Protein C
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Location (UCSC) | Chr 2: 127.42 – 127.43 Mb | Chr 18: 32.26 – 32.27 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
Protein C, also known as autoprothrombin IIA and blood coagulation factor XIV,
The zymogenic form of protein C is a
Research into the clinical use of a
History
Protein C's
In 1993, a heritable resistance to APC was detected by
Genetics
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.[8][16]: 2383 The nucleotide sequence that codes for human protein C is approximately 11,000 bases long.[8]: 4675
Structure and processing
Human protein C is a vitamin K-dependent glycoprotein structurally similar to other vitamin K-dependent proteins affecting blood clotting,
Inactive protein C comprises 419 amino acids in multiple
The Gla domain is particularly useful for binding to negatively charged
Post-translational modifications. Human Protein C has at least five types of post-translational modifications: (1) gamma-carboxylation on the first nine glutamic acid residues in the protein sequence. This modification event is performed by a vitamin K-dependent microsomal carboxylase. The full complement of Gla is required to give full activity to protein C. (2) beta-Hydroxylation of Asp71 in one of the two EGF-like domains to give erythro-L-beta-hydroxy-aspartate (bHA). The modification is required for functional activity as was demonstrated by mutating Asp71 to Glu. (3) N-linked glycosylation at three possible glycosylation sites. Plasma human Protein C has been reported to be 23% carbohydrate by weight. (4) Disulfide formation. (5) Multiple proteolytic cleavages of the polypeptide backbone to remove an 18 amino acid signal peptide, a 24 amino acid propeptide and then cleavages at amino acids 155-156 and 157-158 to yield the two-chain structure of the circulating zymogen.[31]
Physiology
The activation of protein C is strongly promoted by
Protein C in
Pathways
The protein C pathways are the specific chemical reactions that control the level of expression of APC and its activity in the body.
The activity of protein C may be
Anticoagulative effects
Protein C is a major component in anticoagulation in the human body. It acts as a serine protease zymogen: APC proteolyses peptide bonds in activated Factor V and Factor VIII (Factor Va and Factor VIIIa), and one of the amino acids in the bond is serine.[16]: 2381 These proteins that APC inactivates, Factor Va and Factor VIIIa, are highly procoagulant cofactors in the generation of thrombin, which is a crucial element in blood clotting; together they are part of the prothrombinase complex.[34]: 26S Cofactors in the inactivation of Factor Va and Factor VIIIa include protein S, Factor V, high-density lipoprotein, anionic phospholipids and glycosphingolipids.[9]: 3161
Factor Va binds to
APC inactivates Factor Va by making three cleavages (Arg306, Arg506, Arg679). The cleavages at both Arg306 and Arg506 diminish the molecule's attraction to Factor Xa, and though the first of these sites is slow to be cleaved, it is entirely necessary to the functioning of Factor V. Protein S aids this process by catalysing the proteolysis at Arg306, in which the A2 domain of Factor V is dissociated from the rest of the protein.[36] Protein S also binds to Factor Xa, inhibiting the latter from diminishing APC's inactivation of Factor Va.[16]: 2386
The inactivation of Factor VIIIa is not as well understood. The half-life of Factor VIIIa is only around two minutes unless Factor IXa is present to stabilise it. Some have questioned the significance of APC's inactivation of Factor VIIIa, and it is unknown to what degree Factor V and protein S are cofactors in its proteolysis. It is known that APC works on Factor VIIIa by cleaving at two sites, Arg336 and Arg562, either of which is sufficient to disable Factor VIIIa and convert it to Factor VIIIi.[16]: 2387
Cytoprotective effects
When APC is bound to EPCR, it performs a number of important cytoprotective (i.e. cell-protecting) functions, most of which are known to require EPCR and PAR-1. These include regulating gene expression, anti-inflammatory effects, antiapoptotic effects and protecting endothelial barrier function.[9]: 3162
Treatment of cells with APC demonstrates that its gene expression modulation effectively controls major pathways for inflammatory and apoptotic behaviour. There are about 20 genes that are up-regulated by protein C, and 20 genes that are down-regulated: the former are generally anti-inflammatory and antiapoptotic pathways, while the latter tend to be proinflammatory and proapoptotic. APC's mechanisms for altering gene expression profiles are not well understood, but it is believed that they at least partly involve an inhibitory effect on
APC has anti-inflammatory effects on
Scientists recognise activated protein C's antiapoptotic effects, but are unclear as to the exact mechanisms by which apoptosis is inhibited. It is known that APC is neuroprotective. Antiapoptosis is achieved with diminished activation of caspase 3 and caspase 8, improved Bax/Bcl-2 ratio and down-regulation of p53.[16]: 2388
Activated protein C also provides much protection of endothelial barrier function. Endothelial barrier breakdown, and the corresponding increase in endothelial permeability, are associated with
Several studies have indicated that the proteolytic activity of APC contributes to the observed cytoprotective properties of APC, but variants that are proteolytically inactive also are able to regulate formation of PAR-activators thrombin and factor Xa and express cytoprotective properties in vitro and in vivo.[37][38]
Role in disease
A genetic
The frequency of protein C deficiency among asymptomatic individuals is between 1 in 200 and 1 in 500. In contrast, significant symptoms of the deficiency are detectable in 1 in 20,000 individuals. No racial nor ethnic biases have been detected.[21]: 1215
At least 177 disease-causing mutations in this gene have been discovered.
Around 5% of APC resistance are not associated with the above mutation and Factor VLeiden. Other genetic mutations cause APC resistance, but none to the extent that Factor VLeiden does. These mutations include various other versions of Factor V, spontaneous generation of autoantibodies targeting Factor V, and dysfunction of any of APC's cofactors.[16]: 2387 Also, some acquired conditions may reduce the efficacy of APC in performing its anticoagulative functions.[7]: 33 Studies suggest that between 20% and 60% of thrombophilic patients suffer from some form of APC resistance.[7]: 37
Warfarin necrosis is an acquired protein C deficiency due to treatment with warfarin, which is a vitamin K antagonist and an anticoagulant itself. However, warfarin treatment may produce paradoxical skin lesions similar to those seen in purpura fulminans. A variant of this response presents as venous limb gangrene when warfarin is used to treat deep vein thrombosis associated with cancer. In these situations, warfarin may be restarted at a low dosage to ensure that the protein C deficiency does not present before the vitamin K coagulation factors II, IX and X are suppressed.[39]: 211s
Activated protein C cleaves Plasmodium falciparum histones which are released during infection: cleavage of these histones eliminates their pro inflammatory effects.[42]
Role in medicine
In November 2001, the Food and Drug Administration approved Drotrecogin alfa-activated (DrotAA) for the clinical treatment of adults suffering from severe sepsis and with a high risk of death.[43]: 1332 Drotrecogin alfa-activated is a recombinant form of human activated protein C (rhAPC). It is marketed as Xigris by Eli Lilly and Company,[27]: 224
Drotrecogin alfa-activated was the subject of significant controversy while it was approved for clinical use as it was found to increase bleeding and not to reduce mortality.[44] In October 2011 rhAPC (Xigris) was withdrawn from the market by Eli Lilly due to a higher mortality in a trial among adults.[12][44]
APC has been studied as way of treating
Ceprotin was approved for medical used in the European Union in July 2001.[46] Ceprotin is indicated in purpura fulminans and coumarin-induced skin necrosis in people with severe congenital protein C deficiency.[46]
See also
Notes
- GLA domain (residues 47–88). The N-terminus was removed in order to make crystallization of the protein easier.[47]: 5548
- ^ β: In hypereosinophilia, excess eosinophil-specific granule proteins (such as major basic protein, erythropoietin and eosinophil cationic protein) on the endothelial surface bind to thrombomodulin and inhibit its participation in the activation of protein C by electrostatic interaction on the surface of thrombomodulin.[48]: 1728
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000115718 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000024386 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ ISBN 978-0-7514-0499-9.
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- ^ a b "Ceprotin EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 29 November 2020.
- PMID 6304092.
- PMID 8386194.
External links
- The MEROPS online database for peptidases and their inhibitors: S01.218 Archived 2007-09-16 at the Wayback Machine
- Overview of all the structural information available in the PDB for UniProt: P04070 (Vitamin K-dependent protein C) at the PDBe-KB.