EzCatDB: M00212
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DB codeM00212
RLCP classification1.13.30000.10 : Hydrolysis
CATH domainDomain 12.10.25.10 : Laminin
Domain 22.10.25.10 : Laminin
Domain 32.40.10.10 : Thrombin, subunit HCatalytic domain
Domain 42.40.10.10 : Thrombin, subunit HCatalytic domain
E.C.3.4.21.69

CATH domainRelated DB codes (homologues)
2.10.25.10 : LamininM00139,M00133,M00152,M00155,M00315,M00316
2.40.10.10 : Thrombin, subunit HM00139,D00214,M00167,D00426,M00133,D00428,D00429,D00430,D00431,D00432,D00433,D00434,D00435,M00227,M00209,D00194,D00197,D00211,D00212,D00216,D00224,D00497,M00217,M00216,D00528,D00848,D00850,D00851,D00852,D00855,M00152,M00155,M00157,M00181,M00315,M00316,M00317,M00348,M00349,T00074,T00410,T00411

Enzyme Name
UniProtKBKEGG

P04070
Protein nameVitamin K-dependent protein Cprotein C (activated)
blood-coagulation factor XIVa
activated blood coagulation factor XIV
activated protein C
autoprothrombin II-A
protein Ca
APC
GSAPC
SynonymsEC 3.4.21.69
Anticoagulant protein C
Autoprothrombin IIA
Blood coagulation factor XIV
ContainsVitamin K-dependent protein C light chain
Vitamin K-dependent protein C heavy chain
Activation peptide
RefSeqNP_000303.1 (Protein)
NM_000312.3 (DNA/RNA sequence)
MEROPSS01.218 (Serine)
PfamPF00594 (Gla)
PF00089 (Trypsin)
[Graphical view]


UniProtKB:Accession NumberP04070
Entry namePROC_HUMAN
ActivityDegradation of blood coagulation factors Va and VIIIa.
SubunitSynthesized as a single chain precursor, which is cleaved into a light chain and a heavy chain held together by a disulfide bond. The enzyme is then activated by thrombin, which cleaves a tetradecapeptide from the amino end of the heavy chain, this reaction, which occurs at the surface of endothelial cells, is strongly promoted by thrombomodulin.
Subcellular location
Cofactor

Compound table: links to PDB-related databases & PoSSuM

SubstratesProductsintermediates
KEGG-idC03780C04001C00017C00001C00017C00012I00087I00085I00086
CompoundBlood coagulation Factor VaBlood coagulation Factor VIIIaProteinH2OProteinPeptidePeptidyl-tetrahedral intermediateAcyl-enzymeTetrahedral intermediate
Typepeptide/proteinpeptide/proteinpeptide/proteinH2Opeptide/proteinpeptide/protein


ChEBI


15377





PubChem


22247451
962





                 
1autL01UnboundUnboundUnbound UnboundUnboundUnboundUnboundUnbound
1autL02UnboundUnboundUnbound UnboundUnboundUnboundUnboundUnbound
1autC01UnboundUnboundUnbound UnboundUnboundUnboundUnboundTransition-state-analogue:DPN-PRO-MAI(chain P)
1autC02UnboundUnboundUnbound UnboundUnboundUnboundUnboundUnbound

Active-site residues
resource
Swiss-prot;P04070 & literature [29], [35]
pdbCatalytic residuesMain-chain involved in catalysis
          
1autL01 
 
1autL02 
 
1autC01SER 195
GLY 193;SER 195
1autC02HIS 57;ASP 102
 

References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[29]


references
[1]
PubMed ID3584108
JournalJ Biol Chem
Year1987
Volume262
Pages7105-8
AuthorsHill KA, Castellino FJ
TitleTopographical relationships between the monovalent and divalent cation binding sites of des-1-41-light chain bovine plasma protein C and des-1-41-light chain-activated bovine plasma protein C.
[2]
PubMed ID3584107
JournalJ Biol Chem
Year1987
Volume262
Pages7098-104
AuthorsHill KA, Steiner SA, Castellino FJ
Title205Tl+ as a spectroscopic probe of the monovalent cation binding sites of bovine plasma activated protein C and des-1-41-light-chain-activated protein C.
[3]
PubMed ID2839161
JournalBiochem J
Year1988
Volume251
Pages229-36
AuthorsHill KA, Steiner SA, Castellino FJ
TitleEstimation of the distance between the divalent cation binding site of des-1-41-light chain-activated bovine plasma protein C and a nitroxide spin label attached to the active-site serine residue.
[4]
PubMed ID2538457
JournalJ Biol Chem
Year1989
Volume264
Pages4743-6
AuthorsEsmon CT
TitleThe roles of protein C and thrombomodulin in the regulation of blood coagulation.
[5]
PubMed ID1939075
JournalJ Biol Chem
Year1991
Volume266
Pages20139-45
AuthorsFay PJ, Smudzin TM, Walker FJ
TitleActivated protein C-catalyzed inactivation of human factor VIII and factor VIIIa. Identification of cleavage sites and correlation of proteolysis with cofactor activity.
[6]
PubMed ID1761551
JournalJ Biol Chem
Year1991
Volume266
Pages24514-9
AuthorsMesters RM, Houghten RA, Griffin JH
TitleIdentification of a sequence of human activated protein C (residues 390-404) essential for its anticoagulant activity.
[7]
PubMed ID1657904
JournalJ Biol Chem
Year1991
Volume266
Pages19886-9
AuthorsZushi M, Gomi K, Honda G, Kondo S, Yamamoto S, Hayashi T, Suzuki K
TitleAspartic acid 349 in the fourth epidermal growth factor-like structure of human thrombomodulin plays a role in its Ca(2+)-mediated binding to protein C.
[8]
PubMed ID1317308
JournalFASEB J
Year1992
Volume6
Pages2561-7
AuthorsWalker FJ, Fay PJ
TitleRegulation of blood coagulation by the protein C system.
[9]
PubMed ID1309772
JournalJ Biol Chem
Year1992
Volume267
Pages703-6
AuthorsHogg PJ, Ohlin AK, Stenflo J
TitleIdentification of structural domains in protein C involved in its interaction with thrombin-thrombomodulin on the surface of endothelial cells.
[10]
PubMed ID1464619
JournalJ Biol Chem
Year1992
Volume267
Pages26078-84
AuthorsZhang L, Castellino FJ
TitleInfluence of specific gamma-carboxyglutamic acid residues on the integrity of the calcium-dependent conformation of human protein C.
[11]
PubMed ID8216224
JournalBiochem J
Year1993
Volume295
Pages239-45
AuthorsHermans JM, Stone SR
TitleInteraction of activated protein C with serpins.
[12]
PubMed ID8251484
JournalBiochemistry
Year1993
Volume32
Pages12656-63
AuthorsMesters RM, Heeb MJ, Griffin JH
TitleA novel exosite in the light chain of human activated protein C essential for interaction with blood coagulation factor Va.
[13]
CommentsVARIANTS TRP-38; CYS-42; HIS-42; GLN-271 AND ASN-294.
Medline ID93313192
PubMed ID8324221
JournalBlood
Year1993
Volume82
Pages159-68
AuthorsGandrille S, Alhenc-Gelas M, Gaussem P, Aillaud MF, Dupuy E, Juhan-Vague I, Aiach M
TitleFive novel mutations located in exons III and IX of the protein C gene in patients presenting with defective protein C anticoagulant activity.
Related UniProtKBP04070
[14]
PubMed ID8130392
JournalGlycobiology
Year1993
Volume3
Pages597-608
AuthorsYan SB, Chao YB, van Halbeek H
TitleNovel Asn-linked oligosaccharides terminating in GalNAc beta (1-->4)[Fuc alpha (1-->3)]GlcNAc beta (1-->.) are present in recombinant human protein C expressed in human kidney 293 cells.
[15]
CommentsNUCLEOTIDE SEQUENCE OF 43-64 FROM NUCLEIC ACID, AND VARIANT GLY-57 (YONAGO).
Medline ID93237511
PubMed ID8477066
JournalInt J Hematol
Year1993
Volume57
Pages9-14
AuthorsMimuro J, Muramatsu S, Kaneko M, Yoshitake S, Iijima K, Nakamura K, Sakata Y, Matsuda M
TitleAn abnormal protein C (protein C Yonago) with an amino acid substitution of Gly for Arg-15 caused by a single base mutation of C to G in codon 57 (CGG-->GGG). Deteriorated calcium-dependent conformation of the gamma-carboxyglutamic acid domain relevant to a thrombotic tendency.
Related UniProtKBP04070
[16]
PubMed ID8104182
JournalJ Biol Chem
Year1993
Volume268
Pages19943-8
AuthorsRezaie AR, Esmon CT
TitleConversion of glutamic acid 192 to glutamine in activated protein C changes the substrate specificity and increases reactivity toward macromolecular inhibitors.
[17]
PubMed ID8505327
JournalJ Biol Chem
Year1993
Volume268
Pages12040-5
AuthorsZhang L, Castellino FJ
TitleThe contributions of individual gamma-carboxyglutamic acid residues in the calcium-dependent binding of recombinant human protein C to acidic phospholipid vesicles.
[18]
PubMed ID8401232
JournalProtein Sci
Year1993
Volume2
Pages1482-9
AuthorsMesters RM, Heeb MJ, Griffin JH
TitleInteractions and inhibition of blood coagulation factor Va involving residues 311-325 of activated protein C.
[19]
CommentsREVIEW ON PROC VARIANTS.
Medline ID93190290
PubMed ID8446940
JournalThromb Haemost
Year1993
Volume69
Pages77-84
AuthorsReitsma PH, Poort SR, Bernardi F, Gandrille S, Long GL, Sala N, Cooper DN
TitleProtein C deficiency: a database of mutations. For the Protein C & S Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis.
Related UniProtKBP04070
[20]
PubMed ID7980464
JournalBiochem J
Year1994
Volume303
Pages929-33
AuthorsGrinnell BW, Gerlitz B, Berg DT
TitleIdentification of a region in protein C involved in thrombomodulin-stimulated activation by thrombin: potential repulsion at anion-binding site I in thrombin.
[21]
PubMed ID8043441
JournalBr J Haematol
Year1994
Volume86
Pages590-600
AuthorsMurakawa M, Okamura T, Kamura T, Kuroiwa M, Harada M, Niho Y
TitleA comparative study of partial primary structures of the catalytic region of mammalian protein C.
[22]
PubMed ID7989361
JournalJ Biol Chem
Year1994
Volume269
Pages31869-80
AuthorsKalafatis M, Rand MD, Mann KG
TitleThe mechanism of inactivation of human factor V and human factor Va by activated protein C.
[23]
PubMed ID7906267
JournalJ Biol Chem
Year1994
Volume269
Pages3151-4
AuthorsRezaie AR, Mather T, Sussman F, Esmon CT
TitleMutation of Glu-80-->Lys results in a protein C mutant that no longer requires Ca2+ for rapid activation by the thrombin-thrombomodulin complex.
[24]
PubMed ID8106403
JournalJ Biol Chem
Year1994
Volume269
Pages3590-5
AuthorsZhang L, Castellino FJ
TitleThe binding energy of human coagulation protein C to acidic phospholipid vesicles contains a major contribution from leucine 5 in the gamma-carboxyglutamic acid domain.
[25]
CommentsModel
Medline ID94272342
PubMed ID8003977
JournalProtein Sci
Year1994
Volume3
Pages588-99
AuthorsFisher CL, Greengard JS, Griffin JH
TitleModels of the serine protease domain of the human antithrombotic plasma factor activated protein C and its zymogen.
Related PDB2pct
[26]
PubMed ID7548032
JournalBiochemistry
Year1995
Volume34
Pages12775-81
AuthorsPersson E, Ezban M, Shymko RM
TitleKinetics of the interaction between the human factor VIIIa subunits: effects of pH, ionic strength, Ca2+ concentration, heparin, and activated protein C-catalyzed proteolysis.
[27]
PubMed ID7547963
JournalBiochemistry
Year1995
Volume34
Pages12221-6
AuthorsRezaie AR, Esmon CT
TitleTryptophans 231 and 234 in protein C report the Ca(2+)-dependent conformational change required for activation by the thrombin-thrombomodulin complex.
[28]
PubMed ID7673148
JournalJ Biol Chem
Year1995
Volume270
Pages21158-66
AuthorsNicolaes GA, Tans G, Thomassen MC, Hemker HC, Pabinger I, Varadi K, Schwarz HP, Rosing J
TitlePeptide bond cleavages and loss of functional activity during inactivation of factor Va and factor VaR506Q by activated protein C.
[29]
CommentsX-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 84-461.
Medline ID97157472
PubMed ID9003757
JournalEMBO J
Year1996
Volume15
Pages6822-31
AuthorsMather T, Oganessyan V, Hof P, Huber R, Foundling S, Esmon C, Bode W
TitleThe 2.8 A crystal structure of Gla-domainless activated protein C.
Related PDB1aut
Related UniProtKBP04070
[30]
PubMed ID8902996
JournalThromb Haemost
Year1996
Volume76
Pages556-60
AuthorsDe Cristofaro R
TitleEffect of thrombomodulin on the molecular recognition and early catalytic events in thrombin-protein C interaction.
[31]
PubMed ID8713779
JournalThromb Haemost
Year1996
Volume75
Pages49-55
AuthorsMori T, Takeya H, Nishioka J, Gabazza EC, Suzuki K
Titlebeta 2-Glycoprotein I modulates the anticoagulant activity of activated protein C on the phospholipid surface.
[32]
PubMed ID8815576
JournalThromb Haemost
Year1996
Volume75
Pages275-82
AuthorsNishioka J, Ido M, Hayashi T, Suzuki K
TitleThe Gla26 residue of protein C is required for the binding of protein C to thrombomodulin and endothelial cell protein C receptor, but not to protein S and factor Va.
[33]
PubMed ID9334197
JournalJ Biol Chem
Year1997
Volume272
Pages26279-84
AuthorsRegan LM, Mollica JS, Rezaie AR, Esmon CT
TitleThe interaction between the endothelial cell protein C receptor and protein C is dictated by the gamma-carboxyglutamic acid domain of protein C.
[34]
PubMed ID9300501
JournalProtein Sci
Year1997
Volume6
Pages2016-27
AuthorsEgan JO, Kalafatis M, Mann KG
TitleThe effect of Arg306-->Ala and Arg506-->Gln substitutions in the inactivation of recombinant human factor Va by activated protein C and protein S.
[35]
PubMed ID9198204
JournalThromb Haemost
Year1997
Volume78
Pages501-11
AuthorsBode W, Brandstetter H, Mather T, Stubbs MT
TitleComparative analysis of haemostatic proteinases: structural aspects of thrombin, factor Xa, factor IXa and protein C.
[36]
PubMed ID9988741
JournalJ Biol Chem
Year1999
Volume274
Pages4970-6
AuthorsHe X, Rezaie AR
TitleIdentification and characterization of the sodium-binding site of activated protein C.
[37]
PubMed ID10096438
JournalLife Sci
Year1999
Volume64
Pages879-85
AuthorsMartinez-Cruz R, Cordoba F, Mireles-Lopez JC, Zenteno E, Perez-Ortega E, Martinez M, Perez-Campos E
TitleEffects of concanavalin A on protein-C activity.
[38]
PubMed ID10223294
JournalProteins
Year1999
Volume35
Pages218-34
AuthorsKnobe KE, Berntsdotter A, Shen L, Morser J, Dahlback B, Villoutreix BO
TitleProbing the activation of protein C by the thrombin-thrombomodulin complex using structural analysis, site-directed mutagenesis, and computer modeling.
[39]
PubMed ID10456457
JournalThromb Haemost
Year1999
Volume82
Pages72-9
AuthorsShen L, Villoutreix BO, Dahlback B
TitleInvolvement of Lys 62(217) and Lys 63(218) of human anticoagulant protein C in heparin stimulation of inhibition by the protein C inhibitor.
[40]
PubMed ID10715104
JournalBiochemistry
Year2000
Volume39
Pages2853-60
AuthorsShen L, Dahlback B, Villoutreix BO
TitleTracking structural features leading to resistance of activated protein C to alpha 1-antitrypsin.
[41]
PubMed ID11106601
JournalBiophys J
Year2000
Volume79
Pages2925-43
AuthorsPerera L, Foley C, Darden TA, Stafford D, Mather T, Esmon CT, Pedersen LG
TitleModeling zymogen protein C.
[42]
PubMed ID10688829
JournalBlood
Year2000
Volume95
Pages1714-20
AuthorsO'Brien LM, Mastri M, Fay PJ
TitleRegulation of factor VIIIa by human activated protein C and protein S: inactivation of cofactor in the intrinsic factor Xase.
[43]
PubMed ID11380450
JournalBr J Haematol
Year2001
Volume113
Pages642-8
AuthorsLind B, Koefoed P, Thorsen S
TitleSymptomatic type 1 protein C deficiency caused by a de novo Ser270Leu mutation in the catalytic domain.
[44]
PubMed ID11309403
JournalJ Biol Chem
Year2001
Volume276
Pages23105-8
AuthorsFriedrich U, Nicolaes GA, Villoutreix BO, Dahlback B
TitleSecondary substrate-binding exosite in the serine protease domain of activated protein C important for cleavage at Arg-506 but not at Arg-306 in factor Va.
[45]
PubMed ID11814362
JournalBiochemistry
Year2002
Volume41
Pages1672-80
AuthorsSilveira JR, Kalafatis M, Tracy PB
TitleCarbohydrate moieties on the procofactor factor V, but not the derived cofactor factor Va, regulate its inactivation by activated protein C.
[46]
PubMed ID11994010
JournalBiochemistry
Year2002
Volume41
Pages6149-57
AuthorsYang L, Manithody C, Rezaie AR
TitleContribution of basic residues of the 70-80-loop to heparin binding and anticoagulant function of activated protein C.
[47]
PubMed ID12034704
JournalJ Biol Chem
Year2002
Volume277
Pages24851-4
AuthorsOganesyan V, Oganesyan N, Terzyan S, Qu D, Dauter Z, Esmon NL, Esmon CT
TitleThe crystal structure of the endothelial protein C receptor and a bound phospholipid.
[48]
PubMed ID12029084
JournalJ Biol Chem
Year2002
Volume277
Pages28987-95
AuthorsSchmidt AE, Padmanabhan K, Underwood MC, Bode W, Mather T, Bajaj SP
TitleThermodynamic linkage between the S1 site, the Na+ site, and the Ca2+ site in the protease domain of human activated protein C (APC). Sodium ion in the APC crystal structure is coordinated to four carbonyl groups from two separate loops.
[49]
PubMed ID12595311
JournalBlood
Year2003
Volume101
Pages4802-7
AuthorsManithody C, Fay PJ, Rezaie AR
TitleExosite-dependent regulation of factor VIIIa by activated protein C.
[50]
PubMed ID12393635
JournalBlood
Year2003
Volume101
Pages20-30
AuthorsMann KG, Kalafatis M
TitleFactor V: a combination of Dr Jekyll and Mr Hyde.
[51]
PubMed ID12446455
JournalBlood
Year2003
Volume101
Pages2277-84
AuthorsSun YH, Shen L, Dahlback B
TitleGla domain-mutated human protein C exhibiting enhanced anticoagulant activity and increased phospholipid binding.
[52]
PubMed ID12970121
JournalChest
Year2003
Volume124
Pages26S-32S
AuthorsEsmon CT
TitleThe protein C pathway.
[53]
PubMed ID12554095
JournalTrends Cardiovasc Med
Year2003
Volume13
Pages8-15
AuthorsRezaie AR
TitleExosite-dependent regulation of the protein C anticoagulant pathway.
[54]
PubMed ID15337738
JournalJ Biol Chem
Year2004
Volume279
Pages47528-35
AuthorsSun YH, Tran S, Norstrom EA, Dahlback B
TitleEnhanced rate of cleavage at Arg-306 and Arg-506 in coagulation factor Va by Gla domain-mutated human-activated protein C.
[55]
PubMed ID14660667
JournalJ Biol Chem
Year2004
Volume279
Pages6567-75
Authorsvan der Neut Kolfschoten M, Dirven RJ, Vos HL, Tans G, Rosing J, Bertina RM
TitleFactor Va is inactivated by activated protein C in the absence of cleavage sites at Arg-306, Arg-506, and Arg-679.
[56]
PubMed ID15254039
JournalJ Biol Chem
Year2004
Volume279
Pages38519-24
AuthorsYang L, Prasad S, Di Cera E, Rezaie AR
TitleThe conformation of the activation peptide of protein C is influenced by Ca2+ and Na+ binding.
[57]
PubMed ID15943976
JournalFEBS Lett
Year2005
Volume579
Pages3310-6
AuthorsDahlback B, Villoutreix BO
TitleThe anticoagulant protein C pathway.
[58]
PubMed ID16113785
JournalThromb Haemost
Year2005
Volume94
Pages60-8
AuthorsYang L, Manithody C, Rezaie AR
TitleThe functional significance of the autolysis loop in protein C and activated protein C.
[59]
PubMed ID16418283
JournalProc Natl Acad Sci U S A
Year2006
Volume103
Pages879-84
AuthorsYang L, Manithody C, Rezaie AR
TitleActivation of protein C by the thrombin-thrombomodulin complex: Cooperative roles of Arg-35 of thrombin and Arg-67 of protein C.

comments
This enzyme belongs to the peptidase family-S1.
This enzyme is composed of a light chain and a heavy chain, which a single polypeptide is cleaved into. The light chain is composed of two EGF-like domains, whereas the heavy chain has the same catalytic domain as that of trypsin (D00197 in EzCatDB).

createdupdated
2004-08-242011-02-21
Copyright: Nozomi Nagano, JST & CBRC-AIST
Funded by PRESTO/Japan Science and Technology Corporation (JST) (December 2001 - November 2004)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2006)
Funded by Grant-in-Aid for Scientific Research (B)/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (September 2005 - September 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (October 2007 - September 2010)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2011 - March 2012)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2012 - March 2013)
Supported by the commission for the Development of Artificial Gene Synthesis Technology for Creating Innovative Biomaterial from the Ministry of Economy, Trade and Industry (METI) (October 2012 - )
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