is the inability of protein C to cleave factors V and/or VIII. This may be hereditary or acquired. The best known and most common hereditary form is Factor V Leiden. Acquired forms occur in the presence of elevated Factor VIII concentrations.
Warfarin necrosis is acquired protein C deficiency due to treatment with the vitamin K inhibitor anticoagulant warfarin. In initial stages of action, inhibition of protein C may be stronger than inhibition of the vitamin K-dependent coagulation factors (II, VII, IX and X), leading to paradoxical activation of coagulation and necrosis of skin areas.
HDL and the effects of activated protein C (APC) on cells is very important.[6]
Pharmacology
Drotrecogin alpha (activated) is recombinant activated protein C from Eli Lilly Co, USA. It is used in the treatment of severe sepsis, septic shock and disseminated intravascular coagulation. Its use has been very controversial[7] since the results of clinical studies have been markedly varied.[8] A new clinical trial of activated protein C for severe sepsis is currently underway.[1]
Genetics
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| Protein C (inactivator of coagulation factors Va and VIIIa) | |||||||||||||
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 PDB rendering based on 1aut. |
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| Identifiers | |||||||||||||
| Symbols | PROC; PROC1 | ||||||||||||
| External IDs | OMIM: 176860 MGI: 97771 HomoloGene: 37288 GeneCards: PROC Gene | ||||||||||||
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| Orthologs | |||||||||||||
| Species | Human | Mouse | |||||||||||
| Entrez | 5624 | 19123 | |||||||||||
| Ensembl | ENSG00000115718 | ENSMUSG00000024386 | |||||||||||
| UniProt | P04070 | P33587 | |||||||||||
| RefSeq (mRNA) | NM_000312 | XM_984063 | |||||||||||
| RefSeq (protein) | NP_000303 | XP_989157 | |||||||||||
| Location (UCSC) | Chr 2: 127.89 - 127.9 Mb |
Chr 18: 32.27 - 32.28 Mb |
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| PubMed search | [1] | [2] | |||||||||||
The PROC gene is located on the second chromosome (2q13-q14).[9]
Interactions
Protein C has been shown to interact with Protein C inhibitor.[10][11]
See also
References
- ^ a b Baillie JK (November 2007). "Activated protein C: controversy and hope in the treatment of sepsis". Curr Opin Investig Drugs 8 (11): 933–8. PMID 17979027.
- ^ Foster DC, Yoshitake S, Davie EW (July 1985). "The nucleotide sequence of the gene for human protein C". Proc. Natl. Acad. Sci. U.S.A. 82 (14): 4673–7. doi:10.1073/pnas.82.14.4673. PMID 2991887.
- ^ Romeo G, Hassan HJ, Staempfli S, Roncuzzi L, Cianetti L, Leonardi A, Vicente V, Mannucci PM, Bertina R, Peschle C (May 1987). "Hereditary thrombophilia: identification of nonsense and missense mutations in the protein C gene". Proc. Natl. Acad. Sci. U.S.A. 84 (9): 2829–32. doi:10.1073/pnas.84.9.2829. PMID 2437584.
- ^ Cheng T, Liu D, Griffin JH, Fernández JA, Castellino F, Rosen ED, Fukudome K, Zlokovic BV (March 2003). "Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective". Nat. Med. 9 (3): 338–42. doi:10.1038/nm826. PMID 12563316.
- ^ Mosnier LO, Griffin JH (July 2003). "Inhibition of staurosporine-induced apoptosis of endothelial cells by activated protein C requires protease-activated receptor-1 and endothelial cell protein C receptor". Biochem. J. 373 (Pt 1): 65–70. doi:10.1042/BJ20030341. PMID 12683950.
- ^ Griffin JH, Fernández JA, Mosnier LO, Liu D, Cheng T, Guo H, Zlokovic BV (2006). "The promise of protein C". Blood Cells Mol. Dis. 36 (2): 211–6. doi:10.1016/j.bcmd.2005.12.023. PMID 16464623.
- ^ Eichacker PQ, Natanson C (March 2007). "Increasing evidence that the risks of rhAPC may outweigh its benefits". Intensive Care Med 33 (3): 396–9. doi:10.1007/s00134-007-0556-8. PMID 17325833.
- ^ Baillie JK, Murray G (January 2006). "Drotrecogin alfa (activated) in severe sepsis". N. Engl. J. Med. 354 (1): 94–6; author reply 94–6. doi:10.1056/NEJMc052759. PMID 16395834.
- ^ Rocchi M, Roncuzzi L, Santamaria R, Archidiacono N, Dente L, Romeo G (September 1986). "Mapping through somatic cell hybrids and cDNA probes of protein C to chromosome 2, factor X to chromosome 13, and alpha 1-acid glycoprotein to chromosome 9". Hum. Genet. 74 (1): 30–3. PMID 3463531.
- ^ España F, Berrettini M, Griffin JH (August 1989). "Purification and characterization of plasma protein C inhibitor". Thromb. Res. 55 (3): 369–84. doi:10.1016/0049-3848(89)90069-8. PMID 2551064.
- ^ Strandberg K, Kjellberg M, Erb EM, Persson U, Mosher DF, Villoutreix BO, Stenflo J (December 2000). "Activated protein C-protein C inhibitor complex formation: characterization of a neoepitope provides evidence for extensive insertion of the reactive center loop". Biochemistry 39 (51): 15713–20. doi:10.1021/bi001640h. PMID 11123896.
Further reading
- Mosnier LO, Zlokovic BV, Griffin JH (April 2007). "The cytoprotective protein C pathway". Blood 109 (8): 3161–72. doi:10.1182/blood-2006-09-003004. PMID 17110453. http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=17110453.
- Gruber A, Marzec UM, Bush L, Di Cera E, Fernández JA, Berny MA, Tucker EI, McCarty OJ, Griffin JH, Hanson SR (May 2007). "Relative antithrombotic and antihemostatic effects of protein C activator versus low-molecular-weight heparin in primates". Blood 109 (9): 3733–40. doi:10.1182/blood-2006-07-035147. PMID 17227834.
External links
- The MEROPS online database for peptidases and their inhibitors: S01.218
- The Protein C Pathway- John H. Griffin, retired, TSRI, La Jolla, California
- Diagram of The Blood Coagulation Pathway and Protein C Pathway
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