ID PROC_HUMAN Reviewed; 461 AA. AC P04070; B4DPQ7; Q15189; Q15190; Q16001; Q53S74; Q9UC55; DT 01-NOV-1986, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1986, sequence version 1. DT 24-JAN-2024, entry version 268. DE RecName: Full=Vitamin K-dependent protein C; DE EC=3.4.21.69; DE AltName: Full=Anticoagulant protein C; DE AltName: Full=Autoprothrombin IIA; DE AltName: Full=Blood coagulation factor XIV; DE Contains: DE RecName: Full=Vitamin K-dependent protein C light chain; DE Contains: DE RecName: Full=Vitamin K-dependent protein C heavy chain; DE Contains: DE RecName: Full=Activation peptide; DE Flags: Precursor; GN Name=PROC; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX PubMed=2991859; DOI=10.1093/nar/13.14.5233; RA Beckmann R.J., Schmidt R.J., Santerre R.F., Plutzky J., Crabtree G.R., RA Long G.L.; RT "The structure and evolution of a 461 amino acid human protein C precursor RT and its messenger RNA, based upon the DNA sequence of cloned human liver RT cDNAs."; RL Nucleic Acids Res. 13:5233-5247(1985). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], HYDROXYLATION AT ASP-113, GLYCOSYLATION RP AT ASN-290; ASN-355 AND ASN-371, AND GAMMA-CARBOXYGLUTAMATION AT GLU-48; RP GLU-49; GLU-56; GLU-58; GLU-61; GLU-62; GLU-67; GLU-68 AND GLU-71. RX PubMed=2991887; DOI=10.1073/pnas.82.14.4673; RA Foster D.C., Yoshitake S., Davie E.W.; RT "The nucleotide sequence of the gene for human protein C."; RL Proc. Natl. Acad. Sci. U.S.A. 82:4673-4677(1985). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=3511471; DOI=10.1073/pnas.83.3.546; RA Plutzky J., Hoskins J.A., Long G.L., Crabtree G.R.; RT "Evolution and organization of the human protein C gene."; RL Proc. Natl. Acad. Sci. U.S.A. 83:546-550(1986). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RG SeattleSNPs variation discovery resource; RL Submitted (JUN-2001) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Liver; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15815621; DOI=10.1038/nature03466; RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., RA Wilson R.K.; RT "Generation and annotation of the DNA sequences of human chromosomes 2 and RT 4."; RL Nature 434:724-731(2005). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Colon; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [9] RP PROTEIN SEQUENCE OF 42-57, AND VARIANT THPH3 SER-42. RC TISSUE=Blood; RX PubMed=8560401; RA Miyata T., Zheng Y.-Z., Sakata T., Kato H.; RT "Protein C Osaka 10 with aberrant propeptide processing: loss of RT anticoagulant activity due to an amino acid substitution in the protein C RT precursor."; RL Thromb. Haemost. 74:1003-1008(1995). RN [10] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 43-64, AND VARIANT PROC DEFICIENCY RP GLY-57. RX PubMed=8477066; RA Mimuro J., Muramatsu S., Kaneko M., Yoshitake S., Iijima K., Nakamura K., RA Sakata Y., Matsuda M.; RT "An abnormal protein C (protein C Yonago) with an amino acid substitution RT of Gly for Arg-15 caused by a single base mutation of C to G in codon 57 RT (CGG-->GGG). Deteriorated calcium-dependent conformation of the gamma- RT carboxyglutamic acid domain relevant to a thrombotic tendency."; RL Int. J. Hematol. 57:9-14(1993). RN [11] RP NUCLEOTIDE SEQUENCE [MRNA] OF 106-461 (ISOFORM 1). RX PubMed=6589623; DOI=10.1073/pnas.81.15.4766; RA Foster D.C., Davie E.W.; RT "Characterization of a cDNA coding for human protein C."; RL Proc. Natl. Acad. Sci. U.S.A. 81:4766-4770(1984). RN [12] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 134-178 AND 267-332, AND VARIANTS RP THPH4 PRO-178 AND HIS-328. RX PubMed=7878626; RA Long G.L., Tomczak J.A., Rainville I.R., Dreyfus M., Schramm W., RA Schwarz H.P.; RT "Homozygous type I protein C deficiency in two unrelated families RT exhibiting thrombophilia related to Ala136-->Pro or Arg286-->His RT mutations."; RL Thromb. Haemost. 72:526-533(1994). RN [13] RP GLYCOSYLATION AT ASN-371. RX PubMed=1694179; DOI=10.1016/s0021-9258(19)38606-5; RA Miletich J.P., Broze G.J. Jr.; RT "Beta protein C is not glycosylated at asparagine 329. The rate of RT translation may influence the frequency of usage at asparagine-X-cysteine RT sites."; RL J. Biol. Chem. 265:11397-11404(1990). RN [14] RP HYDROXYLATION. RX PubMed=1544894; DOI=10.1016/s0021-9258(18)42736-6; RA Harris R.J., Ling V.T., Spellman M.W.; RT "O-linked fucose is present in the first epidermal growth factor domain of RT factor XII but not protein C."; RL J. Biol. Chem. 267:5102-5107(1992). RN [15] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-290. RC TISSUE=Plasma; RX PubMed=16335952; DOI=10.1021/pr0502065; RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E., Moore R.J., RA Smith R.D.; RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction, RT hydrazide chemistry, and mass spectrometry."; RL J. Proteome Res. 4:2070-2080(2005). RN [16] RP GLYCOSYLATION AT THR-19, STRUCTURE OF CARBOHYDRATES, AND IDENTIFICATION BY RP MASS SPECTROMETRY. RX PubMed=22171320; DOI=10.1074/mcp.m111.013649; RA Halim A., Nilsson J., Ruetschi U., Hesse C., Larson G.; RT "Human urinary glycoproteomics; attachment site specific analysis of N- and RT O-linked glycosylations by CID and ECD."; RL Mol. Cell. Proteomics 11:1-17(2012). RN [17] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [18] RP PHOSPHORYLATION AT SER-347. RX PubMed=26091039; DOI=10.1016/j.cell.2015.05.028; RA Tagliabracci V.S., Wiley S.E., Guo X., Kinch L.N., Durrant E., Wen J., RA Xiao J., Cui J., Nguyen K.B., Engel J.L., Coon J.J., Grishin N., RA Pinna L.A., Pagliarini D.J., Dixon J.E.; RT "A single kinase generates the majority of the secreted phosphoproteome."; RL Cell 161:1619-1632(2015). RN [19] RP 3D-STRUCTURE MODELING OF 175-450. RX PubMed=8003977; DOI=10.1002/pro.5560030407; RA Fisher C.L., Greengard J.S., Griffin J.H.; RT "Models of the serine protease domain of the human antithrombotic plasma RT factor activated protein C and its zymogen."; RL Protein Sci. 3:588-599(1994). RN [20] RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 84-461. RX PubMed=9003757; DOI=10.1002/j.1460-2075.1996.tb01073.x; RA Mather T., Oganessyan V., Hof P., Huber R., Foundling S., Esmon C., RA Bode W.; RT "The 2.8 A crystal structure of Gla-domainless activated protein C."; RL EMBO J. 15:6822-6831(1996). RN [21] RP REVIEW ON PROC VARIANTS. RX PubMed=8446940; RA Reitsma P.H., Poort S.R., Bernardi F., Gandrille S., Long G.L., Sala N., RA Cooper D.N.; RT "Protein C deficiency: a database of mutations."; RL Thromb. Haemost. 69:77-84(1993). RN [22] RP VARIANT THPH3 CYS-444. RX PubMed=2437584; DOI=10.1073/pnas.84.9.2829; RA Romeo G., Hassan H.J., Staempfli S., Roncuzzi L., Cianetti L., Leonardi A., RA Vicente V., Mannucci P.M., Bertina R.M., Peschle C., Cortese R.; RT "Hereditary thrombophilia: identification of nonsense and missense RT mutations in the protein C gene."; RL Proc. Natl. Acad. Sci. U.S.A. 84:2829-2832(1987). RN [23] RP VARIANT THPH3 TRP-211. RX PubMed=2602169; DOI=10.1093/nar/17.24.10513; RA Grundy C.B., Chitolie A., Talbot S., Bevan D., Kakkar V.V., Cooper D.N.; RT "Protein C London 1: recurrent mutation at Arg-169 (CGG-->TGG) in the RT protein C gene causing thrombosis."; RL Nucleic Acids Res. 17:10513-10513(1989). RN [24] RP VARIANT THPH3 CYS-272. RX PubMed=1868249; RA Reitsma P.H., Poort S.R., Allaart C.F., Briet E., Bertina R.M.; RT "The spectrum of genetic defects in a panel of 40 Dutch families with RT symptomatic protein C deficiency type I: heterogeneity and founder RT effects."; RL Blood 78:890-894(1991). RN [25] RP VARIANTS THPH3 ALA-62 AND MET-76. RX PubMed=1347706; RA Bovill E.G., Tomczak J.A., Grant B., Bhushan F., Pillemer E., RA Rainville I.R., Long G.L.; RT "Protein CVermont: symptomatic type II protein C deficiency associated with RT two GLA domain mutations."; RL Blood 79:1456-1465(1992). RN [26] RP VARIANT THPH4 ASP-418. RX PubMed=1611081; RA Sugahara Y., Miura O., Yuen P., Aoki N.; RT "Protein C deficiency Hong Kong 1 and 2: hereditary protein C deficiency RT caused by two mutant alleles, a 5-nucleotide deletion and a missense RT mutation."; RL Blood 80:126-133(1992). RN [27] RP VARIANT THPH4 LEU-289. RX PubMed=1511988; DOI=10.1007/bf00221963; RA Grundy C.B., Chisholm M., Kakkar V.V., Cooper D.N.; RT "A novel homozygous missense mutation in the protein C (PROC) gene causing RT recurrent venous thrombosis."; RL Hum. Genet. 89:683-684(1992). RN [28] RP VARIANTS THPH3 GLN-220 AND TRP-220. RX PubMed=1511989; DOI=10.1007/bf00221964; RA Grundy C.B., Schulman S., Tengborn L., Kakkar V.V., Cooper D.N.; RT "Two different missense mutations at Arg 178 of the protein C (PROC) gene RT causing recurrent venous thrombosis."; RL Hum. Genet. 89:685-686(1992). RN [29] RP VARIANT THPH3 GLN-220. RX PubMed=1301959; DOI=10.1002/humu.1380010607; RA Gandrille S., Vidaud M., Aiach M., Alhenc-Gelas M., Fischer A.M., RA Gouault-Heilman M., Toulon P., Fiessinger J.-N., Goossens M.; RT "Two novel mutations responsible for hereditary type I protein C RT deficiency: characterization by denaturing gradient gel electrophoresis."; RL Hum. Mutat. 1:491-500(1992). RN [30] RP VARIANT THPH4 SER-334. RX PubMed=1593215; RA Yamamoto K., Matsushita T., Sugiura I., Takamatsu J., Iwasaki E., Wada H., RA Deguchi K., Shirakawa S., Saito H.; RT "Homozygous protein C deficiency: identification of a novel missense RT mutation that causes impaired secretion of the mutant protein C."; RL J. Lab. Clin. Med. 119:682-689(1992). RN [31] RP VARIANTS TRP-38; CYS-42; HIS-42; GLN-271 AND ASN-294. RX PubMed=8324221; RA Gandrille S., Alhenc-Gelas M., Gaussem P., Aillaud M.-F., Dupuy E., RA Juhan-Vague I., Aiach M.; RT "Five novel mutations located in exons III and IX of the protein C gene in RT patients presenting with defective protein C anticoagulant activity."; RL Blood 82:159-168(1993). RN [32] RP VARIANTS GLY-14; GLN-211; TYR-244; GLN-253; LEU-321; CYS-328; ILE-385; RP THR-388 AND VAL-388. RX PubMed=8499565; DOI=10.1097/00001721-199304000-00009; RA Poort S.R., Pabinger-Fasching I., Mannhalter C., Reitsma P.H., RA Bertina R.M.; RT "Twelve novel and two recurrent mutations in 14 Austrian families with RT hereditary protein C deficiency."; RL Blood Coagul. Fibrinolysis 4:273-280(1993). RN [33] RP VARIANT THPH3 TRP-57. RX PubMed=8499568; DOI=10.1097/00001721-199304000-00014; RA Millar D.S., Grundy C.B., Bignell P., Moffat E.H., Martin R., Kakkar V.V., RA Cooper D.N.; RT "A Gla domain mutation (Arg 15-->Trp) in the protein C (PROC) gene causing RT type 2 protein C deficiency and recurrent venous thrombosis."; RL Blood Coagul. Fibrinolysis 4:345-347(1993). RN [34] RP VARIANTS THPH3 ARG-145; LEU-210; TRP-211; THR-243; LEU-321; MET-340 AND RP TYR-426. RX PubMed=8292730; RA Tsay W., Greengard J.S., Montgomery R.R., McPherson R.A., Fucci J.C., RA Koerper M.A., Coughlin J., Griffin J.H.; RT "Genetic mutations in ten unrelated American patients with symptomatic type RT 1 protein C deficiency."; RL Blood Coagul. Fibrinolysis 4:791-796(1993). RN [35] RP VARIANT THPH3 SER-423. RX PubMed=8398832; DOI=10.1111/j.1365-2141.1993.tb03066.x; RA Marchetti G., Patracchini P., Gemmati D., Castaman G., Rodeghiero F., RA Wacey A., Cooper D.N., Tuddenham E.G., Bernardi F.; RT "Symptomatic type II protein C deficiency caused by a missense mutation RT (Gly 381-->Ser) in the substrate-binding pocket."; RL Br. J. Haematol. 84:285-289(1993). RN [36] RP VARIANT PRO-312. RX PubMed=7919373; RA Gandrille S., Jude B., Alhenc-Gelas M., Emmerich J., Aiach M.; RT "First de novo mutations in the protein C gene of two patients with type I RT deficiency: a missense mutation and a splice site deletion."; RL Blood 84:2566-2570(1994). RN [37] RP VARIANT THPH4 144-ASN-GLY-145 DELINS LYS. RX PubMed=7841323; RA Millar D.S., Allgrove J., Rodeck C., Kakkar V.V., Cooper D.N.; RT "A homozygous deletion/insertion mutation in the protein C (PROC) gene RT causing neonatal Purpura fulminans: prenatal diagnosis in an at-risk RT pregnancy."; RL Blood Coagul. Fibrinolysis 5:647-649(1994). RN [38] RP VARIANT THPH4 ALA-367. RX PubMed=7841324; RA Witt I., Beck S., Seydewitz H.H., Tasangil C., Schenck W.; RT "A novel homozygous missense mutation (Val 325-->Ala) in the protein C gene RT causing neonatal purpura fulminans."; RL Blood Coagul. Fibrinolysis 5:651-653(1994). RN [39] RP VARIANTS THPH3 LEU-369; ARG-392; ASN-401 AND HIS-441. RX PubMed=7865674; DOI=10.1097/00001721-199410000-00003; RA Zheng Y.-Z., Sakata T., Matsusue T., Umeyama H., Kato H., Miyata T.; RT "Six missense mutations associated with type I and type II protein C RT deficiency and implications obtained from molecular modelling."; RL Blood Coagul. Fibrinolysis 5:687-696(1994). RN [40] RP VARIANT ASP-49. RX PubMed=7974343; RA Gaussem P., Gandrille S., Duchemin J., Emmerich J., Alhenc-Gelas M., RA Aillaud M.-F., Aiach M.; RT "Influence of six mutations of the protein C gene on the Gla domain RT conformation and calcium affinity."; RL Thromb. Haemost. 71:748-754(1994). RN [41] RP VARIANTS CYS-89; PRO-220 AND THR-301. RX PubMed=7605880; DOI=10.1097/00001721-199504000-00009; RA Millar D.S., Bevan D., Chitolie A., Reynaud J., Chisholm M., Kakkar V.V., RA Cooper D.N.; RT "Three novel mutations in the protein C (PROC) gene causing venous RT thrombosis."; RL Blood Coagul. Fibrinolysis 6:138-140(1995). RN [42] RP VARIANTS THPH3 TRP-57; ARG-114; ARG-324; CYS-328 AND LEU-369, AND VARIANT RP THR-43. RX PubMed=7792728; RA Lind B., Schwartz M., Thorsen S.; RT "Six different point mutations in seven Danish families with symptomatic RT protein C deficiency."; RL Thromb. Haemost. 73:186-193(1995). RN [43] RP VARIANTS THPH3 CYS-32 AND ASN-436. RX PubMed=8829639; RX DOI=10.1002/(sici)1098-1004(1996)7:2<176::aid-humu16>3.0.co;2-#; RA Ireland H.A., Boisclair M.D., Taylor J., Thompson E., Thein S.L., RA Girolami A., de Caterina M., Scopacasa F., de Stefano V., Leone G., RA Finazzi G., Cohen H., Lane D.A.; RT "Two novel (R(-11)C; T394D) and two repeat missense mutations in the RT protein C gene associated with venous thrombosis in six kindreds."; RL Hum. Mutat. 7:176-179(1996). RN [44] RP VARIANTS THPH3 GLN-220 AND MET-340. RX PubMed=9798967; RA Couture P., Demers C., Morissette J., Delage R., Jomphe M., Couture L., RA Simard J.; RT "Type I protein C deficiency in French Canadians: evidence of a founder RT effect and association of specific protein C gene mutations with plasma RT protein C levels."; RL Thromb. Haemost. 80:551-556(1998). RN [45] RP VARIANT SER-317, CHARACTERIZATION OF SER-317, AND SUBCELLULAR LOCATION. RX PubMed=22531345; DOI=10.1097/pat.0b013e328353a218; RA Yu T., Dai J., Liu H., Wang J., Ding Q., Wang H., Wang X., Fu Q.; RT "Homozygous protein C deficiency with late onset venous thrombosis: RT identification and in vitro expression study of a novel Pro275Ser RT mutation."; RL Pathology 44:348-353(2012). RN [46] RP VARIANTS GLU-70; GLY-106; ALA-118; TYR-175; VAL-181; TRP-189; GLN-211; RP TRP-220; ARG-223; GLY-240; HIS-297; LEU-312; VAL-327 AND LEU-420. RX PubMed=22545135; DOI=10.1371/journal.pone.0035773; RA Tang L., Guo T., Yang R., Mei H., Wang H., Lu X., Yu J., Wang Q., Hu Y.; RT "Genetic background analysis of protein C deficiency demonstrates a RT recurrent mutation associated with venous thrombosis in Chinese RT population."; RL PLoS ONE 7:E35773-E35773(2012). RN [47] RP VARIANT ALA-357, CHARACTERIZATION OF ALA-357, AND FUNCTION. RX PubMed=25651845; DOI=10.1182/blood-2014-12-617274; RA Ding Q., Yang L., Dinarvand P., Wang X., Rezaie A.R.; RT "Protein C Thr315Ala variant results in gain of function but manifests as RT type II deficiency in diagnostic assays."; RL Blood 125:2428-2434(2015). RN [48] RP VARIANTS THPH3 HIS-297 AND LEU-420, CHARACTERIZATION OF VARIANTS THPH3 RP HIS-297 AND LEU-420, AND SUBCELLULAR LOCATION. RX PubMed=25748729; DOI=10.1016/j.gene.2015.03.002; RA Liu H., Wang H.F., Tang L., Yang Y., Wang Q.Y., Zeng W., Wu Y.Y., RA Cheng Z.P., Hu B., Guo T., Hu Y.; RT "Compound heterozygous protein C deficiency in a family with venous RT thrombosis: Identification and in vitro study of p.Asp297His and RT p.Val420Leu mutations."; RL Gene 563:35-40(2015). RN [49] RP VARIANTS THPH4 GLY-77 AND GLU-163, VARIANT THPH3 VAL-163, FUNCTION AS RP ANTICOAGULANT, SUBCELLULAR LOCATION, CHARACTERIZATION OF VARIANTS THPH4 RP GLY-77 AND GLU-163, AND CHARACTERIZATION OF VARIANT THPH3 VAL-163. RX PubMed=25618265; DOI=10.1016/j.thromres.2015.01.011; RA Kovacs K.B., Pataki I., Bardos H., Fekete A., Pfliegler G., Haramura G., RA Gindele R., Komaromi I., Balla G., Adany R., Muszbek L., Bereczky Z.; RT "Molecular characterization of p.Asp77Gly and the novel p.Ala163Val and RT p.Ala163Glu mutations causing protein C deficiency."; RL Thromb. Res. 135:718-726(2015). CC -!- FUNCTION: Protein C is a vitamin K-dependent serine protease that CC regulates blood coagulation by inactivating factors Va and VIIIa in the CC presence of calcium ions and phospholipids (PubMed:25618265). Exerts a CC protective effect on the endothelial cell barrier function CC (PubMed:25651845). {ECO:0000269|PubMed:25618265, CC ECO:0000269|PubMed:25651845}. CC -!- CATALYTIC ACTIVITY: CC Reaction=Degradation of blood coagulation factors Va and VIIIa.; CC EC=3.4.21.69; CC -!- SUBUNIT: Synthesized as a single chain precursor, which is cleaved into CC a light chain and a heavy chain held together by a disulfide bond. The CC enzyme is then activated by thrombin, which cleaves a tetradecapeptide CC from the amino end of the heavy chain; this reaction, which occurs at CC the surface of endothelial cells, is strongly promoted by CC thrombomodulin. CC -!- INTERACTION: CC P04070; A8MQ03: CYSRT1; NbExp=3; IntAct=EBI-1383018, EBI-3867333; CC P04070; P51511: MMP15; NbExp=2; IntAct=EBI-1383018, EBI-1383043; CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:25618265}. Golgi CC apparatus {ECO:0000269|PubMed:22531345, ECO:0000269|PubMed:25748729}. CC Endoplasmic reticulum {ECO:0000269|PubMed:22531345, CC ECO:0000269|PubMed:25748729}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=P04070-1; Sequence=Displayed; CC Name=2; CC IsoId=P04070-2; Sequence=VSP_054393, VSP_054394; CC -!- TISSUE SPECIFICITY: Plasma; synthesized in the liver. CC -!- PTM: The vitamin K-dependent, enzymatic carboxylation of some Glu CC residues allows the modified protein to bind calcium. CC -!- PTM: N- and O-glycosylated. Partial (70%) N-glycosylation of Asn-371 CC with an atypical N-X-C site produces a higher molecular weight form CC referred to as alpha. The lower molecular weight form, not N- CC glycosylated at Asn-371, is beta. O-glycosylated with core 1 or CC possibly core 8 glycans. {ECO:0000269|PubMed:16335952, CC ECO:0000269|PubMed:1694179, ECO:0000269|PubMed:22171320, CC ECO:0000269|PubMed:2991887}. CC -!- PTM: The iron and 2-oxoglutarate dependent 3-hydroxylation of aspartate CC and asparagine is (R) stereospecific within EGF domains. CC {ECO:0000269|PubMed:1544894, ECO:0000269|PubMed:2991887}. CC -!- PTM: May be phosphorylated on a Ser or Thr in a region (AA 25-30) of CC the propeptide. CC -!- DISEASE: Thrombophilia due to protein C deficiency, autosomal dominant CC (THPH3) [MIM:176860]: A hemostatic disorder characterized by impaired CC regulation of blood coagulation and a tendency to recurrent venous CC thrombosis. Individuals with decreased amounts of protein C are CC classically referred to as having type I protein C deficiency and those CC with normal amounts of a functionally defective protein as having type CC II deficiency. {ECO:0000269|PubMed:1301959, ECO:0000269|PubMed:1347706, CC ECO:0000269|PubMed:1511989, ECO:0000269|PubMed:1868249, CC ECO:0000269|PubMed:2437584, ECO:0000269|PubMed:25618265, CC ECO:0000269|PubMed:25748729, ECO:0000269|PubMed:2602169, CC ECO:0000269|PubMed:7792728, ECO:0000269|PubMed:7865674, CC ECO:0000269|PubMed:8292730, ECO:0000269|PubMed:8398832, CC ECO:0000269|PubMed:8499568, ECO:0000269|PubMed:8560401, CC ECO:0000269|PubMed:8829639, ECO:0000269|PubMed:9798967}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- DISEASE: Thrombophilia due to protein C deficiency, autosomal recessive CC (THPH4) [MIM:612304]: A hemostatic disorder characterized by impaired CC regulation of blood coagulation and a tendency to recurrent venous CC thrombosis. It results in a thrombotic condition that can manifest as a CC severe neonatal disorder or as a milder disorder with late-onset CC thrombophilia. The severe form leads to neonatal death through massive CC neonatal venous thrombosis. Often associated with ecchymotic skin CC lesions which can turn necrotic called purpura fulminans, this disorder CC is very rare. {ECO:0000269|PubMed:1511988, ECO:0000269|PubMed:1593215, CC ECO:0000269|PubMed:1611081, ECO:0000269|PubMed:25618265, CC ECO:0000269|PubMed:7841323, ECO:0000269|PubMed:7841324, CC ECO:0000269|PubMed:7878626}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- MISCELLANEOUS: Calcium also binds, with stronger affinity to another CC site, beyond the GLA domain. This GLA-independent binding site is CC necessary for the recognition of the thrombin-thrombomodulin complex. CC -!- SIMILARITY: Belongs to the peptidase S1 family. {ECO:0000255|PROSITE- CC ProRule:PRU00274}. CC -!- SEQUENCE CAUTION: CC Sequence=S76088; Type=Erroneous termination; Note=Truncated C-terminus.; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=Wikipedia; Note=Protein C entry; CC URL="https://en.wikipedia.org/wiki/Protein_C"; CC -!- WEB RESOURCE: Name=SeattleSNPs; CC URL="http://pga.gs.washington.edu/data/proc/"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; X02750; CAA26528.1; -; mRNA. DR EMBL; M11228; AAA60166.1; -; Genomic_DNA. DR EMBL; M12712; AAA60165.1; -; Genomic_DNA. DR EMBL; M12683; AAA60165.1; JOINED; Genomic_DNA. DR EMBL; M12684; AAA60165.1; JOINED; Genomic_DNA. DR EMBL; M12685; AAA60165.1; JOINED; Genomic_DNA. DR EMBL; M12686; AAA60165.1; JOINED; Genomic_DNA. DR EMBL; M12687; AAA60165.1; JOINED; Genomic_DNA. DR EMBL; AF378903; AAK56377.1; -; Genomic_DNA. DR EMBL; AK298454; BAG60669.1; -; mRNA. DR EMBL; AC068282; AAY15044.1; -; Genomic_DNA. DR EMBL; CH471103; EAW95320.1; -; Genomic_DNA. DR EMBL; BC034377; AAH34377.1; -; mRNA. DR EMBL; S58668; AAB26335.1; -; Genomic_DNA. DR EMBL; K02059; AAA60164.1; -; mRNA. DR EMBL; S76088; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; S76090; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR CCDS; CCDS2145.1; -. [P04070-1] DR PIR; A22331; KXHU. DR RefSeq; NP_000303.1; NM_000312.3. [P04070-1] DR PDB; 1AUT; X-ray; 2.80 A; C=212-461, L=84-197. DR PDB; 1LQV; X-ray; 1.60 A; C/D=43-75. DR PDB; 3F6U; X-ray; 2.80 A; H=212-451, L=91-188. DR PDB; 3JTC; X-ray; 1.60 A; C/D=43-75. DR PDB; 4DT7; X-ray; 1.90 A; E/F=204-223. DR PDB; 6M3B; X-ray; 2.20 A; A=212-461, D=43-197. DR PDB; 6M3C; X-ray; 3.70 A; A/C/G=212-461, B/D/I=43-197. DR PDB; 8JRU; EM; 3.50 A; R=205-216. DR PDB; 8JRV; EM; 3.30 A; R=205-216. DR PDBsum; 1AUT; -. DR PDBsum; 1LQV; -. DR PDBsum; 3F6U; -. DR PDBsum; 3JTC; -. DR PDBsum; 4DT7; -. DR PDBsum; 6M3B; -. DR PDBsum; 6M3C; -. DR PDBsum; 8JRU; -. DR PDBsum; 8JRV; -. DR AlphaFoldDB; P04070; -. DR SASBDB; P04070; -. DR SMR; P04070; -. DR BioGRID; 111608; 18. DR ComplexPortal; CPX-6224; Active Protein C complex. DR ELM; P04070; -. DR IntAct; P04070; 11. DR MINT; P04070; -. DR STRING; 9606.ENSP00000234071; -. DR BindingDB; P04070; -. DR ChEMBL; CHEMBL4444; -. DR DrugBank; DB13192; Antihemophilic factor human. DR DrugBank; DB00025; Antihemophilic factor, human recombinant. DR DrugBank; DB09131; Cupric Chloride. DR DrugBank; DB09332; Kappadione. DR DrugBank; DB13998; Lonoctocog alfa. DR DrugBank; DB00170; Menadione. DR DrugBank; DB13999; Moroctocog alfa. DR DrugBank; DB13149; Protein S human. DR DrugBank; DB00464; Sodium tetradecyl sulfate. DR DrugBank; DB14738; Turoctocog alfa pegol. DR DrugCentral; P04070; -. DR GuidetoPHARMACOLOGY; 2396; -. DR MEROPS; S01.218; -. DR GlyConnect; 620; 17 N-Linked glycans (2 sites), 1 O-Linked glycan (1 site). DR GlyCosmos; P04070; 6 sites, 45 glycans. DR GlyGen; P04070; 7 sites, 43 N-linked glycans (5 sites), 3 O-linked glycans (3 sites). DR iPTMnet; P04070; -. DR PhosphoSitePlus; P04070; -. DR BioMuta; PROC; -. DR DMDM; 131067; -. DR jPOST; P04070; -. DR MassIVE; P04070; -. DR MaxQB; P04070; -. DR PaxDb; 9606-ENSP00000234071; -. DR PeptideAtlas; P04070; -. DR ProteomicsDB; 4804; -. DR ProteomicsDB; 51646; -. [P04070-1] DR ABCD; P04070; 2 sequenced antibodies. DR Antibodypedia; 791; 802 antibodies from 41 providers. DR DNASU; 5624; -. DR Ensembl; ENST00000234071.8; ENSP00000234071.4; ENSG00000115718.18. [P04070-1] DR GeneID; 5624; -. DR KEGG; hsa:5624; -. DR MANE-Select; ENST00000234071.8; ENSP00000234071.4; NM_000312.4; NP_000303.1. DR UCSC; uc002tok.4; human. [P04070-1] DR AGR; HGNC:9451; -. DR CTD; 5624; -. DR DisGeNET; 5624; -. DR GeneCards; PROC; -. DR HGNC; HGNC:9451; PROC. DR HPA; ENSG00000115718; Tissue enriched (liver). DR MalaCards; PROC; -. DR MIM; 176860; phenotype. DR MIM; 612283; gene. DR MIM; 612304; phenotype. DR neXtProt; NX_P04070; -. DR OpenTargets; ENSG00000115718; -. DR Orphanet; 64738; NON RARE IN EUROPE: Non rare thrombophilia. DR Orphanet; 745; Severe hereditary thrombophilia due to congenital protein C deficiency. DR PharmGKB; PA33799; -. DR VEuPathDB; HostDB:ENSG00000115718; -. DR eggNOG; ENOG502QQ3W; Eukaryota. DR GeneTree; ENSGT00940000154505; -. DR HOGENOM; CLU_006842_19_5_1; -. DR InParanoid; P04070; -. DR OrthoDB; 4629979at2759; -. DR PhylomeDB; P04070; -. DR TreeFam; TF327329; -. DR BRENDA; 3.4.21.69; 2681. DR PathwayCommons; P04070; -. DR Reactome; R-HSA-140837; Intrinsic Pathway of Fibrin Clot Formation. DR Reactome; R-HSA-140875; Common Pathway of Fibrin Clot Formation. DR Reactome; R-HSA-159740; Gamma-carboxylation of protein precursors. DR Reactome; R-HSA-159763; Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus. DR Reactome; R-HSA-159782; Removal of aminoterminal propeptides from gamma-carboxylated proteins. DR Reactome; R-HSA-202733; Cell surface interactions at the vascular wall. DR Reactome; R-HSA-381426; Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs). DR Reactome; R-HSA-8957275; Post-translational protein phosphorylation. DR SABIO-RK; P04070; -. DR SignaLink; P04070; -. DR SIGNOR; P04070; -. DR BioGRID-ORCS; 5624; 6 hits in 1152 CRISPR screens. DR ChiTaRS; PROC; human. DR EvolutionaryTrace; P04070; -. DR GeneWiki; Protein_C; -. DR GenomeRNAi; 5624; -. DR Pharos; P04070; Tchem. DR PRO; PR:P04070; -. DR Proteomes; UP000005640; Chromosome 2. DR RNAct; P04070; Protein. DR Bgee; ENSG00000115718; Expressed in right lobe of liver and 102 other cell types or tissues. DR ExpressionAtlas; P04070; baseline and differential. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:UniProtKB. DR GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome. DR GO; GO:0005576; C:extracellular region; TAS:Reactome. DR GO; GO:0005615; C:extracellular space; IBA:GO_Central. DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB. DR GO; GO:0005796; C:Golgi lumen; TAS:Reactome. DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro. DR GO; GO:0004252; F:serine-type endopeptidase activity; IMP:UniProtKB. DR GO; GO:0007596; P:blood coagulation; IEA:UniProtKB-KW. DR GO; GO:0043066; P:negative regulation of apoptotic process; IMP:UniProtKB. DR GO; GO:0030195; P:negative regulation of blood coagulation; IBA:GO_Central. DR GO; GO:0050819; P:negative regulation of coagulation; IMP:UniProtKB. DR GO; GO:0050728; P:negative regulation of inflammatory response; IMP:UniProtKB. DR GO; GO:1903142; P:positive regulation of establishment of endothelial barrier; IMP:UniProtKB. DR GO; GO:0006508; P:proteolysis; NAS:UniProtKB. DR CDD; cd00054; EGF_CA; 1. DR CDD; cd00190; Tryp_SPc; 1. DR Gene3D; 4.10.740.10; Coagulation Factor IX; 1. DR Gene3D; 2.10.25.10; Laminin; 2. DR Gene3D; 2.40.10.10; Trypsin-like serine proteases; 2. DR InterPro; IPR017857; Coagulation_fac-like_Gla_dom. DR InterPro; IPR001881; EGF-like_Ca-bd_dom. DR InterPro; IPR000742; EGF-like_dom. DR InterPro; IPR000152; EGF-type_Asp/Asn_hydroxyl_site. DR InterPro; IPR018097; EGF_Ca-bd_CS. DR InterPro; IPR035972; GLA-like_dom_SF. DR InterPro; IPR000294; GLA_domain. DR InterPro; IPR012224; Pept_S1A_FX. DR InterPro; IPR009003; Peptidase_S1_PA. DR InterPro; IPR043504; Peptidase_S1_PA_chymotrypsin. DR InterPro; IPR001314; Peptidase_S1A. DR InterPro; IPR001254; Trypsin_dom. DR InterPro; IPR018114; TRYPSIN_HIS. DR InterPro; IPR033116; TRYPSIN_SER. DR PANTHER; PTHR24278; COAGULATION FACTOR; 1. DR PANTHER; PTHR24278:SF0; VITAMIN K-DEPENDENT PROTEIN C; 1. DR Pfam; PF14670; FXa_inhibition; 1. DR Pfam; PF00594; Gla; 1. DR Pfam; PF00089; Trypsin; 1. DR PIRSF; PIRSF001143; Factor_X; 1. DR PRINTS; PR00722; CHYMOTRYPSIN. DR PRINTS; PR00001; GLABLOOD. DR SMART; SM00181; EGF; 2. DR SMART; SM00179; EGF_CA; 1. DR SMART; SM00069; GLA; 1. DR SMART; SM00020; Tryp_SPc; 1. DR SUPFAM; SSF57196; EGF/Laminin; 1. DR SUPFAM; SSF57630; GLA-domain; 1. DR SUPFAM; SSF50494; Trypsin-like serine proteases; 1. DR PROSITE; PS00010; ASX_HYDROXYL; 1. DR PROSITE; PS00022; EGF_1; 1. DR PROSITE; PS01186; EGF_2; 2. DR PROSITE; PS50026; EGF_3; 1. DR PROSITE; PS01187; EGF_CA; 1. DR PROSITE; PS00011; GLA_1; 1. DR PROSITE; PS50998; GLA_2; 1. DR PROSITE; PS50240; TRYPSIN_DOM; 1. DR PROSITE; PS00134; TRYPSIN_HIS; 1. DR PROSITE; PS00135; TRYPSIN_SER; 1. DR Genevisible; P04070; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Blood coagulation; Calcium; KW Cleavage on pair of basic residues; Direct protein sequencing; KW Disease variant; Disulfide bond; EGF-like domain; Endoplasmic reticulum; KW Gamma-carboxyglutamic acid; Glycoprotein; Golgi apparatus; Hemostasis; KW Hydrolase; Hydroxylation; Phosphoprotein; Protease; Reference proteome; KW Repeat; Secreted; Serine protease; Signal; Thrombophilia; Zymogen. FT SIGNAL 1..18 FT /evidence="ECO:0000255" FT PROPEP 19..42 FT /id="PRO_0000028107" FT CHAIN 43..461 FT /note="Vitamin K-dependent protein C" FT /id="PRO_0000028108" FT CHAIN 43..197 FT /note="Vitamin K-dependent protein C light chain" FT /id="PRO_0000028109" FT CHAIN 200..461 FT /note="Vitamin K-dependent protein C heavy chain" FT /id="PRO_0000028110" FT PEPTIDE 200..211 FT /note="Activation peptide" FT /id="PRO_0000028111" FT DOMAIN 43..88 FT /note="Gla" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00463" FT DOMAIN 97..132 FT /note="EGF-like 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 136..176 FT /note="EGF-like 2" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00076" FT DOMAIN 212..450 FT /note="Peptidase S1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00274" FT ACT_SITE 253 FT /note="Charge relay system" FT ACT_SITE 299 FT /note="Charge relay system" FT ACT_SITE 402 FT /note="Charge relay system" FT SITE 211..212 FT /note="Cleavage; by thrombin" FT MOD_RES 48 FT /note="4-carboxyglutamate" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00463, FT ECO:0000269|PubMed:2991887" FT MOD_RES 49 FT /note="4-carboxyglutamate" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00463, FT ECO:0000269|PubMed:2991887" FT MOD_RES 56 FT /note="4-carboxyglutamate" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00463, FT ECO:0000269|PubMed:2991887" FT MOD_RES 58 FT /note="4-carboxyglutamate" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00463, FT ECO:0000269|PubMed:2991887" FT MOD_RES 61 FT /note="4-carboxyglutamate" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00463, FT ECO:0000269|PubMed:2991887" FT MOD_RES 62 FT /note="4-carboxyglutamate" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00463, FT ECO:0000269|PubMed:2991887" FT MOD_RES 67 FT /note="4-carboxyglutamate" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00463, FT ECO:0000269|PubMed:2991887" FT MOD_RES 68 FT /note="4-carboxyglutamate" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00463, FT ECO:0000269|PubMed:2991887" FT MOD_RES 71 FT /note="4-carboxyglutamate" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00463, FT ECO:0000269|PubMed:2991887" FT MOD_RES 113 FT /note="(3R)-3-hydroxyaspartate" FT /evidence="ECO:0000269|PubMed:2991887" FT MOD_RES 347 FT /note="Phosphoserine; by FAM20C" FT /evidence="ECO:0000269|PubMed:26091039" FT CARBOHYD 19 FT /note="O-linked (GalNAc...) threonine" FT /evidence="ECO:0000269|PubMed:22171320" FT CARBOHYD 139 FT /note="N-linked (GlcNAc...) asparagine" FT CARBOHYD 290 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:16335952, FT ECO:0000269|PubMed:2991887" FT CARBOHYD 355 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:2991887" FT CARBOHYD 371 FT /note="N-linked (GlcNAc...) asparagine; atypical; partial" FT /evidence="ECO:0000269|PubMed:1694179, FT ECO:0000269|PubMed:2991887" FT DISULFID 59..64 FT DISULFID 92..111 FT DISULFID 101..106 FT DISULFID 105..120 FT DISULFID 122..131 FT DISULFID 140..151 FT DISULFID 147..160 FT DISULFID 162..175 FT DISULFID 183..319 FT /note="Interchain (between light and heavy chains)" FT DISULFID 238..254 FT DISULFID 373..387 FT DISULFID 398..426 FT VAR_SEQ 1 FT /note="M -> MAAGRRTCSISTTRPCASASRM (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_054393" FT VAR_SEQ 133 FT /note="R -> RGEGERWMLAGGGAGLGPGWGRGTSTSCPRPPLPA (in isoform FT 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_054394" FT VARIANT 14 FT /note="W -> G (in patients with PROC deficiency)" FT /evidence="ECO:0000269|PubMed:8499565" FT /id="VAR_006634" FT VARIANT 32 FT /note="R -> C (in THPH3)" FT /evidence="ECO:0000269|PubMed:8829639" FT /id="VAR_006635" FT VARIANT 38 FT /note="R -> W (in patients with PROC deficiency; FT dbSNP:rs769900251)" FT /evidence="ECO:0000269|PubMed:8324221" FT /id="VAR_006636" FT VARIANT 42 FT /note="R -> C (in patients with PROC deficiency; FT dbSNP:rs774572099)" FT /evidence="ECO:0000269|PubMed:8324221" FT /id="VAR_006638" FT VARIANT 42 FT /note="R -> H (in Malakoff; low anticoagulant activity; FT dbSNP:rs369504169)" FT /evidence="ECO:0000269|PubMed:8324221" FT /id="VAR_006637" FT VARIANT 42 FT /note="R -> S (in THPH3; type II; Osaka-10; alters FT proteolytic processing so that S-42 is the N-terminus of FT the mature protein; dbSNP:rs774572099)" FT /evidence="ECO:0000269|PubMed:8560401" FT /id="VAR_055074" FT VARIANT 43 FT /note="A -> T (in dbSNP:rs767626189)" FT /evidence="ECO:0000269|PubMed:7792728" FT /id="VAR_006639" FT VARIANT 49 FT /note="E -> D (in patients with PROC deficiency)" FT /evidence="ECO:0000269|PubMed:7974343" FT /id="VAR_006640" FT VARIANT 51 FT /note="R -> C (in patients with PROC deficiency; FT dbSNP:rs764546127)" FT /id="VAR_006641" FT VARIANT 57 FT /note="R -> G (in Yonago; defective anticoagulant FT activity)" FT /evidence="ECO:0000269|PubMed:8477066" FT /id="VAR_006643" FT VARIANT 57 FT /note="R -> Q (in patients with PROC deficiency; FT dbSNP:rs574949343)" FT /id="VAR_006644" FT VARIANT 57 FT /note="R -> W (in THPH3; dbSNP:rs757583846)" FT /evidence="ECO:0000269|PubMed:7792728, FT ECO:0000269|PubMed:8499568" FT /id="VAR_006642" FT VARIANT 62 FT /note="E -> A (in THPH3; Vermont-1; dbSNP:rs121918148)" FT /evidence="ECO:0000269|PubMed:1347706" FT /id="VAR_006645" FT VARIANT 70 FT /note="K -> E (in patients with PROC deficiency; FT dbSNP:rs199469481)" FT /evidence="ECO:0000269|PubMed:22545135" FT /id="VAR_074296" FT VARIANT 76 FT /note="V -> M (in THPH3; Vermont-1; dbSNP:rs121918149)" FT /evidence="ECO:0000269|PubMed:1347706" FT /id="VAR_006646" FT VARIANT 77 FT /note="D -> G (in THPH4; no effect on secretion; no effect FT on catalytic activity in vitro)" FT /evidence="ECO:0000269|PubMed:25618265" FT /id="VAR_073145" FT VARIANT 89 FT /note="G -> C (in patients with PROC deficiency)" FT /evidence="ECO:0000269|PubMed:7605880" FT /id="VAR_006647" FT VARIANT 106 FT /note="C -> G (in patients with PROC deficiency; FT dbSNP:rs199469479)" FT /evidence="ECO:0000269|PubMed:22545135" FT /id="VAR_074297" FT VARIANT 108 FT /note="H -> N (in patients with PROC deficiency; La FT Jolla-1; dbSNP:rs200234655)" FT /id="VAR_006648" FT VARIANT 109 FT /note="G -> R (in patients with PROC deficiency)" FT /id="VAR_006649" FT VARIANT 114..118 FT /note="Missing (in patients with PROC deficiency)" FT /id="VAR_006650" FT VARIANT 114 FT /note="G -> R (in THPH3; dbSNP:rs374476971)" FT /evidence="ECO:0000269|PubMed:7792728" FT /id="VAR_006651" FT VARIANT 118 FT /note="F -> A (in patients with PROC deficiency; requires 2 FT nucleotide substitutions)" FT /evidence="ECO:0000269|PubMed:22545135" FT /id="VAR_074298" FT VARIANT 118 FT /note="F -> L (in patients with PROC deficiency; FT dbSNP:rs1553424043)" FT /id="VAR_006652" FT VARIANT 119..124 FT /note="Missing (in patients with PROC deficiency; St FT Louis-2)" FT /id="VAR_006653" FT VARIANT 120..125 FT /note="Missing (in patients with PROC deficiency; St FT Louis-3)" FT /id="VAR_006654" FT VARIANT 144..145 FT /note="NG -> K (in THPH4; neonatal purpura fulminans)" FT /evidence="ECO:0000269|PubMed:7841323" FT /id="VAR_006655" FT VARIANT 145 FT /note="G -> R (in THPH3; dbSNP:rs370813536)" FT /evidence="ECO:0000269|PubMed:8292730" FT /id="VAR_006656" FT VARIANT 147 FT /note="C -> Y (in patients with PROC deficiency; FT dbSNP:rs1247269491)" FT /id="VAR_006657" FT VARIANT 149 FT /note="H -> P (in patients with PROC deficiency; FT dbSNP:rs121918159)" FT /id="VAR_006658" FT VARIANT 161 FT /note="S -> R (in patients with PROC deficiency; FT dbSNP:rs1433503391)" FT /id="VAR_006659" FT VARIANT 163 FT /note="A -> E (in THPH4; drastically reduced secretion; FT colocalizes with 26S proteasome)" FT /evidence="ECO:0000269|PubMed:25618265" FT /id="VAR_073146" FT VARIANT 163 FT /note="A -> V (in THPH3; drastically reduced secretion; FT colocalizes with 26S proteasome)" FT /evidence="ECO:0000269|PubMed:25618265" FT /id="VAR_073147" FT VARIANT 175 FT /note="C -> Y (in patients with PROC deficiency; FT dbSNP:rs199469474)" FT /evidence="ECO:0000269|PubMed:22545135" FT /id="VAR_074299" FT VARIANT 178 FT /note="A -> P (in THPH4; Clamart; dbSNP:rs1254257945)" FT /evidence="ECO:0000269|PubMed:7878626" FT /id="VAR_006660" FT VARIANT 181 FT /note="F -> V (in patients with PROC deficiency; FT dbSNP:rs199469470)" FT /evidence="ECO:0000269|PubMed:22545135" FT /id="VAR_074300" FT VARIANT 183 FT /note="C -> R (in patients with PROC deficiency; FT dbSNP:rs748920874)" FT /id="VAR_006661" FT VARIANT 189 FT /note="R -> W (in patients with PROC deficiency; La FT Jolla-3; dbSNP:rs146922325)" FT /evidence="ECO:0000269|PubMed:22545135" FT /id="VAR_006662" FT VARIANT 194 FT /note="R -> C (in patients with PROC deficiency; FT dbSNP:rs371071104)" FT /id="VAR_006663" FT VARIANT 210 FT /note="P -> L (in THPH3; dbSNP:rs121918145)" FT /evidence="ECO:0000269|PubMed:8292730" FT /id="VAR_006664" FT VARIANT 211 FT /note="R -> Q (in patients with PROC deficiency; FT dbSNP:rs199469476)" FT /evidence="ECO:0000269|PubMed:22545135, FT ECO:0000269|PubMed:8499565" FT /id="VAR_006666" FT VARIANT 211 FT /note="R -> W (in THPH3; London-1/Tochigi; FT dbSNP:rs121918143)" FT /evidence="ECO:0000269|PubMed:2602169, FT ECO:0000269|PubMed:8292730" FT /id="VAR_006665" FT VARIANT 220 FT /note="R -> P (in patients with PROC deficiency)" FT /evidence="ECO:0000269|PubMed:7605880" FT /id="VAR_006667" FT VARIANT 220 FT /note="R -> Q (in THPH3; Vermont-3; dbSNP:rs121918153)" FT /evidence="ECO:0000269|PubMed:1301959, FT ECO:0000269|PubMed:1511989, ECO:0000269|PubMed:9798967" FT /id="VAR_006669" FT VARIANT 220 FT /note="R -> W (in THPH3; dbSNP:rs121918152)" FT /evidence="ECO:0000269|PubMed:1511989, FT ECO:0000269|PubMed:22545135" FT /id="VAR_006668" FT VARIANT 223 FT /note="S -> R (in patients with PROC deficiency; FT dbSNP:rs199469483)" FT /evidence="ECO:0000269|PubMed:22545135" FT /id="VAR_074301" FT VARIANT 226 FT /note="Q -> H (in patients with PROC deficiency; FT dbSNP:rs121918155)" FT /id="VAR_006670" FT VARIANT 240 FT /note="A -> G (in patients with PROC deficiency)" FT /evidence="ECO:0000269|PubMed:22545135" FT /id="VAR_074302" FT VARIANT 243 FT /note="I -> T (in THPH3; dbSNP:rs774584131)" FT /evidence="ECO:0000269|PubMed:8292730" FT /id="VAR_006671" FT VARIANT 244 FT /note="H -> Y (in patients with PROC deficiency; FT dbSNP:rs759557871)" FT /evidence="ECO:0000269|PubMed:8499565" FT /id="VAR_006672" FT VARIANT 253 FT /note="H -> Q (in patients with PROC deficiency; FT dbSNP:rs1458669732)" FT /evidence="ECO:0000269|PubMed:8499565" FT /id="VAR_006673" FT VARIANT 265 FT /note="L -> F (in patients with PROC deficiency; FT dbSNP:rs121918156)" FT /id="VAR_006674" FT VARIANT 271 FT /note="R -> Q (in Marseille; low anticoagulant activity; FT dbSNP:rs752290840)" FT /evidence="ECO:0000269|PubMed:8324221" FT /id="VAR_006675" FT VARIANT 271 FT /note="R -> W (in patients with PROC deficiency; FT dbSNP:rs767112991)" FT /id="VAR_006676" FT VARIANT 272 FT /note="R -> C (in THPH3; dbSNP:rs121918154)" FT /evidence="ECO:0000269|PubMed:1868249" FT /id="VAR_006677" FT VARIANT 281 FT /note="D -> DLD (in patients with PROC deficiency)" FT /id="VAR_006678" FT VARIANT 289 FT /note="P -> L (in THPH4; dbSNP:rs121918151)" FT /evidence="ECO:0000269|PubMed:1511988" FT /id="VAR_006679" FT VARIANT 294 FT /note="S -> N (in Paris; low anticoagulant activity; FT dbSNP:rs200721675)" FT /evidence="ECO:0000269|PubMed:8324221" FT /id="VAR_006680" FT VARIANT 297 FT /note="D -> H (in THPH3; also found in patients with PROC FT deficiency; decrease in vitamin-K dependent serine protease FT activity; decreased Golgi localization; dbSNP:rs199469471)" FT /evidence="ECO:0000269|PubMed:22545135, FT ECO:0000269|PubMed:25748729" FT /id="VAR_074303" FT VARIANT 298 FT /note="N -> D (in patients with PROC deficiency)" FT /id="VAR_006681" FT VARIANT 301 FT /note="A -> T (in patients with PROC deficiency; FT dbSNP:rs1343264503)" FT /evidence="ECO:0000269|PubMed:7605880" FT /id="VAR_006682" FT VARIANT 301 FT /note="A -> V (in patients with PROC deficiency; FT dbSNP:rs121918144)" FT /id="VAR_006683" FT VARIANT 309 FT /note="A -> T (in patients with PROC deficiency; FT dbSNP:rs121918146)" FT /id="VAR_006684" FT VARIANT 312 FT /note="S -> L (in patients with PROC deficiency; FT dbSNP:rs121918160)" FT /evidence="ECO:0000269|PubMed:22545135" FT /id="VAR_006685" FT VARIANT 312 FT /note="S -> P (in a patient with PROC deficiency; sporadic FT case)" FT /evidence="ECO:0000269|PubMed:7919373" FT /id="VAR_006686" FT VARIANT 317 FT /note="P -> S (in patients with PROC deficiency; abolishes FT Golgi localization)" FT /evidence="ECO:0000269|PubMed:22531345" FT /id="VAR_074304" FT VARIANT 321 FT /note="P -> L (in THPH3; dbSNP:rs1321566264)" FT /evidence="ECO:0000269|PubMed:8292730, FT ECO:0000269|PubMed:8499565" FT /id="VAR_006687" FT VARIANT 324 FT /note="G -> R (in THPH3)" FT /evidence="ECO:0000269|PubMed:7792728" FT /id="VAR_006688" FT VARIANT 327 FT /note="E -> V (in patients with PROC deficiency; FT dbSNP:rs199469480)" FT /evidence="ECO:0000269|PubMed:22545135" FT /id="VAR_074305" FT VARIANT 328 FT /note="R -> C (in THPH3; dbSNP:rs201907715)" FT /evidence="ECO:0000269|PubMed:7792728, FT ECO:0000269|PubMed:8499565" FT /id="VAR_006689" FT VARIANT 328 FT /note="R -> H (in THPH4; Muenchen)" FT /evidence="ECO:0000269|PubMed:7878626" FT /id="VAR_006690" FT VARIANT 334 FT /note="G -> S (in THPH4; dbSNP:rs121918150)" FT /evidence="ECO:0000269|PubMed:1593215" FT /id="VAR_006691" FT VARIANT 340 FT /note="T -> M (in THPH3; Vermont-2; dbSNP:rs766261022)" FT /evidence="ECO:0000269|PubMed:8292730, FT ECO:0000269|PubMed:9798967" FT /id="VAR_006692" FT VARIANT 343 FT /note="G -> D (in patients with PROC deficiency)" FT /id="VAR_006693" FT VARIANT 357 FT /note="T -> A (gain of function mutation; abolishes FT glycosylation at N-313; decreases its catalytic activity; FT significant loss of its protective effect on endothelial FT barrier function; increased activation by thrombin)" FT /evidence="ECO:0000269|PubMed:25651845" FT /id="VAR_074306" FT VARIANT 363 FT /note="Missing (in patients with PROC deficiency)" FT /id="VAR_006694" FT VARIANT 367 FT /note="V -> A (in THPH4; neonatal purpura fulminans; FT dbSNP:rs767730328)" FT /evidence="ECO:0000269|PubMed:7841324" FT /id="VAR_006695" FT VARIANT 369 FT /note="P -> L (in THPH3; Osaka-6; dbSNP:rs1211098698)" FT /evidence="ECO:0000269|PubMed:7792728, FT ECO:0000269|PubMed:7865674" FT /id="VAR_006696" FT VARIANT 385 FT /note="M -> I (in patients with PROC deficiency; FT dbSNP:rs1688692415)" FT /evidence="ECO:0000269|PubMed:8499565" FT /id="VAR_006697" FT VARIANT 388 FT /note="A -> T (in patients with PROC deficiency)" FT /evidence="ECO:0000269|PubMed:8499565" FT /id="VAR_006698" FT VARIANT 388 FT /note="A -> V (in patients with PROC deficiency; FT dbSNP:rs769277939)" FT /evidence="ECO:0000269|PubMed:8499565" FT /id="VAR_006699" FT VARIANT 392 FT /note="G -> R (in THPH3; Osaka-9; dbSNP:rs756467027)" FT /evidence="ECO:0000269|PubMed:7865674" FT /id="VAR_006700" FT VARIANT 394 FT /note="R -> W (in patients with PROC deficiency; FT dbSNP:rs759316085)" FT /id="VAR_006701" FT VARIANT 401 FT /note="D -> N (in THPH3; La Jolla-2/Osaka-7 and -8; FT dbSNP:rs142742242)" FT /evidence="ECO:0000269|PubMed:7865674" FT /id="VAR_006702" FT VARIANT 418 FT /note="G -> D (in THPH4; Hong Kong-2)" FT /evidence="ECO:0000269|PubMed:1611081" FT /id="VAR_006703" FT VARIANT 420 FT /note="V -> L (in THPH3; also found in patients with PROC FT deficiency; decrease in vitamin-K dependent serine protease FT activity; dbSNP:rs199469472)" FT /evidence="ECO:0000269|PubMed:22545135, FT ECO:0000269|PubMed:25748729" FT /id="VAR_074307" FT VARIANT 423 FT /note="G -> S (in THPH3)" FT /evidence="ECO:0000269|PubMed:8398832" FT /id="VAR_006704" FT VARIANT 426 FT /note="C -> Y (in THPH3)" FT /evidence="ECO:0000269|PubMed:8292730" FT /id="VAR_006705" FT VARIANT 433 FT /note="G -> S (in patients with PROC deficiency; Purmerend; FT dbSNP:rs1266965698)" FT /id="VAR_006706" FT VARIANT 436 FT /note="T -> N (in THPH3)" FT /evidence="ECO:0000269|PubMed:8829639" FT /id="VAR_006707" FT VARIANT 441 FT /note="Y -> H (in THPH3; Osaka-4; dbSNP:rs753436021)" FT /evidence="ECO:0000269|PubMed:7865674" FT /id="VAR_006708" FT VARIANT 444 FT /note="W -> C (in THPH3; dbSNP:rs121918142)" FT /evidence="ECO:0000269|PubMed:2437584" FT /id="VAR_006709" FT VARIANT 445 FT /note="I -> M (in patients with PROC deficiency; FT dbSNP:rs121918157)" FT /id="VAR_006710" FT CONFLICT 106 FT /note="C -> Q (in Ref. 11; AAA60164)" FT /evidence="ECO:0000305" FT CONFLICT 445 FT /note="I -> IL (in Ref. 3; AAA60165)" FT /evidence="ECO:0000305" FT HELIX 48..50 FT /evidence="ECO:0007829|PDB:1LQV" FT HELIX 55..59 FT /evidence="ECO:0007829|PDB:1LQV" FT HELIX 66..73 FT /evidence="ECO:0007829|PDB:1LQV" FT STRAND 101..103 FT /evidence="ECO:0007829|PDB:6M3B" FT TURN 104..107 FT /evidence="ECO:0007829|PDB:6M3B" FT STRAND 108..111 FT /evidence="ECO:0007829|PDB:6M3B" FT STRAND 120..122 FT /evidence="ECO:0007829|PDB:6M3B" FT STRAND 126..128 FT /evidence="ECO:0007829|PDB:6M3B" FT STRAND 138..142 FT /evidence="ECO:0007829|PDB:6M3B" FT HELIX 143..146 FT /evidence="ECO:0007829|PDB:6M3B" FT STRAND 148..153 FT /evidence="ECO:0007829|PDB:6M3B" FT STRAND 158..161 FT /evidence="ECO:0007829|PDB:6M3B" FT STRAND 166..168 FT /evidence="ECO:0007829|PDB:6M3B" FT STRAND 175..177 FT /evidence="ECO:0007829|PDB:6M3B" FT STRAND 179..181 FT /evidence="ECO:0007829|PDB:6M3B" FT STRAND 226..230 FT /evidence="ECO:0007829|PDB:6M3B" FT STRAND 236..244 FT /evidence="ECO:0007829|PDB:6M3B" FT STRAND 247..250 FT /evidence="ECO:0007829|PDB:6M3B" FT HELIX 252..255 FT /evidence="ECO:0007829|PDB:6M3B" FT STRAND 262..266 FT /evidence="ECO:0007829|PDB:6M3B" FT STRAND 269..272 FT /evidence="ECO:0007829|PDB:6M3B" FT STRAND 278..287 FT /evidence="ECO:0007829|PDB:6M3B" FT TURN 293..295 FT /evidence="ECO:0007829|PDB:6M3B" FT STRAND 301..307 FT /evidence="ECO:0007829|PDB:6M3B" FT HELIX 323..328 FT /evidence="ECO:0007829|PDB:6M3B" FT TURN 329..331 FT /evidence="ECO:0007829|PDB:6M3B" FT STRAND 336..341 FT /evidence="ECO:0007829|PDB:6M3B" FT STRAND 357..359 FT /evidence="ECO:0007829|PDB:1AUT" FT STRAND 361..368 FT /evidence="ECO:0007829|PDB:6M3B" FT HELIX 370..376 FT /evidence="ECO:0007829|PDB:6M3B" FT STRAND 385..388 FT /evidence="ECO:0007829|PDB:6M3B" FT TURN 399..403 FT /evidence="ECO:0007829|PDB:6M3B" FT STRAND 405..410 FT /evidence="ECO:0007829|PDB:6M3B" FT STRAND 413..422 FT /evidence="ECO:0007829|PDB:6M3B" FT STRAND 424..427 FT /evidence="ECO:0007829|PDB:6M3B" FT STRAND 433..437 FT /evidence="ECO:0007829|PDB:6M3B" FT HELIX 438..441 FT /evidence="ECO:0007829|PDB:6M3B" FT HELIX 442..449 FT /evidence="ECO:0007829|PDB:6M3B" SQ SEQUENCE 461 AA; 52071 MW; 3531B0AE5345B39A CRC64; MWQLTSLLLF VATWGISGTP APLDSVFSSS ERAHQVLRIR KRANSFLEEL RHSSLERECI EEICDFEEAK EIFQNVDDTL AFWSKHVDGD QCLVLPLEHP CASLCCGHGT CIDGIGSFSC DCRSGWEGRF CQREVSFLNC SLDNGGCTHY CLEEVGWRRC SCAPGYKLGD DLLQCHPAVK FPCGRPWKRM EKKRSHLKRD TEDQEDQVDP RLIDGKMTRR GDSPWQVVLL DSKKKLACGA VLIHPSWVLT AAHCMDESKK LLVRLGEYDL RRWEKWELDL DIKEVFVHPN YSKSTTDNDI ALLHLAQPAT LSQTIVPICL PDSGLAEREL NQAGQETLVT GWGYHSSREK EAKRNRTFVL NFIKIPVVPH NECSEVMSNM VSENMLCAGI LGDRQDACEG DSGGPMVASF HGTWFLVGLV SWGEGCGLLH NYGVYTKVSR YLDWIHGHIR DKEAPQKSWA P //