Protein C: Definition from Answers.com

Blood coagulation and protein C pathway

The Protein C Anticoagulant Pathway: Thrombin escaping from a site of vascular injury binds to its receptor thrombomodulin (TM) on the intact cell surface. As a result, thrombin loses its procoagulant properties and instead becomes a potent activator of protein C. Activated protein C (APC) functions as a circulating anticoagulant, which specifically degrades and inactivates the phospholipid-bound factors Va and VIIIa.^[1] This effectively down-regulates the coagulation cascade and limits clot formation to sites of vascular injury. T = Thrombin, PC= Protein C, Activated Protein C= APC, PS= Protein S (see also activated protein C resistance).

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. It should not be confused with C peptide or c-reactive protein or protein kinase C.

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]}

1 Role in disease
2 Pharmacology
3 Genetics
4 Interactions
5 See also
6 References
7 Further reading
8 External links

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)

PDB rendering based on 1aut.

Available structures

1aut, 1lqv

Identifiers

Symbols

PROC; PROC1

External IDs

OMIM: 176860 MGI: 97771 HomoloGene: 37288

Gene ontology
Molecular function	• protein C (activated) activity • calcium ion binding • peptidase activity
Cellular component	• extracellular region
Biological process	• proteolysis • blood coagulation • negative regulation of blood coagulation • negative regulation of apoptosis

RNA expression pattern

More reference expression data

Orthologs

Species

Human

Mouse

RefSeq

NM_000312 (mRNA)

XM_984063 (mRNA)

NP_000303 (protein)

XP_989157 (protein)

Location

Chr 2:
127.89 - 127.9 Mb

Chr 18:
32.27 - 32.28 Mb

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]

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. 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. 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. 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. 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. PMID 11123896.

External links

The Protein C Pathway- John H. Griffin, retired, TSRI, La Jolla, California
Diagram of The Blood Coagulation Pathway and Protein C Pathway

PDB Gallery

1aut: Human activated protein C

1lqv: Crystal structure of the Endothelial protein C receptor with phospholipid in the groove in complex with Gla domain of protein C.

Proteins: coagulation

Coagulation factors

Primary hemostasis	vWF platelet membrane glycoproteins: Ib (A, B, IX) · IIb/IIIa (IIb, IIIa) · VI

Intrinsic pathway	HMWK/Bradykinin · Prekallikrein/Kallikrein · XII "Hageman" XI · IX · VIII

Extrinsic pathway	III "Tissue factor" · VII

Common pathway	X · V · II "(Pro)thrombin" · I "Fibrin" XIII

Coagulation inhibitors

Antithrombin (inhibits II, IX, X, XI, XII) · Protein C (inhibits V, VIII)/Protein S (cofactor for protein C) · Protein Z (inhibits X) · ZPI (inhibits X, XI) · TFPI (inhibits III)

Thrombolysis/fibrinolysis

Plasmin · tPA/urokinase · PAI-1/2 · α2-AP · α2-macroglobulin · TAFI

v • d • e Protein, glycoconjugate: glycoproteins

Activin and inhibin - ADAM protein - Alpha 1-antichymotrypsin - Apolipoprotein H - CD70 - Asialoglycoprotein - Avidin - B-cell activating factor - 4-1BB ligand - Cholesterylester transfer protein - Clusterin - Colony-stimulating factor - Haemopexin - Lactoferrin - Membrane glycoproteins - Mucoprotein - Myelin protein zero - Osteonectin - Protein C - Protein S - Proteoglycan - Serum amyloid P component - Sialoglycoprotein (CD43, Glycophorin, Glycophorin C) - Thrombopoietin - Thyroglobulin - Thyroxine-binding proteins - Transcortin - Tumor necrosis factor-alpha - Uteroglobin - Vitronectin

see also enzymes, glycoproteinoses

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Protein C

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