P04070 (PROC_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Vitamin K-dependent protein C
EC=3.4.21.69

Alternative name(s):
Anticoagulant protein C
Autoprothrombin IIA
Blood coagulation factor XIV

Cleaved into the following 3 chains:

1. Vitamin K-dependent protein C light chain
2. Vitamin K-dependent protein C heavy chain
3. Activation peptide

Gene names

Name:

PROC

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	461 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

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.
Catalytic activity	Degradation of blood coagulation factors Va and VIIIa.
Subunit structure	Synthesized 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.
Tissue specificity	Plasma; synthesized in the liver.
Post-translational modification	The vitamin K-dependent, enzymatic carboxylation of some Glu residues allows the modified protein to bind calcium. N- and O-glycosylated. Partial (70%) N-glycosylation of Asn-371 with an atypical N-X-C site produces a higher molecular weight form referred to as alpha. The lower molecular weight form, not N-glycosylated at Asn-371, is beta. O-glycosylated with core 1 or possibly core 8 glycans. Ref.12 Ref.15 The iron and 2-oxoglutarate dependent 3-hydroxylation of aspartate and asparagine is (R) stereospecific within EGF domains. May be phosphorylated on a Ser or Thr in a region (AA 25-30) of the propeptide.
Involvement in disease	Thrombophilia due to protein C deficiency, autosomal dominant (THPH3) [MIM:176860]: A hemostatic disorder characterized by impaired regulation of blood coagulation and a tendency to recurrent venous thrombosis. Individuals with decreased amounts of protein C are classically referred to as having type I protein C deficiency and those with normal amounts of a functionally defective protein as having type II deficiency. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.8 Ref.19 Ref.20 Ref.21 Ref.22 Ref.25 Ref.26 Ref.30 Ref.31 Ref.32 Ref.36 Ref.39 Ref.40 Ref.41 Thrombophilia due to protein C deficiency, autosomal recessive (THPH4) [MIM:612304]: A hemostatic disorder characterized by impaired regulation of blood coagulation and a tendency to recurrent venous thrombosis. It results in a thrombotic condition that can manifest as a severe neonatal disorder or as a milder disorder with late-onset thrombophilia. The severe form leads to neonatal death through massive neonatal venous thrombosis. Often associated with ecchymotic skin lesions which can turn necrotic called purpura fulminans, this disorder is very rare. Note: The disease is caused by mutations affecting the gene represented in this entry.
Miscellaneous	Calcium also binds, with stronger affinity to another site, beyond the GLA domain. This GLA-independent binding site is necessary for the recognition of the thrombin-thrombomodulin complex.
Sequence similarities	Belongs to the peptidase S1 family. Contains 2 EGF-like domains. Contains 1 Gla (gamma-carboxy-glutamate) domain. Contains 1 peptidase S1 domain.
Sequence caution	The sequence S76088 differs from that shown. Reason: Erroneous termination at position 151. Translated as Cys.

Ontologies

Keywords
Biological process	Blood coagulation Hemostasis
Coding sequence diversity	Polymorphism
Disease	Disease mutation Thrombophilia
Domain	EGF-like domain Repeat Signal
Ligand	Calcium
Molecular function	Hydrolase Protease Serine protease
PTM	Cleavage on pair of basic residues Disulfide bond Gamma-carboxyglutamic acid Glycoprotein Hydroxylation Zymogen
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	blood coagulation Traceable author statement. Source: Reactome leukocyte migration Traceable author statement. Source: Reactome negative regulation of apoptotic process Inferred from mutant phenotype PubMed 12563316. Source: UniProtKB negative regulation of blood coagulation Traceable author statement PubMed 15005336. Source: UniProtKB peptidyl-glutamic acid carboxylation Traceable author statement. Source: Reactome post-translational protein modification Traceable author statement. Source: Reactome proteolysis Non-traceable author statement PubMed 12052963. Source: UniProtKB
Cellular_component	Golgi lumen Traceable author statement. Source: Reactome endoplasmic reticulum lumen Traceable author statement. Source: Reactome extracellular region Non-traceable author statement PubMed 14718574. Source: UniProtKB plasma membrane Traceable author statement. Source: Reactome
Molecular_function	calcium ion binding Inferred from electronic annotation. Source: InterPro serine-type endopeptidase activity Traceable author statement PubMed 15005336. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
MMP15	P51511	2	EBI-1383018,EBI-1383043

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 18

18

Potential

Propeptide

19 – 42

24

PRO_0000028107

Chain

43 – 461

419

Vitamin K-dependent protein C

PRO_0000028108

Chain

43 – 197

155

Vitamin K-dependent protein C light chain

PRO_0000028109

Chain

200 – 461

262

Vitamin K-dependent protein C heavy chain

PRO_0000028110

Peptide

200 – 211

12

Activation peptide

PRO_0000028111

Regions

Domain

43 – 88

46

Gla

Domain

97 – 132

36

EGF-like 1

Domain

136 – 176

41

EGF-like 2

Domain

212 – 450

239

Peptidase S1

Sites

Active site

253

1

Charge relay system

Active site

299

1

Charge relay system

Active site

402

1

Charge relay system

Site

211 – 212

2

Cleavage; by thrombin

Amino acid modifications

Modified residue

48

1

4-carboxyglutamate

Modified residue

49

1

4-carboxyglutamate

Modified residue

56

1

4-carboxyglutamate

Modified residue

58

1

4-carboxyglutamate Ref.2

Modified residue

61

1

4-carboxyglutamate

Modified residue

62

1

4-carboxyglutamate

Modified residue

67

1

4-carboxyglutamate

Modified residue

68

1

4-carboxyglutamate

Modified residue

71

1

4-carboxyglutamate

Modified residue

113

1

(3R)-3-hydroxyaspartate

Glycosylation

19

1

O-linked (GalNAc...) Ref.15

Glycosylation

139

1

N-linked (GlcNAc...)

Glycosylation

290

1

N-linked (GlcNAc...) Ref.14

Glycosylation

355

1

N-linked (GlcNAc...)

Glycosylation

371

1

N-linked (GlcNAc...); partial; atypical Ref.12

Disulfide bond

59 ↔ 64

Disulfide bond

92 ↔ 111

Disulfide bond

101 ↔ 106

Disulfide bond

105 ↔ 120

Disulfide bond

122 ↔ 131

Disulfide bond

140 ↔ 151

Disulfide bond

147 ↔ 160

Disulfide bond

162 ↔ 175

Disulfide bond

183 ↔ 319

Interchain (between light and heavy chains)

Disulfide bond

238 ↔ 254

Disulfide bond

373 ↔ 387

Disulfide bond

398 ↔ 426

Natural variations

Natural variant

14

1

W → G in patients with PROC deficiency. Ref.29 Ref.34

VAR_006634

Natural variant

32

1

R → C in THPH3. Ref.40

VAR_006635

Natural variant

38

1

R → W in patients with PROC deficiency. Ref.28

VAR_006636

Natural variant

42

1

R → C in patients with PROC deficiency. Ref.28

VAR_006638

Natural variant

42

1

R → H in Malakoff; low anticoagulant activity. Ref.28

VAR_006637

Natural variant

42

1

R → S in THPH3; type II; Osaka-10; alters proteolytic processing so that S-42 is the N-terminus of the mature protein. Ref.8

VAR_055074

Natural variant

43

1

A → T. Ref.39

VAR_006639

Natural variant

49

1

E → D in patients with PROC deficiency. Ref.37

VAR_006640

Natural variant

51

1

R → C in patients with PROC deficiency.

VAR_006641

Natural variant

57

1

R → G in Yonago; defective anticoagulant activity. Ref.9

VAR_006643

Natural variant

57

1

R → Q in patients with PROC deficiency.

VAR_006644

Natural variant

57

1

R → W in THPH3. Ref.30 Ref.39

VAR_006642

Natural variant

62

1

E → A in THPH3; Vermont-1. Ref.22

VAR_006645

Natural variant

76

1

V → M in THPH3; Vermont-1. Ref.22

VAR_006646

Natural variant

89

1

G → C in patients with PROC deficiency. Ref.38

VAR_006647

Natural variant

108

1

H → N in patients with PROC deficiency; La Jolla-1.

VAR_006648

Natural variant

109

1

G → R in patients with PROC deficiency.

VAR_006649

Natural variant

114 – 118

5

Missing in patients with PROC deficiency.

VAR_006650

Natural variant

114

1

G → R in THPH3. Ref.39

VAR_006651

Natural variant

118

1

F → L in patients with PROC deficiency.

VAR_006652

Natural variant

119 – 124

6

Missing in patients with PROC deficiency; St Louis-2.

VAR_006653

Natural variant

120 – 125

6

Missing in patients with PROC deficiency; St Louis-3.

VAR_006654

Natural variant

144 – 145

2

NG → K in THPH4; neonatal purpura fulminans.

VAR_006655

Natural variant

145

1

G → R in THPH3. Ref.31

VAR_006656

Natural variant

147

1

C → Y in patients with PROC deficiency.

VAR_006657

Natural variant

149

1

H → P in patients with PROC deficiency.

VAR_006658

Natural variant

161

1

S → R in patients with PROC deficiency.

VAR_006659

Natural variant

178

1

A → P in THPH4; Clamart. Ref.11

VAR_006660

Natural variant

183

1

C → R in patients with PROC deficiency.

VAR_006661

Natural variant

189

1

R → W in patients with PROC deficiency; La Jolla-3.

VAR_006662

Natural variant

194

1

R → C in patients with PROC deficiency.

VAR_006663

Natural variant

210

1

P → L in THPH3. Ref.31

VAR_006664

Natural variant

211

1

R → Q in patients with PROC deficiency. Ref.29
Corresponds to variant rs28933987 [ dbSNP | Ensembl ].

VAR_006666

Natural variant

211

1

R → W in THPH3; London-1/Tochigi. Ref.20 Ref.31
Corresponds to variant rs28933986 [ dbSNP | Ensembl ].

VAR_006665

Natural variant

220

1

R → P in patients with PROC deficiency. Ref.38

VAR_006667

Natural variant

220

1

R → Q in THPH3; Vermont-3. Ref.25 Ref.26 Ref.41

VAR_006669

Natural variant

220

1

R → W in THPH3. Ref.25

VAR_006668

Natural variant

226

1

Q → H in patients with PROC deficiency.

VAR_006670

Natural variant

243

1

I → T in THPH3. Ref.31

VAR_006671

Natural variant

244

1

H → Y in patients with PROC deficiency. Ref.29

VAR_006672

Natural variant

253

1

H → Q in patients with PROC deficiency. Ref.29

VAR_006673

Natural variant

265

1

L → F in patients with PROC deficiency.

VAR_006674

Natural variant

271

1

R → Q in Marseille; low anticoagulant activity. Ref.28

VAR_006675

Natural variant

271

1

R → W in patients with PROC deficiency.

VAR_006676

Natural variant

272

1

R → C in THPH3. Ref.21

VAR_006677

Natural variant

281

1

D → DLD in patients with PROC deficiency.

VAR_006678

Natural variant

289

1

P → L in THPH4. Ref.24

VAR_006679

Natural variant

294

1

S → N in Paris; low anticoagulant activity. Ref.28

VAR_006680

Natural variant

298

1

N → D in patients with PROC deficiency.

VAR_006681

Natural variant

301

1

A → T in patients with PROC deficiency. Ref.38

VAR_006682

Natural variant

301

1

A → V in patients with PROC deficiency.

VAR_006683

Natural variant

309

1

A → T in patients with PROC deficiency.

VAR_006684

Natural variant

312

1

S → L in patients with PROC deficiency.

VAR_006685

Natural variant

312

1

S → P in a patient with PROC deficiency; sporadic case. Ref.33

VAR_006686

Natural variant

321

1

P → L in THPH3. Ref.29 Ref.31

VAR_006687

Natural variant

324

1

G → R in THPH3. Ref.39

VAR_006688

Natural variant

328

1

R → C in THPH3. Ref.29 Ref.39

VAR_006689

Natural variant

328

1

R → H in THPH4; Muenchen. Ref.11

VAR_006690

Natural variant

334

1

G → S in THPH4. Ref.27

VAR_006691

Natural variant

340

1

T → M in THPH3; Vermont-2. Ref.31 Ref.41

VAR_006692

Natural variant

343

1

G → D in patients with PROC deficiency.

VAR_006693

Natural variant

363

1

Missing in patients with PROC deficiency.

VAR_006694

Natural variant

367

1

V → A in THPH4; neonatal purpura fulminans. Ref.35

VAR_006695

Natural variant

369

1

P → L in THPH3; Osaka-6. Ref.36 Ref.39

VAR_006696

Natural variant

385

1

M → I in patients with PROC deficiency. Ref.29

VAR_006697

Natural variant

388

1

A → T in patients with PROC deficiency. Ref.29

VAR_006698

Natural variant

388

1

A → V in patients with PROC deficiency. Ref.29

VAR_006699

Natural variant

392

1

G → R in THPH3; Osaka-9. Ref.36

VAR_006700

Natural variant

394

1

R → W in patients with PROC deficiency.

VAR_006701

Natural variant

401

1

D → N in THPH3; La Jolla-2/Osaka-7 and -8. Ref.36

VAR_006702

Natural variant

418

1

G → D in THPH4; Hong Kong-2. Ref.23

VAR_006703

Natural variant

423

1

G → S in THPH3. Ref.32

VAR_006704

Natural variant

426

1

C → Y in THPH3. Ref.31

VAR_006705

Natural variant

433

1

G → S in patients with PROC deficiency; Purmerend.

VAR_006706

Natural variant

436

1

T → N in THPH3. Ref.40

VAR_006707

Natural variant

441

1

Y → H in THPH3; Osaka-4. Ref.36

VAR_006708

Natural variant

444

1

W → C in THPH3. Ref.19

VAR_006709

Natural variant

445

1

I → M in patients with PROC deficiency.

VAR_006710

Experimental info

Sequence conflict

106

1

C → Q in AAA60164. Ref.10

Sequence conflict

445

1

I → IL in AAA60165. Ref.3

Secondary structure

1

.

.

.

.

.

.

.

461

Helix Strand Turn

Details...

Helix

48 – 50

3

Helix

55 – 59

5

Helix

66 – 73

8

Sequences

	Sequence		Length	Mass (Da)
	P04070 [UniParc]. Last modified November 1, 1986. Version 1. Checksum: 3531B0AE5345B39A	FASTA	461	52,071
	10 20 30 40 50 60 MWQLTSLLLF VATWGISGTP APLDSVFSSS ERAHQVLRIR KRANSFLEEL RHSSLERECI 70 80 90 100 110 120 EEICDFEEAK EIFQNVDDTL AFWSKHVDGD QCLVLPLEHP CASLCCGHGT CIDGIGSFSC 130 140 150 160 170 180 DCRSGWEGRF CQREVSFLNC SLDNGGCTHY CLEEVGWRRC SCAPGYKLGD DLLQCHPAVK 190 200 210 220 230 240 FPCGRPWKRM EKKRSHLKRD TEDQEDQVDP RLIDGKMTRR GDSPWQVVLL DSKKKLACGA 250 260 270 280 290 300 VLIHPSWVLT AAHCMDESKK LLVRLGEYDL RRWEKWELDL DIKEVFVHPN YSKSTTDNDI 310 320 330 340 350 360 ALLHLAQPAT LSQTIVPICL PDSGLAEREL NQAGQETLVT GWGYHSSREK EAKRNRTFVL 370 380 390 400 410 420 NFIKIPVVPH NECSEVMSNM VSENMLCAGI LGDRQDACEG DSGGPMVASF HGTWFLVGLV 430 440 450 460 SWGEGCGLLH NYGVYTKVSR YLDWIHGHIR DKEAPQKSWA P

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"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." Beckmann R.J., Schmidt R.J., Santerre R.F., Plutzky J., Crabtree G.R., Long G.L. Nucleic Acids Res. 13:5233-5247(1985) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"The nucleotide sequence of the gene for human protein C." Foster D.C., Yoshitake S., Davie E.W. Proc. Natl. Acad. Sci. U.S.A. 82:4673-4677(1985) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"Evolution and organization of the human protein C gene." Plutzky J., Hoskins J.A., Long G.L., Crabtree G.R. Proc. Natl. Acad. Sci. U.S.A. 83:546-550(1986) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]	SeattleSNPs variation discovery resource Submitted (JUN-2001) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[5]	"Generation and annotation of the DNA sequences of human chromosomes 2 and 4." Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., Du H. , Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., Wilson R.K. Nature 434:724-731(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Colon.
[8]	"Protein C Osaka 10 with aberrant propeptide processing: loss of anticoagulant activity due to an amino acid substitution in the protein C precursor." Miyata T., Zheng Y.-Z., Sakata T., Kato H. Thromb. Haemost. 74:1003-1008(1995) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 42-57, VARIANT THPH3 SER-42. Tissue: Blood.
[9]	"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." Mimuro J., Muramatsu S., Kaneko M., Yoshitake S., Iijima K., Nakamura K., Sakata Y., Matsuda M. Int. J. Hematol. 57:9-14(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 43-64, VARIANT PROC DEFICIENCY GLY-57.
[10]	"Characterization of a cDNA coding for human protein C." Foster D.C., Davie E.W. Proc. Natl. Acad. Sci. U.S.A. 81:4766-4770(1984) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 106-461.
[11]	"Homozygous type I protein C deficiency in two unrelated families exhibiting thrombophilia related to Ala136-->Pro or Arg286-->His mutations." Long G.L., Tomczak J.A., Rainville I.R., Dreyfus M., Schramm W., Schwarz H.P. Thromb. Haemost. 72:526-533(1994) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 134-178 AND 267-332, VARIANTS THPH4 PRO-178 AND HIS-328.
[12]	"Beta protein C is not glycosylated at asparagine 329. The rate of translation may influence the frequency of usage at asparagine-X-cysteine sites." Miletich J.P., Broze G.J. Jr. J. Biol. Chem. 265:11397-11404(1990) [PubMed] [Europe PMC] [Abstract] Cited for: GLYCOSYLATION AT ASN-371.
[13]	"O-linked fucose is present in the first epidermal growth factor domain of factor XII but not protein C." Harris R.J., Ling V.T., Spellman M.W. J. Biol. Chem. 267:5102-5107(1992) [PubMed] [Europe PMC] [Abstract] Cited for: HYDROXYLATION.
[14]	"Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry." Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E., Moore R.J., Smith R.D. J. Proteome Res. 4:2070-2080(2005) [PubMed] [Europe PMC] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-290, MASS SPECTROMETRY. Tissue: Plasma.
[15]	"Human urinary glycoproteomics; attachment site specific analysis of N-and O-linked glycosylations by CID and ECD." Halim A., Nilsson J., Ruetschi U., Hesse C., Larson G. Mol. Cell. Proteomics 0:0-0(2011) [PubMed] [Europe PMC] [Abstract] Cited for: GLYCOSYLATION AT THR-19, STRUCTURE OF CARBOHYDRATES, MASS SPECTROMETRY.
[16]	"Models of the serine protease domain of the human antithrombotic plasma factor activated protein C and its zymogen." Fisher C.L., Greengard J.S., Griffin J.H. Protein Sci. 3:588-599(1994) [PubMed] [Europe PMC] [Abstract] Cited for: 3D-STRUCTURE MODELING OF 175-450.
[17]	"The 2.8 A crystal structure of Gla-domainless activated protein C." Mather T., Oganessyan V., Hof P., Huber R., Foundling S., Esmon C., Bode W. EMBO J. 15:6822-6831(1996) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 84-461.
[18]	"Protein C deficiency: a database of mutations." Reitsma P.H., Poort S.R., Bernardi F., Gandrille S., Long G.L., Sala N., Cooper D.N. Thromb. Haemost. 69:77-84(1993) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON PROC VARIANTS.
[19]	"Hereditary thrombophilia: identification of nonsense and missense mutations in the protein C gene." Romeo G., Hassan H.J., Staempfli S., Roncuzzi L., Cianetti L., Leonardi A., Vicente V., Mannucci P.M., Bertina R.M., Peschle C., Cortese R. Proc. Natl. Acad. Sci. U.S.A. 84:2829-2832(1987) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT THPH3 CYS-444.
[20]	"Protein C London 1: recurrent mutation at Arg-169 (CGG-->TGG) in the protein C gene causing thrombosis." Grundy C.B., Chitolie A., Talbot S., Bevan D., Kakkar V.V., Cooper D.N. Nucleic Acids Res. 17:10513-10513(1989) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT THPH3 TRP-211.
[21]	"The spectrum of genetic defects in a panel of 40 Dutch families with symptomatic protein C deficiency type I: heterogeneity and founder effects." Reitsma P.H., Poort S.R., Allaart C.F., Briet E., Bertina R.M. Blood 78:890-894(1991) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT THPH3 CYS-272.
[22]	"Protein CVermont: symptomatic type II protein C deficiency associated with two GLA domain mutations." Bovill E.G., Tomczak J.A., Grant B., Bhushan F., Pillemer E., Rainville I.R., Long G.L. Blood 79:1456-1465(1992) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS THPH3 ALA-62 AND MET-76.
[23]	"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." Sugahara Y., Miura O., Yuen P., Aoki N. Blood 80:126-133(1992) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT THPH4 ASP-418.
[24]	"A novel homozygous missense mutation in the protein C (PROC) gene causing recurrent venous thrombosis." Grundy C.B., Chisholm M., Kakkar V.V., Cooper D.N. Hum. Genet. 89:683-684(1992) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT THPH4 LEU-289.
[25]	"Two different missense mutations at Arg 178 of the protein C (PROC) gene causing recurrent venous thrombosis." Grundy C.B., Schulman S., Tengborn L., Kakkar V.V., Cooper D.N. Hum. Genet. 89:685-686(1992) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS THPH3 GLN-220 AND TRP-220.
[26]	"Two novel mutations responsible for hereditary type I protein C deficiency: characterization by denaturing gradient gel electrophoresis." Gandrille S., Vidaud M., Aiach M., Alhenc-Gelas M., Fischer A.M., Gouault-Heilman M., Toulon P., Fiessinger J.-N., Goossens M. Hum. Mutat. 1:491-500(1992) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT THPH3 GLN-220.
[27]	"Homozygous protein C deficiency: identification of a novel missense mutation that causes impaired secretion of the mutant protein C." Yamamoto K., Matsushita T., Sugiura I., Takamatsu J., Iwasaki E., Wada H., Deguchi K., Shirakawa S., Saito H. J. Lab. Clin. Med. 119:682-689(1992) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT THPH4 SER-334.
[28]	"Five novel mutations located in exons III and IX of the protein C gene in patients presenting with defective protein C anticoagulant activity." Gandrille S., Alhenc-Gelas M., Gaussem P., Aillaud M.-F., Dupuy E., Juhan-Vague I., Aiach M. Blood 82:159-168(1993) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS TRP-38; CYS-42; HIS-42; GLN-271 AND ASN-294.
[29]	"Twelve novel and two recurrent mutations in 14 Austrian families with hereditary protein C deficiency." Poort S.R., Pabinger-Fasching I., Mannhalter C., Reitsma P.H., Bertina R.M. Blood Coagul. Fibrinolysis 4:273-280(1993) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS GLY-14; GLN-211; TYR-244; GLN-253; LEU-321; CYS-328; ILE-385; THR-388 AND VAL-388.
[30]	"A Gla domain mutation (Arg 15-->Trp) in the protein C (PROC) gene causing type 2 protein C deficiency and recurrent venous thrombosis." Millar D.S., Grundy C.B., Bignell P., Moffat E.H., Martin R., Kakkar V.V., Cooper D.N. Blood Coagul. Fibrinolysis 4:345-347(1993) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT THPH3 TRP-57.
[31]	"Genetic mutations in ten unrelated American patients with symptomatic type 1 protein C deficiency." Tsay W., Greengard J.S., Montgomery R.R., McPherson R.A., Fucci J.C., Koerper M.A., Coughlin J., Griffin J.H. Blood Coagul. Fibrinolysis 4:791-796(1993) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS THPH3 ARG-145; LEU-210; TRP-211; THR-243; LEU-321; MET-340 AND TYR-426.
[32]	"Symptomatic type II protein C deficiency caused by a missense mutation (Gly 381-->Ser) in the substrate-binding pocket." Marchetti G., Patracchini P., Gemmati D., Castaman G., Rodeghiero F., Wacey A., Cooper D.N., Tuddenham E.G., Bernardi F. Br. J. Haematol. 84:285-289(1993) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT THPH3 SER-423.
[33]	"First de novo mutations in the protein C gene of two patients with type I deficiency: a missense mutation and a splice site deletion." Gandrille S., Jude B., Alhenc-Gelas M., Emmerich J., Aiach M. Blood 84:2566-2570(1994) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT PRO-312.
[34]	"A homozygous deletion/insertion mutation in the protein C (PROC) gene causing neonatal Purpura fulminans: prenatal diagnosis in an at-risk pregnancy." Millar D.S., Allgrove J., Rodeck C., Kakkar V.V., Cooper D.N. Blood Coagul. Fibrinolysis 5:647-649(1994) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT THPH4 144-ASN-GLY-145 DELINS LYS.
[35]	"A novel homozygous missense mutation (Val 325-->Ala) in the protein C gene causing neonatal purpura fulminans." Witt I., Beck S., Seydewitz H.H., Tasangil C., Schenck W. Blood Coagul. Fibrinolysis 5:651-653(1994) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT THPH4 ALA-367.
[36]	"Six missense mutations associated with type I and type II protein C deficiency and implications obtained from molecular modelling." Zheng Y.-Z., Sakata T., Matsusue T., Umeyama H., Kato H., Miyata T. Blood Coagul. Fibrinolysis 5:687-696(1994) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS THPH3 LEU-369; ARG-392; ASN-401 AND HIS-441.
[37]	"Influence of six mutations of the protein C gene on the Gla domain conformation and calcium affinity." Gaussem P., Gandrille S., Duchemin J., Emmerich J., Alhenc-Gelas M., Aillaud M.-F., Aiach M. Thromb. Haemost. 71:748-754(1994) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT ASP-49.
[38]	"Three novel mutations in the protein C (PROC) gene causing venous thrombosis." Millar D.S., Bevan D., Chitolie A., Reynaud J., Chisholm M., Kakkar V.V., Cooper D.N. Blood Coagul. Fibrinolysis 6:138-140(1995) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS CYS-89; PRO-220 AND THR-301.
[39]	"Six different point mutations in seven Danish families with symptomatic protein C deficiency." Lind B., Schwartz M., Thorsen S. Thromb. Haemost. 73:186-193(1995) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS THPH3 TRP-57; ARG-114; ARG-324; CYS-328 AND LEU-369, VARIANT THR-43.
[40]	"Two novel (R(-11)C; T394D) and two repeat missense mutations in the protein C gene associated with venous thrombosis in six kindreds." Ireland H.A., Boisclair M.D., Taylor J., Thompson E., Thein S.L., Girolami A., de Caterina M., Scopacasa F., de Stefano V., Leone G., Finazzi G., Cohen H., Lane D.A. Hum. Mutat. 7:176-179(1996) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS THPH3 CYS-32 AND ASN-436.
[41]	"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." Couture P., Demers C., Morissette J., Delage R., Jomphe M., Couture L., Simard J. Thromb. Haemost. 80:551-556(1998) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS THPH3 GLN-220 AND MET-340.
+	Additional computationally mapped references.

Web resources

Wikipedia

Protein C entry

GeneReviews

SeattleSNPs

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

X02750 mRNA. Translation: CAA26528.1.
M11228 Genomic DNA. Translation: AAA60166.1.
M12712 , M12683, M12684, M12685, M12686, M12687 Genomic DNA. Translation: AAA60165.1.
AF378903 Genomic DNA. Translation: AAK56377.1.
AC068282 Genomic DNA. Translation: AAY15044.1.
CH471103 Genomic DNA. Translation: EAW95320.1.
BC034377 mRNA. Translation: AAH34377.1.
S58668 Genomic DNA. Translation: AAB26335.1.
K02059 mRNA. Translation: AAA60164.1.
S76088 Genomic DNA. No translation available.
S76090 Genomic DNA. No translation available.

IPI

IPI00021817.

PIR

KXHU. A22331.

RefSeq

NP_000303.1. NM_000312.3.

UniGene

Hs.224698.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1AUT	X-ray	2.80	C	212-461	[»]
			L	84-197	[»]
1LQV	X-ray	1.60	C/D	43-75	[»]
1PCU	model	-	A	175-450	[»]
2PCT	model	-	A	175-450	[»]
3F6U	X-ray	2.80	H	212-451	[»]
			L	91-188	[»]
3JTC	X-ray	1.60	C/D	43-75	[»]
4DT7	X-ray	1.90	E/F	204-223	[»]

ProteinModelPortal

P04070.

ModBase

Search...

Protein-protein interaction databases

IntAct

P04070. 1 interaction.

STRING

9606.ENSP00000234071.

Protein family/group databases

MEROPS

S01.218.

PTM databases

GlycoSuiteDB

P04070.

PhosphoSite

P04070.

Polymorphism databases

DMDM

131067.

Proteomic databases

PaxDb

P04070.

PeptideAtlas

P04070.

PRIDE

P04070.

Protocols and materials databases

DNASU

5624.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000234071; ENSP00000234071; ENSG00000115718.
ENST00000422777; ENSP00000409543; ENSG00000115718.

GeneID

5624.

KEGG

hsa:5624.

UCSC

uc002tok.3. human.

Organism-specific databases

CTD

5624.

GeneCards

GC02P128176.

HGNC

HGNC:9451. PROC.

HPA

CAB016721.
CAB016792.
HPA005550.

MIM

176860. phenotype.
612283. gene.
612304. phenotype.

neXtProt

NX_P04070.

Orphanet

745. Hereditary thrombophilia due to congenital protein C deficiency.

PharmGKB

PA33799.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG5640.

HOGENOM

HOG000251821.

HOVERGEN

HBG013304.

KO

K01344.

PhylomeDB

P04070.

Enzyme and pathway databases

Reactome

REACT_17015. Metabolism of proteins.
REACT_604. Hemostasis.

Gene expression databases

ArrayExpress

P04070.

Bgee

P04070.

CleanEx

HS_PROC.

Genevestigator

P04070.

GermOnline

ENSG00000115718. Homo sapiens.

Family and domain databases

Gene3D

4.10.740.10. 1 hit.

InterPro

IPR017857. Coagulation_fac_subgr_Gla_dom.
IPR000742. EG-like_dom.
IPR001881. EGF-like_Ca-bd.
IPR013032. EGF-like_CS.
IPR000152. EGF-type_Asp/Asn_hydroxyl_site.
IPR018097. EGF_Ca-bd_CS.
IPR000294. GLA_domain.
IPR012224. Pept_S1A_FX.
IPR001254. Peptidase_S1.
IPR018114. Peptidase_S1_AS.
IPR001314. Peptidase_S1A.
IPR009003. Trypsin-like_Pept_dom.
[Graphical view]

Pfam

PF00594. Gla. 1 hit.
PF00089. Trypsin. 1 hit.
[Graphical view]

PIRSF

PIRSF001143. Factor_X. 1 hit.

PRINTS

PR00722. CHYMOTRYPSIN.
PR00001. GLABLOOD.

SMART

SM00181. EGF. 1 hit.
SM00179. EGF_CA. 1 hit.
SM00069. GLA. 1 hit.
SM00020. Tryp_SPc. 1 hit.
[Graphical view]

SUPFAM

SSF50494. Pept_Ser_Cys. 1 hit.
SSF57630. VitK_dep_GLA. 1 hit.

PROSITE

PS00010. ASX_HYDROXYL. 1 hit.
PS00022. EGF_1. 1 hit.
PS01186. EGF_2. 2 hits.
PS50026. EGF_3. 1 hit.
PS01187. EGF_CA. 1 hit.
PS00011. GLA_1. 1 hit.
PS50998. GLA_2. 1 hit.
PS50240. TRYPSIN_DOM. 1 hit.
PS00134. TRYPSIN_HIS. 1 hit.
PS00135. TRYPSIN_SER. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P04070.

ChEMBL

CHEMBL4444.

DrugBank

DB00025. Antihemophilic Factor.
DB00055. Drotrecogin alfa.
DB00170. Menadione.
DB00464. Sodium Tetradecyl Sulfate.

EvolutionaryTrace

P04070.

GenomeRNAi

5624.

NextBio

21860.

PMAP-CutDB

P04070.

SOURCE

Search...

Entry information

Entry name

PROC_HUMAN

Accession

Primary (citable) accession number: P04070
Secondary accession number(s): Q15189 , Q15190, Q16001, Q53S74, Q9UC55

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1986
Last sequence update:	November 1, 1986
Last modified:	May 1, 2013
This is version 182 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.