Vitamin K-dependent protein C

Details

Name
Vitamin K-dependent protein C
Synonyms
  • 3.4.21.69
  • Anticoagulant protein C
  • Autoprothrombin IIA
  • Blood coagulation factor XIV
Gene Name
PROC
Organism
Humans
Amino acid sequence
>lcl|BSEQ0000757|Vitamin K-dependent protein C
MWQLTSLLLFVATWGISGTPAPLDSVFSSSERAHQVLRIRKRANSFLEELRHSSLERECI
EEICDFEEAKEIFQNVDDTLAFWSKHVDGDQCLVLPLEHPCASLCCGHGTCIDGIGSFSC
DCRSGWEGRFCQREVSFLNCSLDNGGCTHYCLEEVGWRRCSCAPGYKLGDDLLQCHPAVK
FPCGRPWKRMEKKRSHLKRDTEDQEDQVDPRLIDGKMTRRGDSPWQVVLLDSKKKLACGA
VLIHPSWVLTAAHCMDESKKLLVRLGEYDLRRWEKWELDLDIKEVFVHPNYSKSTTDNDI
ALLHLAQPATLSQTIVPICLPDSGLAERELNQAGQETLVTGWGYHSSREKEAKRNRTFVL
NFIKIPVVPHNECSEVMSNMVSENMLCAGILGDRQDACEGDSGGPMVASFHGTWFLVGLV
SWGEGCGLLHNYGVYTKVSRYLDWIHGHIRDKEAPQKSWAP
Number of residues
461
Molecular Weight
52070.82
Theoretical pI
6.23
GO Classification
Functions
calcium ion binding / serine-type endopeptidase activity
Processes
blood coagulation / cellular protein metabolic process / leukocyte migration / negative regulation of apoptotic process / negative regulation of blood coagulation / negative regulation of coagulation / negative regulation of inflammatory response / peptidyl-glutamic acid carboxylation / positive regulation of establishment of endothelial barrier / post-translational protein modification / proteolysis
Components
endoplasmic reticulum / endoplasmic reticulum lumen / extracellular region / extracellular space / Golgi apparatus / Golgi lumen
General Function
Serine-type endopeptidase activity
Specific Function
Protein C is a vitamin K-dependent serine protease that regulates blood coagulation by inactivating factors Va and VIIIa in the presence of calcium ions and phospholipids (PubMed:25618265). Exerts a protective effect on the endothelial cell barrier function (PubMed:25651845).
Pfam Domain Function
Transmembrane Regions
Not Available
Cellular Location
Secreted
Gene sequence
>lcl|BSEQ0020458|Vitamin K-dependent protein C (PROC)
ATGTGGCAGCTCACAAGCCTCCTGCTGTTCGTGGCCACCTGGGGAATTTCCGGCACACCA
GCTCCTCTTGACTCAGTGTTCTCCAGCAGCGAGCGTGCCCACCAGGTGCTGCGGATCCGC
AAACGTGCCAACTCCTTCCTGGAGGAGCTCCGTCACAGCAGCCTGGAGCGGGAGTGCATA
GAGGAGATCTGTGACTTCGAGGAGGCCAAGGAAATTTTCCAAAATGTGGATGACACACTG
GCCTTCTGGTCCAAGCACGTCGACGGTGACCAGTGCTTGGTCTTGCCCTTGGAGCACCCG
TGCGCCAGCCTGTGCTGCGGGCACGGCACGTGCATCGACGGCATCGGCAGCTTCAGCTGC
GACTGCCGCAGCGGCTGGGAGGGCCGCTTCTGCCAGCGCGAGGTGAGCTTCCTCAATTGC
TCGCTGGACAACGGCGGCTGCACGCATTACTGCCTAGAGGAGGTGGGCTGGCGGCGCTGT
AGCTGTGCGCCTGGCTACAAGCTGGGGGACGACCTCCTGCAGTGTCACCCCGCAGTGAAG
TTCCCTTGTGGGAGGCCCTGGAAGCGGATGGAGAAGAAGCGCAGTCACCTGAAACGAGAC
ACAGAAGACCAAGAAGACCAAGTAGATCCGCGGCTCATTGATGGGAAGATGACCAGGCGG
GGAGACAGCCCCTGGCAGGTGGTCCTGCTGGACTCAAAGAAGAAGCTGGCCTGCGGGGCA
GTGCTCATCCACCCCTCCTGGGTGCTGACAGCGGCCCACTGCATGGATGAGTCCAAGAAG
CTCCTTGTCAGGCTTGGAGAGTATGACCTGCGGCGCTGGGAGAAGTGGGAGCTGGACCTG
GACATCAAGGAGGTCTTCGTCCACCCCAACTACAGCAAGAGCACCACCGACAATGACATC
GCACTGCTGCACCTGGCCCAGCCCGCCACCCTCTCGCAGACCATAGTGCCCATCTGCCTC
CCGGACAGCGGCCTTGCAGAGCGCGAGCTCAATCAGGCCGGCCAGGAGACCCTCGTGACG
GGCTGGGGCTACCACAGCAGCCGAGAGAAGGAGGCCAAGAGAAACCGCACCTTCGTCCTC
AACTTCATCAAGATTCCCGTGGTCCCGCACAATGAGTGCAGCGAGGTCATGAGCAACATG
GTGTCTGAGAACATGCTGTGTGCGGGCATCCTCGGGGACCGGCAGGATGCCTGCGAGGGC
GACAGTGGGGGGCCCATGGTCGCCTCCTTCCACGGCACCTGGTTCCTGGTGGGCCTGGTG
AGCTGGGGTGAGGGCTGTGGGCTCCTTCACAACTACGGCGTTTACACCAAAGTCAGCCGC
TACCTCGACTGGATCCATGGGCACATCAGAGACAAGGAAGCCCCCCAGAAGAGCTGGGCA
CCTTAG
Chromosome Location
2
Locus
2q13-q14
External Identifiers
ResourceLink
UniProtKB IDP04070
UniProtKB Entry NamePROC_HUMAN
GenBank Protein ID190334
GenBank Gene IDM11228
GenAtlas IDPROC
HGNC IDHGNC:9451
General References
  1. Beckmann RJ, Schmidt RJ, Santerre RF, Plutzky J, Crabtree GR, Long GL: The structure and evolution of a 461 amino acid human protein C precursor and its messenger RNA, based upon the DNA sequence of cloned human liver cDNAs. Nucleic Acids Res. 1985 Jul 25;13(14):5233-47. [Article]
  2. Foster DC, Yoshitake S, Davie EW: The nucleotide sequence of the gene for human protein C. Proc Natl Acad Sci U S A. 1985 Jul;82(14):4673-7. [Article]
  3. Plutzky J, Hoskins JA, Long GL, Crabtree GR: Evolution and organization of the human protein C gene. Proc Natl Acad Sci U S A. 1986 Feb;83(3):546-50. [Article]
  4. Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. Epub 2003 Dec 21. [Article]
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  7. Miyata T, Zheng YZ, Sakata T, Kato H: Protein C Osaka 10 with aberrant propeptide processing: loss of anticoagulant activity due to an amino acid substitution in the protein C precursor. Thromb Haemost. 1995 Oct;74(4):1003-8. [Article]
  8. Mimuro J, Muramatsu S, Kaneko M, Yoshitake S, Iijima K, Nakamura K, Sakata Y, Matsuda M: An 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. Int J Hematol. 1993 Jan;57(1):9-14. [Article]
  9. Foster D, Davie EW: Characterization of a cDNA coding for human protein C. Proc Natl Acad Sci U S A. 1984 Aug;81(15):4766-70. [Article]
  10. Long GL, Tomczak JA, Rainville IR, Dreyfus M, Schramm W, Schwarz HP: Homozygous type I protein C deficiency in two unrelated families exhibiting thrombophilia related to Ala136-->Pro or Arg286-->His mutations. Thromb Haemost. 1994 Oct;72(4):526-33. [Article]
  11. Miletich JP, Broze GJ Jr: Beta protein C is not glycosylated at asparagine 329. The rate of translation may influence the frequency of usage at asparagine-X-cysteine sites. J Biol Chem. 1990 Jul 5;265(19):11397-404. [Article]
  12. Harris RJ, Ling VT, Spellman MW: O-linked fucose is present in the first epidermal growth factor domain of factor XII but not protein C. J Biol Chem. 1992 Mar 15;267(8):5102-7. [Article]
  13. Liu T, Qian WJ, Gritsenko MA, Camp DG 2nd, Monroe ME, Moore RJ, Smith RD: Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry. J Proteome Res. 2005 Nov-Dec;4(6):2070-80. [Article]
  14. Halim A, Nilsson J, Ruetschi U, Hesse C, Larson G: Human urinary glycoproteomics; attachment site specific analysis of N- and O-linked glycosylations by CID and ECD. Mol Cell Proteomics. 2012 Apr;11(4):M111.013649. doi: 10.1074/mcp.M111.013649. Epub 2011 Dec 14. [Article]
  15. Bian Y, Song C, Cheng K, Dong M, Wang F, Huang J, Sun D, Wang L, Ye M, Zou H: An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J Proteomics. 2014 Jan 16;96:253-62. doi: 10.1016/j.jprot.2013.11.014. Epub 2013 Nov 22. [Article]
  16. Tagliabracci VS, Wiley SE, Guo X, Kinch LN, Durrant E, Wen J, Xiao J, Cui J, Nguyen KB, Engel JL, Coon JJ, Grishin N, Pinna LA, Pagliarini DJ, Dixon JE: A Single Kinase Generates the Majority of the Secreted Phosphoproteome. Cell. 2015 Jun 18;161(7):1619-32. doi: 10.1016/j.cell.2015.05.028. [Article]
  17. Fisher CL, Greengard JS, Griffin JH: Models of the serine protease domain of the human antithrombotic plasma factor activated protein C and its zymogen. Protein Sci. 1994 Apr;3(4):588-99. [Article]
  18. Mather T, Oganessyan V, Hof P, Huber R, Foundling S, Esmon C, Bode W: The 2.8 A crystal structure of Gla-domainless activated protein C. EMBO J. 1996 Dec 16;15(24):6822-31. [Article]
  19. Reitsma PH, Poort SR, Bernardi F, Gandrille S, Long GL, Sala N, Cooper DN: Protein 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. Thromb Haemost. 1993 Jan 11;69(1):77-84. [Article]
  20. Romeo G, Hassan HJ, Staempfli S, Roncuzzi L, Cianetti L, Leonardi A, Vicente V, Mannucci PM, Bertina R, Peschle C, et al.: Hereditary thrombophilia: identification of nonsense and missense mutations in the protein C gene. Proc Natl Acad Sci U S A. 1987 May;84(9):2829-32. [Article]
  21. Grundy C, Chitolie A, Talbot S, Bevan D, Kakkar V, Cooper DN: Protein C London 1: recurrent mutation at Arg 169 (CGG----TGG) in the protein C gene causing thrombosis. Nucleic Acids Res. 1989 Dec 25;17(24):10513. [Article]
  22. Reitsma PH, Poort SR, Allaart CF, Briet E, Bertina RM: The spectrum of genetic defects in a panel of 40 Dutch families with symptomatic protein C deficiency type I: heterogeneity and founder effects. Blood. 1991 Aug 15;78(4):890-4. [Article]
  23. Bovill EG, Tomczak JA, Grant B, Bhushan F, Pillemer E, Rainville IR, Long GL: Protein CVermont: symptomatic type II protein C deficiency associated with two GLA domain mutations. Blood. 1992 Mar 15;79(6):1456-65. [Article]
  24. Sugahara Y, Miura O, Yuen P, Aoki N: Protein C deficiency Hong Kong 1 and 2: hereditary protein C deficiency caused by two mutant alleles, a 5-nucleotide deletion and a missense mutation. Blood. 1992 Jul 1;80(1):126-33. [Article]
  25. Grundy CB, Chisholm M, Kakkar VV, Cooper DN: A novel homozygous missense mutation in the protein C (PROC) gene causing recurrent venous thrombosis. Hum Genet. 1992 Aug;89(6):683-4. [Article]
  26. Grundy CB, Schulman S, Tengborn L, Kakkar VV, Cooper DN: Two different missense mutations at Arg 178 of the protein C (PROC) gene causing recurrent venous thrombosis. Hum Genet. 1992 Aug;89(6):685-6. [Article]
  27. Gandrille S, Vidaud M, Aiach M, Alhenc-Gelas M, Fischer AM, Gouault-Heilman M, Toulon P, Fiessinger JN, Goossens M: Two novel mutations responsible for hereditary type I protein C deficiency: characterization by denaturing gradient gel electrophoresis. Hum Mutat. 1992;1(6):491-500. [Article]
  28. Yamamoto K, Matsushita T, Sugiura I, Takamatsu J, Iwasaki E, Wada H, Deguchi K, Shirakawa S, Saito H: Homozygous protein C deficiency: identification of a novel missense mutation that causes impaired secretion of the mutant protein C. J Lab Clin Med. 1992 Jun;119(6):682-9. [Article]
  29. Gandrille S, Alhenc-Gelas M, Gaussem P, Aillaud MF, Dupuy E, Juhan-Vague I, Aiach M: Five novel mutations located in exons III and IX of the protein C gene in patients presenting with defective protein C anticoagulant activity. Blood. 1993 Jul 1;82(1):159-68. [Article]
  30. Poort SR, Pabinger-Fasching I, Mannhalter C, Reitsma PH, Bertina RM: Twelve novel and two recurrent mutations in 14 Austrian families with hereditary protein C deficiency. Blood Coagul Fibrinolysis. 1993 Apr;4(2):273-80. [Article]
  31. Millar DS, Grundy CB, Bignell P, Moffat EH, Martin R, Kakkar VV, Cooper DN: A Gla domain mutation (Arg 15-->Trp) in the protein C (PROC) gene causing type 2 protein C deficiency and recurrent venous thrombosis. Blood Coagul Fibrinolysis. 1993 Apr;4(2):345-7. [Article]
  32. Tsay W, Greengard JS, Montgomery RR, McPherson RA, Fucci JC, Koerper MA, Coughlin J, Griffin JH: Genetic mutations in ten unrelated American patients with symptomatic type 1 protein C deficiency. Blood Coagul Fibrinolysis. 1993 Oct;4(5):791-6. [Article]
  33. Marchetti G, Patracchini P, Gemmati D, Castaman G, Rodeghiero F, Wacey A, Cooper DN, Tuddenham EG, Bernardi F: Symptomatic type II protein C deficiency caused by a missense mutation (Gly 381-->Ser) in the substrate-binding pocket. Br J Haematol. 1993 Jun;84(2):285-9. [Article]
  34. Gandrille S, Jude B, Alhenc-Gelas M, Emmerich J, Aiach M: First de novo mutations in the protein C gene of two patients with type I deficiency: a missense mutation and a splice site deletion. Blood. 1994 Oct 15;84(8):2566-70. [Article]
  35. Millar DS, Allgrove J, Rodeck C, Kakkar VV, Cooper DN: A homozygous deletion/insertion mutation in the protein C (PROC) gene causing neonatal Purpura fulminans: prenatal diagnosis in an at-risk pregnancy. Blood Coagul Fibrinolysis. 1994 Aug;5(4):647-9. [Article]
  36. Witt I, Beck S, Seydewitz HH, Tasangil C, Schenck W: A novel homozygous missense mutation (Val 325-->Ala) in the protein C gene causing neonatal purpura fulminans. Blood Coagul Fibrinolysis. 1994 Aug;5(4):651-3. [Article]
  37. Zheng YZ, Sakata T, Matsusue T, Umeyama H, Kato H, Miyata T: Six missense mutations associated with type I and type II protein C deficiency and implications obtained from molecular modelling. Blood Coagul Fibrinolysis. 1994 Oct;5(5):687-96. [Article]
  38. Gaussem P, Gandrille S, Duchemin J, Emmerich J, Alhenc-Gelas M, Aillaud MF, Aiach M: Influence of six mutations of the protein C gene on the Gla domain conformation and calcium affinity. Thromb Haemost. 1994 Jun;71(6):748-54. [Article]
  39. Millar DS, Bevan D, Chitolie A, Reynaud J, Chisholm M, Kakkar VV, Cooper DN: Three novel mutations in the protein C (PROC) gene causing venous thrombosis. Blood Coagul Fibrinolysis. 1995 Apr;6(2):138-40. [Article]
  40. Lind B, Schwartz M, Thorsen S: Six different point mutations in seven Danish families with symptomatic protein C deficiency. Thromb Haemost. 1995 Feb;73(2):186-93. [Article]
  41. Ireland HA, Boisclair MD, Taylor J, Thompson E, Thein SL, Girolami A, De Caterina M, Scopacasa F, De Stefano V, Leone G, Finazzi G, Cohen H, Lane DA: Two novel (R(-11)C; T394D) and two repeat missense mutations in the protein C gene associated with venous thrombosis in six kindreds. Hum Mutat. 1996;7(2):176-9. [Article]
  42. Couture P, Demers C, Morissette J, Delage R, Jomphe M, Couture L, Simard J: Type I protein C deficiency in French Canadians: evidence of a founder effect and association of specific protein C gene mutations with plasma protein C levels. Thromb Haemost. 1998 Oct;80(4):551-6. [Article]
  43. Yu T, Dai J, Liu H, Wang J, Ding Q, Wang H, Wang X, Fu Q: Homozygous protein C deficiency with late onset venous thrombosis: identification and in vitro expression study of a novel Pro275Ser mutation. Pathology. 2012 Jun;44(4):348-53. doi: 10.1097/PAT.0b013e328353a218. [Article]
  44. Tang L, Guo T, Yang R, Mei H, Wang H, Lu X, Yu J, Wang Q, Hu Y: Genetic background analysis of protein C deficiency demonstrates a recurrent mutation associated with venous thrombosis in Chinese population. PLoS One. 2012;7(4):e35773. doi: 10.1371/journal.pone.0035773. Epub 2012 Apr 24. [Article]
  45. Ding Q, Yang L, Dinarvand P, Wang X, Rezaie AR: Protein C Thr315Ala variant results in gain of function but manifests as type II deficiency in diagnostic assays. Blood. 2015 Apr 9;125(15):2428-34. doi: 10.1182/blood-2014-12-617274. Epub 2015 Feb 4. [Article]
  46. Liu H, Wang HF, Tang L, Yang Y, Wang QY, Zeng W, Wu YY, Cheng ZP, Hu B, Guo T, Hu Y: Compound heterozygous protein C deficiency in a family with venous thrombosis: Identification and in vitro study of p.Asp297His and p.Val420Leu mutations. Gene. 2015 May 25;563(1):35-40. doi: 10.1016/j.gene.2015.03.002. Epub 2015 Mar 4. [Article]
  47. Kovacs KB, Pataki I, Bardos H, Fekete A, Pfliegler G, Haramura G, Gindele R, Komaromi I, Balla G, Adany R, Muszbek L, Bereczky Z: Molecular characterization of p.Asp77Gly and the novel p.Ala163Val and p.Ala163Glu mutations causing protein C deficiency. Thromb Res. 2015 Apr;135(4):718-26. doi: 10.1016/j.thromres.2015.01.011. Epub 2015 Jan 15. [Article]

Drug Relations

Drug Relations
DrugBank IDNameDrug groupPharmacological action?ActionsDetails
DB00464Sodium tetradecyl sulfateapproved, investigationalyesinhibitorDetails
DB00170Menadioneapproved, nutraceuticalunknownactivatorDetails
DB00025Antihemophilic factor, human recombinantapproved, investigationalunknownsubstrateDetails
DB13149Protein S humanapprovedyescofactorDetails
DB09131Cupric Chlorideapproved, investigationalunknownDetails
DB13192Antihemophilic factor humanapprovednosubstrateDetails
DB09332KappadioneapprovedunknownagonistDetails
DB13998Lonoctocog alfaapproved, investigationalunknowninactivatorDetails
DB13999Moroctocog alfaapprovedunknowninactivatorDetails
DB14738Turoctocog alfa pegolapprovedunknownsubstrateDetails