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Protein C

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Not to be confused withC-peptide,C-reactive protein,orprotein kinase C.
PROC
Available structures
PDBOrtholog search:PDBeRCSB
Identifiers
AliasesPROC,APC, PC, PROC1, THPH3, THPH4, protein C, inactivator of coagulation factors Va and VIIIa
External IDsOMIM:612283;MGI:97771;HomoloGene:37288;GeneCards:PROC;OMA:PROC - orthologs
Orthologs
SpeciesHumanMouse
Entrez

5624

19123

Ensembl

ENSG00000115718

ENSMUSG00000024386

UniProt

P04070

P33587

RefSeq (mRNA)

NM_000312

NM_001042767
NM_001042768
NM_008934
NM_001313938

RefSeq (protein)

NP_001036232
NP_001036233
NP_001300867
NP_032960

Location (UCSC)Chr 2: 127.42 – 127.43 MbChr 18: 32.26 – 32.27 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Protein C,also known asautoprothrombin IIAandblood coagulation factor XIV,[5]: 6822 [6]is azymogen,that is, an inactive enzyme. The activated form plays an important role in regulatinganticoagulation,inflammation,andcell deathand maintaining thepermeabilityof blood vessel walls in humans and other animals.Activated protein C(APC) performs these operations primarily byproteolyticallyinactivating proteinsFactor VaandFactor VIIIa.APC is classified as aserine proteasesince it contains aresidueofserinein itsactive site.[7]: 35 In humans, protein C is encoded by thePROCgene,which is found onchromosome 2.[8]

The zymogenic form of protein C is avitamin K-dependentglycoproteinthat circulates inblood plasma.Its structure is that of a two-chain polypeptide consisting of a light chain and a heavy chain connected by adisulfide bond.[8]: 4673 The protein C zymogen is activated when it binds tothrombin,another protein heavily involved in coagulation, and protein C's activation is greatly promoted by the presence ofthrombomodulinandendothelial 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 andleukocytes(white blood cells) that APC affects.[7]: 34 [9]: 3162 Because of the crucial role that protein C plays as ananticoagulant,those with deficiencies in protein C, or some kind ofresistance to APC,suffer from a significantly increased risk of forming dangerous blood clots (thrombosis).

Research into the clinical use of arecombinantform of human Activated Protein C (rhAPC) known asDrotrecogin alfa-activated,branded Xigris byEli Lilly and Company,has been surrounded by controversy. Eli Lilly ran an aggressive marketing campaign to promote its use for people with severesepsisand septic shock and sponsored the 2004Surviving Sepsis CampaignGuidelines.[10]However, a 2012Cochrane reviewfound that its use cannot be recommended since it does not improve survival and increases bleeding risk.[11]In October 2011, Xigris was withdrawn from the market by Eli Lilly due to a higher mortality in a trial among adults.[12]

History

[edit]

Protein C'santicoagulantrole in the human body was first noted by Seegerset al.in 1960,[13]who gave protein C its original name,autoprothrombin II-a.[5]: 6822 Protein C was first isolated byJohan Stenflofrombovineplasmain 1976, and Stenflo determined it to be avitamin K-dependent protein.[14]He named it proteinCbecause it was the third protein ( "peak C" ) thatelutedfrom aDEAE-Sepharoseion-exchange chromotograph.Seegers was, at the time, searching for vitamin K-dependent coagulation factors undetected byclotting assays,which measure global clotting function. Soon after this, Seegers recognised Stenflo's discovery was identical with his own.[5]: 6822 Activated protein C was discovered later that year,[15]and in 1977 it was first recognised that APC inactivates Factor Va.[16]: 2382 [17]In 1980, Vehar and Davie discovered that APC also inactivates Factor VIIIa,[18]and soon after,Protein Swas recognised as acofactorby Walker.[19]In 1982, a family study by Griffinet al.first associatedprotein C deficiencywith symptoms ofvenous thrombosis.[20]Homozygous protein C deficiency and the consequent serious health effects were described in 1984 by several scientists.[21]: 1214 cDNA cloning of protein C was first performed in 1984 by Beckmannet al.which produced a map of the gene responsible for producing protein C in the liver.[22]In 1987 a seminal experiment was performed (Tayloret al.) whereby it was demonstrated that activated protein C preventedcoagulopathyand death in baboonsinfusedwith lethal concentrations ofE. coli.[16]: 2382 [23]

In 1993, a heritable resistance to APC was detected byDahlbäcket al.and associated with familialthrombophilia.[24]In 1994, the relatively common genetic mutation that producesFactor VLeidenwas noted (Bertinaet al.).[25]Two years later, Gla-domainless APC was imaged at a resolution of 2.8Ångströms.[α][5]Beginning with the PROWESSclinical trialof 2001,[26]it was recognised that many of the symptoms ofsepsismay be ameliorated by infusion of APC, and mortality rates of septic patients may be significantly decreased.[9]: 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.FDAfor treating severesepsis.[27]In 2002,Sciencepublished an article that first showed protein C activatesprotease-activated receptor-1(PAR-1) and this process accounts for the protein's modulation of the immune system.[16]: 2382 [28]

Genetics

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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 theHUGO Gene Nomenclature Committeeis "PROC" from "proteinC".It is located on the secondchromosome(2q13-q14) and comprises nineexons.[8][16]: 2383 The nucleotide sequence that codes for human protein C is approximately 11,000 bases long.[8]: 4675 

Structure and processing

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Human protein C is a vitamin K-dependent glycoprotein structurally similar to other vitamin K-dependent proteins affecting blood clotting,[29]such asprothrombin,Factor VII,Factor IXandFactor X.[21]: 1215 Protein C synthesis occurs in the liver and begins with a single-chain precursor molecule: a 32 amino acidN-terminussignal peptidepreceding apropeptide.[30]: S11 Protein C is formed when adipeptideof Lys198and Arg199is removed; this causes the transformation into aheterodimerwithN-linked carbohydrates on each chain. The protein has one light chain (21kDa) and one heavy chain (41 kDa) connected by adisulfide bondbetween Cys183and Cys319.

A tube diagram representing the linear amino acid sequence of the preproprotein C (461 amino acids long) and mature heterodimer (light + heavy chains) highlighting the locations of the signal (1-32), gla (43-88), EGF-1 (97-132), EGF-2 (136–176), activation peptide (200–211), and serine protease (212–450) domains. The light (43-197) and heavy (212–461) chains of the heterodimer are joined by a line representing a disulfide bond between cysteine residues 183 and 319.
Domainstructure of preproprotein C (top) and the mature heterodimer (bottom).

Inactive protein C comprises 419 amino acids in multipledomains:[16]: 2383 oneGla domain(residues 43–88); a helicalaromaticsegment (89–96); twoepidermal growth factor (EGF)-like domains(97–132 and 136–176); an activation peptide (200–211); and atrypsin-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 azymogen,waiting to be activated.[5]: 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 theN-terminusof the heavy chain.[8]: 4673  [30]: S11 The active site contains acatalytic triadtypical of serine proteases (His253,Asp299and Ser402).[16]: 2833 

The Gla domain is particularly useful for binding to negatively chargedphospholipidsfor anticoagulation and to EPCR forcytoprotection.One particularexositeaugments protein C's ability to inactivate Factor Vaefficiently. Another is necessary for interacting with thrombomodulin.[16]: 2833 

Post-translational modifications.Human Protein C has at least five types ofpost-translational modifications:(1) gamma-carboxylationon the first nineglutamic acidresidues 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-Hydroxylationof Asp71 in one of the twoEGF-like domainsto give erythro-L-beta-hydroxy-aspartate (bHA). The modification is required for functional activity as was demonstrated by mutating Asp71 to Glu. (3) N-linkedglycosylationat three possible glycosylation sites. Plasma human Protein C has been reported to be 23% carbohydrate by weight. (4) Disulfide formation. (5) Multipleproteolytic cleavagesof the polypeptide backbone to remove an 18 amino acidsignal 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

[edit]

The activation of protein C is strongly promoted bythrombomodulinandendothelial protein C receptor(EPCR), the latter of which is found primarily onendothelial cells(cells on the inside of blood vessels). The presence of thrombomodulin accelerates activation by several orders of magnitude,[7]: 34 and EPCR speeds up activation by a factor of 20. If either of these two proteins is absent inmurinespecimens, the mouse dies from excessive blood-clotting while still in anembryonicstate.[32]: 1983 [33]: 43335 On the endothelium, APC performs a major role in regulating blood clotting, inflammation, and cell death (apoptosis).[34]: 28S Because of the accelerating effect of thrombomodulin on the activation of protein C, the protein may be said to be activated not by thrombin but the thrombin–thrombomodulin (or even thrombin–thrombomodulin–EPCR) complex.[16]: 2381 Once in active form, APC may or may not remain bound to EPCR, to which it has approximately the same affinity as the protein zymogen.[9]: 3162 

Protein C inzymogenform is present in normal adult humanblood plasmaat concentrations between 65 and 135IU/dL.Activated protein C is found at levels approximately 2000 times lower than this.[9]: 3161 Mild protein C deficiency corresponds to plasma levels above 20 IU/dL, but below the normal range. Moderately severe deficiencies describe blood concentrations between 1 and 20 IU/dL; severe deficiencies yield levels of protein C that are below 1 IU/dL or are undetectable. Protein C levels in a healthyterm infantaverage 40 IU/dL. The concentration of protein C increases until six months, when the mean level is 60 IU/dL; the level stays low through childhood until it reaches adult levels afteradolescence.[21]: 1216 Thehalf-lifeof activated protein C is around 15 minutes.[5]: 6823 

Pathways

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The protein C pathways are the specific chemical reactions that control the level of expression of APC and its activity in the body.[7]: 34 Protein C ispleiotropic,with two main classes of functions: anticoagulation and cytoprotection (its direct effect on cells). Which function protein C performs depends on whether or not APC remains bound to EPCR after it is activated; the anticoagulative effects of APC occur when it does not. In this case, protein C functions as an anticoagulant by irreversibly proteolytically inactivatingFactor VaandFactor VIIIa,turning them into Factor Viand Factor VIIIirespectively. When still bound to EPCR, activated protein C performs its cytoprotective effects, acting on theeffectorsubstratePAR-1,protease-activated receptor-1.To a degree, APC's anticoagulant properties are independent of its cytoprotective ones, in that expression of one pathway is not affected by the existence of the other.[9]: 3162 [34]: 26S 

The activity of protein C may bedown-regulatedby reducing the amount either of available thrombomodulin or of EPCR. This may be done by inflammatorycytokines,such asinterleukin-1β(IL-1β ) andtumor necrosis factor-α(TNF-α). Activated leukocytes release these inflammatory mediators during inflammation, inhibiting the creation of both thrombomodulin and EPCR, and inducing their shedding from the endothelial surface. Both of these actions down-regulate protein C activation. Thrombin itself may also have an effect on the levels of EPCR. In addition, proteins released from cells can impede protein C activation, for exampleeosinophil,which may explain thrombosis inhypereosinophilicheart disease.[β]Protein C may beup-regulatedbyplatelet factor 4.This cytokine is conjectured to improve activation of protein C by forming anelectrostatic bridgefrom protein C's Gla domain to theglycosaminoglycan(GAG) domain of thrombomodulin, reducing theMichaelis constant(KM) for their reaction.[16]: 2386 [34]: 29S In addition, Protein C is inhibited byprotein C inhibitor.[35]: 369 

Anticoagulative effects

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Schematic diagram of the blood coagulation (thrombin; left) and protein C (right) pathways. In the blood coagulation pathway, thrombin acts to convert factor Xi to XIa, VIII to VIIIa, V to Va, fibrinogen to fibrin. In addition, thrombin promotes platelet activation and aggregation via activation of protease-activated receptors on the cell membrane of the platelet. Thrombin also cross over into the protein C pathway by converting protein C into APC. APC in turn converts factor V into Vi, and VIIIa into VIIIi. Finally APC activates PAR-1 and EPCR.
Blood coagulation and the protein C anticoagulation pathway

Protein C is a major component in anticoagulation in the human body. It acts as aserine proteasezymogen:APC proteolyses peptide bonds in activatedFactor VandFactor VIII(Factor Vaand Factor VIIIa), and one of the amino acids in the bond isserine.[16]: 2381 These proteins that APC inactivates, Factor Vaand Factor VIIIa,are highly procoagulant cofactors in the generation ofthrombin,which is a crucial element in blood clotting; together they are part of theprothrombinase complex.[34]: 26S Cofactors in the inactivation of Factor Vaand Factor VIIIaincludeprotein S,Factor V,high-density lipoprotein,anionicphospholipidsandglycosphingolipids.[9]: 3161 

Factor Vabinds toprothrombinand Factor Xa,increasing the rate at which thrombin is produced by four orders of magnitude (10,000x). Inactivation of Factor Vathus practically halts the production of thrombin. Factor VIII, on the other hand, is a cofactor in production of activated Factor X, which in turn converts prothrombin into thrombin. Factor VIIIaaugments Factor X activation by a factor of around 200,000. Because of its importance in clotting, Factor VIII is also known as anti-haemophilic factor, and deficiencies of Factor VIII causehaemophilia A.[16]: 2382, 3 

APC inactivates Factor Vaby making three cleavages (Arg306,Arg506,Arg679). The cleavages at both Arg306and Arg506diminish 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 VIIIais not as well understood. The half-life of Factor VIIIais only around two minutes unless Factor IXais 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 VIIIaby cleaving at two sites, Arg336and Arg562,either of which is sufficient to disable Factor VIIIaand convert it to Factor VIIIi.[16]: 2387 

Cytoprotective effects

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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 ontranscription factoractivity.[9]: 3162, 4 Important proteins that APC up-regulates includeBcl-2,eNOSandIAP.APC effects significant down-regulation ofp53andBax.[16]: 2388 

APC has anti-inflammatory effects onendothelialcells andleukocytes.APC affects endothelial cells by inhibitinginflammatory mediator releaseand down-regulatingvascular adhesion molecules.This reduces leukocyte adhesion and infiltration into tissues, while also limiting damage to underlying tissue. APC supports endothelial barrier function and reduceschemotaxis.APC inhibits the release of inflammatory-response mediators in leukocytes as well as endothelial cells, by reducing cytokine response, and maybe diminishing systemic inflammatory response, such as is seen insepsis.Studies on both rats and humans have demonstrated that APC reducesendotoxin-induced pulmonary injury and inflammation.[9]: 3164 

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 isneuroprotective.Antiapoptosis is achieved with diminished activation ofcaspase 3andcaspase 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 withswelling,hypotensionand inflammation, all problems of sepsis. APC protects endothelial barrier function by inducing PAR-1 dependentsphingosine kinase-1activation and up-regulatingsphingosine-1-phosphatewithsphingosine kinase.[9]: 3165 

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

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A geneticprotein C deficiency,in its mild form associated withsimple heterozygosity,causes a significantly increased risk ofvenous thrombosisin adults. If a fetus ishomozygousorcompound heterozygousfor the deficiency, there may be a presentation ofpurpura fulminans,severedisseminated intravascular coagulationand simultaneousvenous thromboembolismin the womb;[21]: 1214 this is very severe and usually fatal.[39]: 211s Deletion of the protein C gene in mice causes fetal death around the time of birth. Fetal mice with no protein C develop normally at first, but experience severe bleeding,coagulopathy,deposition offibrinandnecrosisof the liver.[9]: 3161 

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.[40]Activated protein C resistanceoccurs when APC is unable to perform its functions. This disease has similar symptoms to protein C deficiency. The most common mutation leading to activated protein C resistance among Caucasians is at the cleavage site in Factor V for APC. There, Arg506is replaced with Gln, producingFactor V Leiden.This mutation is also called a R506Q.[16]: 2382 The mutation leading to the loss of this cleavage site actually stops APC from effectively inactivating both Factor Vaand Factor VIIIa.Thus, the person's blood clots too readily, and he is perpetually at an increased risk for thrombosis.[41]: 3 Individuals heterozygous for the Factor VLeidenmutation carry a risk of venous thrombosis 5–7 times higher than in the general population. Homozygous subjects have a risk 80 times higher.[7]: 40 This mutation is also the most common hereditary risk for venous thrombosis amongCaucasians.[16]: 2382 

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 VLeidendoes. These mutations include various other versions of Factor V, spontaneous generation ofautoantibodiestargeting 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 necrosisis an acquired protein C deficiency due to treatment withwarfarin,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 limbgangrenewhen 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 cleavesPlasmodium falciparumhistoneswhich are released during infection: cleavage of these histones eliminates their pro inflammatory effects.[42]

Role in medicine

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See also:drotrecogin alfa

In November 2001, theFood and Drug AdministrationapprovedDrotrecogin 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 arecombinantform of human activated protein C (rhAPC). It is marketed as Xigris byEli 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 treatinglunginjury, after studies showed that in patients with lung injury, reduced APC levels in specific parts of the lungs correlated with worse outcomes.[9]: 3167, 8 APC also has been considered for use in improving patient outcome in cases ofischemic stroke,a medical emergency in which arterial blockage deprives a region of brain of oxygen, causing tissue death. Promising studies suggest that APC could be coupled with the only currently approved treatment,tissue plasminogen activator(tPA), to protect the brain from tPA's very harmfulside effects,in addition to preventing cell death from lack of oxygen (hypoxia).[45]: 211 Clinical use of APC has also been proposed for improving the outcome ofpancreatic islet transplantationin treatingtype I diabetes.[16]: 2392 

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

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Notes

[edit]
  • ^α:GLA-domainless protein C is produced by selective proteolysis between residues 82 and 83 to remove theN-terminalportion of the protein that includes essentially all of theGLA 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 asmajor basic protein,erythropoietinandeosinophil 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

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