Full text data of PROZ
PROZ
[Confidence: low (only semi-automatic identification from reviews)]
Vitamin K-dependent protein Z; Flags: Precursor
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Vitamin K-dependent protein Z; Flags: Precursor
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P22891
ID PROZ_HUMAN Reviewed; 400 AA.
AC P22891; A6NMB4; Q15213; Q5JVF5; Q5JVF6;
DT 01-AUG-1991, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1991, sequence version 2.
DT 22-JAN-2014, entry version 155.
DE RecName: Full=Vitamin K-dependent protein Z;
DE Flags: Precursor;
GN Name=PROZ;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PARTIAL PROTEIN SEQUENCE.
RC TISSUE=Liver;
RX PubMed=2244898; DOI=10.1016/0006-291X(90)91566-B;
RA Ichinose A., Takeya H., Espling E., Iwanaga S., Kisiel W., Davie E.W.;
RT "Amino acid sequence of human protein Z, a vitamin K-dependent plasma
RT glycoprotein.";
RL Biochem. Biophys. Res. Commun. 172:1139-1144(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND ALTERNATIVE SPLICING.
RX PubMed=9578570; DOI=10.1021/bi972002a;
RA Fujimaki K., Yamazaki T., Taniwaki M., Ichinose A.;
RT "The gene for human protein Z is localized to chromosome 13 at band
RT q34 and is coded by eight regular exons and one alternative exon.";
RL Biochemistry 37:6838-6846(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS LYS-70 AND HIS-295.
RG SeattleSNPs variation discovery resource;
RL Submitted (OCT-2001) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NHLBI resequencing and genotyping service (RS&G;);
RL Submitted (FEB-2007) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057823; DOI=10.1038/nature02379;
RA Dunham A., Matthews L.H., Burton J., Ashurst J.L., Howe K.L.,
RA Ashcroft K.J., Beare D.M., Burford D.C., Hunt S.E.,
RA Griffiths-Jones S., Jones M.C., Keenan S.J., Oliver K., Scott C.E.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Andrews D.T.,
RA Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Bannerjee R.,
RA Barlow K.F., Bates K., Beasley H., Bird C.P., Bray-Allen S.,
RA Brown A.J., Brown J.Y., Burrill W., Carder C., Carter N.P.,
RA Chapman J.C., Clamp M.E., Clark S.Y., Clarke G., Clee C.M.,
RA Clegg S.C., Cobley V., Collins J.E., Corby N., Coville G.J.,
RA Deloukas P., Dhami P., Dunham I., Dunn M., Earthrowl M.E.,
RA Ellington A.G., Faulkner L., Frankish A.G., Frankland J., French L.,
RA Garner P., Garnett J., Gilbert J.G.R., Gilson C.J., Ghori J.,
RA Grafham D.V., Gribble S.M., Griffiths C., Hall R.E., Hammond S.,
RA Harley J.L., Hart E.A., Heath P.D., Howden P.J., Huckle E.J.,
RA Hunt P.J., Hunt A.R., Johnson C., Johnson D., Kay M., Kimberley A.M.,
RA King A., Laird G.K., Langford C.J., Lawlor S., Leongamornlert D.A.,
RA Lloyd D.M., Lloyd C., Loveland J.E., Lovell J., Martin S.,
RA Mashreghi-Mohammadi M., McLaren S.J., McMurray A., Milne S.,
RA Moore M.J.F., Nickerson T., Palmer S.A., Pearce A.V., Peck A.I.,
RA Pelan S., Phillimore B., Porter K.M., Rice C.M., Searle S.,
RA Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Steward C.A.,
RA Sycamore N., Tester J., Thomas D.W., Tracey A., Tromans A., Tubby B.,
RA Wall M., Wallis J.M., West A.P., Whitehead S.L., Willey D.L.,
RA Wilming L., Wray P.W., Wright M.W., Young L., Coulson A., Durbin R.M.,
RA Hubbard T., Sulston J.E., Beck S., Bentley D.R., Rogers J., Ross M.T.;
RT "The DNA sequence and analysis of human chromosome 13.";
RL Nature 428:522-528(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 81-400, AND PROTEIN SEQUENCE OF 63-103.
RX PubMed=2403355; DOI=10.1016/0006-291X(90)91197-Z;
RA Sejima H., Hayashi T., Deyashiki Y., Nishioka J., Suzuki K.;
RT "Primary structure of vitamin K-dependent human protein Z.";
RL Biochem. Biophys. Res. Commun. 171:661-668(1990).
RN [9]
RP STRUCTURE OF CARBOHYDRATE ON SER-93.
RX PubMed=2511201;
RA Nishimura H., Kawabata S., Kisiel W., Hase S., Ikenaka T., Takao T.,
RA Shimonishi Y., Iwanaga S.;
RT "Identification of a disaccharide (Xyl-Glc) and a trisaccharide (Xyl2-
RT Glc) O-glycosidically linked to a serine residue in the first
RT epidermal growth factor-like domain of human factors VII and IX and
RT protein Z and bovine protein Z.";
RL J. Biol. Chem. 264:20320-20325(1989).
RN [10]
RP STRUCTURE OF CARBOHYDRATE ON SER-93.
RX PubMed=2129367;
RA Iwanaga S., Nishimura H., Kawabata S., Kisiel W., Hase S., Ikenaka T.;
RT "A new trisaccharide sugar chain linked to a serine residue in the
RT first EGF-like domain of clotting factors VII and IX and protein Z.";
RL Adv. Exp. Med. Biol. 281:121-131(1990).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 125-400 IN COMPLEX WITH
RP SERPINA10, GLYCOSYLATION AT ASN-233, DISULFIDE BONDS, AND SUBUNIT.
RX PubMed=19528533; DOI=10.1182/blood-2009-04-210021;
RA Wei Z., Yan Y., Carrell R.W., Zhou A.;
RT "Crystal structure of protein Z-dependent inhibitor complex shows how
RT protein Z functions as a cofactor in the membrane inhibition of factor
RT X.";
RL Blood 114:3662-3667(2009).
RN [12]
RP X-RAY CRYSTALLOGRAPHY (3.26 ANGSTROMS) OF 84-400 IN COMPLEX WITH
RP SERPINA10, GLYCOSYLATION AT ASN-99; ASN-225; ASN-233 AND ASN-332,
RP DISULFIDE BONDS, AND SUBUNIT.
RX PubMed=20427285; DOI=10.1074/jbc.M110.112748;
RA Huang X., Dementiev A., Olson S.T., Gettins P.G.;
RT "Basis for the specificity and activation of the serpin protein Z-
RT dependent proteinase inhibitor (ZPI) as an inhibitor of membrane-
RT associated factor Xa.";
RL J. Biol. Chem. 285:20399-20409(2010).
CC -!- FUNCTION: Appears to assist hemostasis by binding thrombin and
CC promoting its association with phospholipid vesicles. Inhibits
CC activity of the coagulation protease factor Xa in the presence of
CC SERPINA10, calcium and phospholipids.
CC -!- SUBUNIT: Interacts with SERPINA10.
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P22891-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P22891-2; Sequence=VSP_005415;
CC -!- TISSUE SPECIFICITY: Plasma.
CC -!- PTM: The iron and 2-oxoglutarate dependent 3-hydroxylation of
CC aspartate and asparagine is (R) stereospecific within EGF domains
CC (By similarity).
CC -!- SIMILARITY: Belongs to the peptidase S1 family.
CC -!- SIMILARITY: Contains 2 EGF-like domains.
CC -!- SIMILARITY: Contains 1 Gla (gamma-carboxy-glutamate) domain.
CC -!- SIMILARITY: Contains 1 peptidase S1 domain.
CC -!- CAUTION: Although related to peptidase S1 family vitamin K-
CC dependent clotting factors, it has lost two of the essential
CC catalytic residues and therefore lacks protease activity.
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/proz/";
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DR EMBL; M55670; AAA36500.1; -; mRNA.
DR EMBL; M55671; AAA36501.1; -; mRNA.
DR EMBL; AB033749; BAA85763.1; -; Genomic_DNA.
DR EMBL; AB033749; BAA85764.1; -; Genomic_DNA.
DR EMBL; AF440358; AAL27631.1; -; Genomic_DNA.
DR EMBL; EF445049; ACA06105.1; -; Genomic_DNA.
DR EMBL; AL137002; CAI41389.1; -; Genomic_DNA.
DR EMBL; AL137002; CAI41388.1; -; Genomic_DNA.
DR EMBL; CH471085; EAX09186.1; -; Genomic_DNA.
DR EMBL; CH471085; EAX09187.1; -; Genomic_DNA.
DR EMBL; BC074906; AAH74906.1; -; mRNA.
DR EMBL; BC074907; AAH74907.1; -; mRNA.
DR EMBL; M59303; AAA36499.1; -; mRNA.
DR PIR; A36244; KXHUZ.
DR RefSeq; NP_001243063.1; NM_001256134.1.
DR RefSeq; NP_003882.1; NM_003891.2.
DR UniGene; Hs.1011; -.
DR PDB; 3F1S; X-ray; 2.30 A; B=125-400.
DR PDB; 3H5C; X-ray; 3.26 A; B=84-400.
DR PDBsum; 3F1S; -.
DR PDBsum; 3H5C; -.
DR ProteinModelPortal; P22891; -.
DR SMR; P22891; 46-85, 89-400.
DR STRING; 9606.ENSP00000364697; -.
DR DrugBank; DB00170; Menadione.
DR MEROPS; S01.979; -.
DR PhosphoSite; P22891; -.
DR UniCarbKB; P22891; -.
DR DMDM; 131092; -.
DR PaxDb; P22891; -.
DR PRIDE; P22891; -.
DR Ensembl; ENST00000342783; ENSP00000344458; ENSG00000126231.
DR Ensembl; ENST00000375547; ENSP00000364697; ENSG00000126231.
DR GeneID; 8858; -.
DR KEGG; hsa:8858; -.
DR UCSC; uc001vta.2; human.
DR CTD; 8858; -.
DR GeneCards; GC13P113812; -.
DR H-InvDB; HIX0037352; -.
DR HGNC; HGNC:9460; PROZ.
DR HPA; HPA016503; -.
DR MIM; 176895; gene.
DR neXtProt; NX_P22891; -.
DR PharmGKB; PA33813; -.
DR eggNOG; NOG145536; -.
DR HOGENOM; HOG000251821; -.
DR HOVERGEN; HBG013304; -.
DR OMA; WFLTGIL; -.
DR OrthoDB; EOG761BTN; -.
DR Reactome; REACT_17015; Metabolism of proteins.
DR EvolutionaryTrace; P22891; -.
DR GenomeRNAi; 8858; -.
DR NextBio; 33263; -.
DR PRO; PR:P22891; -.
DR ArrayExpress; P22891; -.
DR Bgee; P22891; -.
DR CleanEx; HS_PROZ; -.
DR Genevestigator; P22891; -.
DR GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
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; IEA:InterPro.
DR GO; GO:0007596; P:blood coagulation; IEA:UniProtKB-KW.
DR GO; GO:0017187; P:peptidyl-glutamic acid carboxylation; TAS:Reactome.
DR GO; GO:0043687; P:post-translational protein modification; TAS:Reactome.
DR GO; GO:0006508; P:proteolysis; TAS:Reactome.
DR Gene3D; 4.10.740.10; -; 1.
DR InterPro; IPR017857; Coagulation_fac_subgr_Gla_dom.
DR InterPro; IPR000742; EG-like_dom.
DR InterPro; IPR013032; EGF-like_CS.
DR InterPro; IPR000152; EGF-type_Asp/Asn_hydroxyl_site.
DR InterPro; IPR000294; GLA_domain.
DR InterPro; IPR012224; Pept_S1A_FX.
DR InterPro; IPR001254; Peptidase_S1.
DR InterPro; IPR009003; Trypsin-like_Pept_dom.
DR Pfam; PF00008; EGF; 1.
DR Pfam; PF00594; Gla; 1.
DR Pfam; PF00089; Trypsin; 1.
DR PIRSF; PIRSF001143; Factor_X; 1.
DR PRINTS; PR00001; GLABLOOD.
DR SMART; SM00181; EGF; 2.
DR SMART; SM00069; GLA; 1.
DR SMART; SM00020; Tryp_SPc; 1.
DR SUPFAM; SSF50494; SSF50494; 1.
DR SUPFAM; SSF57630; SSF57630; 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; PS00011; GLA_1; 1.
DR PROSITE; PS50998; GLA_2; 1.
DR PROSITE; PS50240; TRYPSIN_DOM; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Blood coagulation; Calcium;
KW Cleavage on pair of basic residues; Complete proteome;
KW Direct protein sequencing; Disulfide bond; EGF-like domain;
KW Gamma-carboxyglutamic acid; Glycoprotein; Hemostasis; Hydroxylation;
KW Polymorphism; Reference proteome; Repeat; Secreted;
KW Serine protease homolog; Signal.
FT SIGNAL 1 23
FT PROPEP 24 40
FT /FTId=PRO_0000028488.
FT CHAIN 41 400 Vitamin K-dependent protein Z.
FT /FTId=PRO_0000028489.
FT DOMAIN 41 86 Gla.
FT DOMAIN 87 123 EGF-like 1.
FT DOMAIN 125 166 EGF-like 2.
FT DOMAIN 175 400 Peptidase S1.
FT MOD_RES 47 47 4-carboxyglutamate.
FT MOD_RES 48 48 4-carboxyglutamate.
FT MOD_RES 51 51 4-carboxyglutamate.
FT MOD_RES 55 55 4-carboxyglutamate.
FT MOD_RES 57 57 4-carboxyglutamate.
FT MOD_RES 60 60 4-carboxyglutamate.
FT MOD_RES 61 61 4-carboxyglutamate.
FT MOD_RES 66 66 4-carboxyglutamate.
FT MOD_RES 67 67 4-carboxyglutamate.
FT MOD_RES 70 70 4-carboxyglutamate.
FT MOD_RES 73 73 4-carboxyglutamate.
FT MOD_RES 75 75 4-carboxyglutamate.
FT MOD_RES 80 80 4-carboxyglutamate.
FT MOD_RES 104 104 (3R)-3-hydroxyaspartate (By similarity).
FT CARBOHYD 93 93 O-linked (Glc...).
FT CARBOHYD 99 99 N-linked (GlcNAc...).
FT CARBOHYD 225 225 N-linked (GlcNAc...).
FT CARBOHYD 233 233 N-linked (GlcNAc...).
FT CARBOHYD 306 306 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 332 332 N-linked (GlcNAc...).
FT DISULFID 58 63 By similarity.
FT DISULFID 91 102
FT DISULFID 96 111
FT DISULFID 113 122
FT DISULFID 129 141
FT DISULFID 137 150
FT DISULFID 152 165
FT DISULFID 203 219
FT DISULFID 327 341
FT VAR_SEQ 24 24 V -> ATSLKERHGLHSDSACTGVQESL (in isoform
FT 2).
FT /FTId=VSP_005415.
FT VARIANT 70 70 E -> K (in dbSNP:rs3024778).
FT /FTId=VAR_013124.
FT VARIANT 295 295 R -> H (in dbSNP:rs3024772).
FT /FTId=VAR_013125.
FT TURN 97 99
FT STRAND 106 108
FT STRAND 114 116
FT STRAND 119 122
FT STRAND 126 128
FT STRAND 134 136
FT STRAND 138 140
FT STRAND 145 147
FT STRAND 149 151
FT STRAND 156 158
FT STRAND 165 167
FT STRAND 191 195
FT STRAND 197 199
FT STRAND 201 209
FT STRAND 212 215
FT HELIX 217 220
FT STRAND 227 230
FT STRAND 240 249
FT TURN 255 258
FT STRAND 263 269
FT TURN 273 276
FT HELIX 285 290
FT TURN 291 295
FT STRAND 298 302
FT STRAND 309 311
FT STRAND 315 322
FT HELIX 324 331
FT STRAND 339 343
FT HELIX 348 350
FT STRAND 356 360
FT STRAND 365 371
FT HELIX 376 378
FT STRAND 380 387
FT HELIX 388 391
FT HELIX 392 399
SQ SEQUENCE 400 AA; 44744 MW; 7EBD2DCC48860268 CRC64;
MAGCVPLLQG LVLVLALHRV EPSVFLPASK ANDVLVRWKR AGSYLLEELF EGNLEKECYE
EICVYEEARE VFENEVVTDE FWRRYKGGSP CISQPCLHNG SCQDSIWGYT CTCSPGYEGS
NCELAKNECH PERTDGCQHF CLPGQESYTC SCAQGYRLGE DHKQCVPHDQ CACGVLTSEK
RAPDLQDLPW QVKLTNSEGK DFCGGVIIRE NFVLTTAKCS LLHRNITVKT YFNRTSQDPL
MIKITHVHVH MRYDADAGEN DLSLLELEWP IQCPGAGLPV CTPEKDFAEH LLIPRTRGLL
SGWARNGTDL GNSLTTRPVT LVEGEECGQV LNVTVTTRTY CERSSVAAMH WMDGSVVTRE
HRGSWFLTGV LGSQPVGGQA HMVLVTKVSR YSLWFKQIMN
//
ID PROZ_HUMAN Reviewed; 400 AA.
AC P22891; A6NMB4; Q15213; Q5JVF5; Q5JVF6;
DT 01-AUG-1991, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1991, sequence version 2.
DT 22-JAN-2014, entry version 155.
DE RecName: Full=Vitamin K-dependent protein Z;
DE Flags: Precursor;
GN Name=PROZ;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PARTIAL PROTEIN SEQUENCE.
RC TISSUE=Liver;
RX PubMed=2244898; DOI=10.1016/0006-291X(90)91566-B;
RA Ichinose A., Takeya H., Espling E., Iwanaga S., Kisiel W., Davie E.W.;
RT "Amino acid sequence of human protein Z, a vitamin K-dependent plasma
RT glycoprotein.";
RL Biochem. Biophys. Res. Commun. 172:1139-1144(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND ALTERNATIVE SPLICING.
RX PubMed=9578570; DOI=10.1021/bi972002a;
RA Fujimaki K., Yamazaki T., Taniwaki M., Ichinose A.;
RT "The gene for human protein Z is localized to chromosome 13 at band
RT q34 and is coded by eight regular exons and one alternative exon.";
RL Biochemistry 37:6838-6846(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS LYS-70 AND HIS-295.
RG SeattleSNPs variation discovery resource;
RL Submitted (OCT-2001) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NHLBI resequencing and genotyping service (RS&G;);
RL Submitted (FEB-2007) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057823; DOI=10.1038/nature02379;
RA Dunham A., Matthews L.H., Burton J., Ashurst J.L., Howe K.L.,
RA Ashcroft K.J., Beare D.M., Burford D.C., Hunt S.E.,
RA Griffiths-Jones S., Jones M.C., Keenan S.J., Oliver K., Scott C.E.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Andrews D.T.,
RA Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Bannerjee R.,
RA Barlow K.F., Bates K., Beasley H., Bird C.P., Bray-Allen S.,
RA Brown A.J., Brown J.Y., Burrill W., Carder C., Carter N.P.,
RA Chapman J.C., Clamp M.E., Clark S.Y., Clarke G., Clee C.M.,
RA Clegg S.C., Cobley V., Collins J.E., Corby N., Coville G.J.,
RA Deloukas P., Dhami P., Dunham I., Dunn M., Earthrowl M.E.,
RA Ellington A.G., Faulkner L., Frankish A.G., Frankland J., French L.,
RA Garner P., Garnett J., Gilbert J.G.R., Gilson C.J., Ghori J.,
RA Grafham D.V., Gribble S.M., Griffiths C., Hall R.E., Hammond S.,
RA Harley J.L., Hart E.A., Heath P.D., Howden P.J., Huckle E.J.,
RA Hunt P.J., Hunt A.R., Johnson C., Johnson D., Kay M., Kimberley A.M.,
RA King A., Laird G.K., Langford C.J., Lawlor S., Leongamornlert D.A.,
RA Lloyd D.M., Lloyd C., Loveland J.E., Lovell J., Martin S.,
RA Mashreghi-Mohammadi M., McLaren S.J., McMurray A., Milne S.,
RA Moore M.J.F., Nickerson T., Palmer S.A., Pearce A.V., Peck A.I.,
RA Pelan S., Phillimore B., Porter K.M., Rice C.M., Searle S.,
RA Sehra H.K., Shownkeen R., Skuce C.D., Smith M., Steward C.A.,
RA Sycamore N., Tester J., Thomas D.W., Tracey A., Tromans A., Tubby B.,
RA Wall M., Wallis J.M., West A.P., Whitehead S.L., Willey D.L.,
RA Wilming L., Wray P.W., Wright M.W., Young L., Coulson A., Durbin R.M.,
RA Hubbard T., Sulston J.E., Beck S., Bentley D.R., Rogers J., Ross M.T.;
RT "The DNA sequence and analysis of human chromosome 13.";
RL Nature 428:522-528(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 81-400, AND PROTEIN SEQUENCE OF 63-103.
RX PubMed=2403355; DOI=10.1016/0006-291X(90)91197-Z;
RA Sejima H., Hayashi T., Deyashiki Y., Nishioka J., Suzuki K.;
RT "Primary structure of vitamin K-dependent human protein Z.";
RL Biochem. Biophys. Res. Commun. 171:661-668(1990).
RN [9]
RP STRUCTURE OF CARBOHYDRATE ON SER-93.
RX PubMed=2511201;
RA Nishimura H., Kawabata S., Kisiel W., Hase S., Ikenaka T., Takao T.,
RA Shimonishi Y., Iwanaga S.;
RT "Identification of a disaccharide (Xyl-Glc) and a trisaccharide (Xyl2-
RT Glc) O-glycosidically linked to a serine residue in the first
RT epidermal growth factor-like domain of human factors VII and IX and
RT protein Z and bovine protein Z.";
RL J. Biol. Chem. 264:20320-20325(1989).
RN [10]
RP STRUCTURE OF CARBOHYDRATE ON SER-93.
RX PubMed=2129367;
RA Iwanaga S., Nishimura H., Kawabata S., Kisiel W., Hase S., Ikenaka T.;
RT "A new trisaccharide sugar chain linked to a serine residue in the
RT first EGF-like domain of clotting factors VII and IX and protein Z.";
RL Adv. Exp. Med. Biol. 281:121-131(1990).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 125-400 IN COMPLEX WITH
RP SERPINA10, GLYCOSYLATION AT ASN-233, DISULFIDE BONDS, AND SUBUNIT.
RX PubMed=19528533; DOI=10.1182/blood-2009-04-210021;
RA Wei Z., Yan Y., Carrell R.W., Zhou A.;
RT "Crystal structure of protein Z-dependent inhibitor complex shows how
RT protein Z functions as a cofactor in the membrane inhibition of factor
RT X.";
RL Blood 114:3662-3667(2009).
RN [12]
RP X-RAY CRYSTALLOGRAPHY (3.26 ANGSTROMS) OF 84-400 IN COMPLEX WITH
RP SERPINA10, GLYCOSYLATION AT ASN-99; ASN-225; ASN-233 AND ASN-332,
RP DISULFIDE BONDS, AND SUBUNIT.
RX PubMed=20427285; DOI=10.1074/jbc.M110.112748;
RA Huang X., Dementiev A., Olson S.T., Gettins P.G.;
RT "Basis for the specificity and activation of the serpin protein Z-
RT dependent proteinase inhibitor (ZPI) as an inhibitor of membrane-
RT associated factor Xa.";
RL J. Biol. Chem. 285:20399-20409(2010).
CC -!- FUNCTION: Appears to assist hemostasis by binding thrombin and
CC promoting its association with phospholipid vesicles. Inhibits
CC activity of the coagulation protease factor Xa in the presence of
CC SERPINA10, calcium and phospholipids.
CC -!- SUBUNIT: Interacts with SERPINA10.
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P22891-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P22891-2; Sequence=VSP_005415;
CC -!- TISSUE SPECIFICITY: Plasma.
CC -!- PTM: The iron and 2-oxoglutarate dependent 3-hydroxylation of
CC aspartate and asparagine is (R) stereospecific within EGF domains
CC (By similarity).
CC -!- SIMILARITY: Belongs to the peptidase S1 family.
CC -!- SIMILARITY: Contains 2 EGF-like domains.
CC -!- SIMILARITY: Contains 1 Gla (gamma-carboxy-glutamate) domain.
CC -!- SIMILARITY: Contains 1 peptidase S1 domain.
CC -!- CAUTION: Although related to peptidase S1 family vitamin K-
CC dependent clotting factors, it has lost two of the essential
CC catalytic residues and therefore lacks protease activity.
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/proz/";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; M55670; AAA36500.1; -; mRNA.
DR EMBL; M55671; AAA36501.1; -; mRNA.
DR EMBL; AB033749; BAA85763.1; -; Genomic_DNA.
DR EMBL; AB033749; BAA85764.1; -; Genomic_DNA.
DR EMBL; AF440358; AAL27631.1; -; Genomic_DNA.
DR EMBL; EF445049; ACA06105.1; -; Genomic_DNA.
DR EMBL; AL137002; CAI41389.1; -; Genomic_DNA.
DR EMBL; AL137002; CAI41388.1; -; Genomic_DNA.
DR EMBL; CH471085; EAX09186.1; -; Genomic_DNA.
DR EMBL; CH471085; EAX09187.1; -; Genomic_DNA.
DR EMBL; BC074906; AAH74906.1; -; mRNA.
DR EMBL; BC074907; AAH74907.1; -; mRNA.
DR EMBL; M59303; AAA36499.1; -; mRNA.
DR PIR; A36244; KXHUZ.
DR RefSeq; NP_001243063.1; NM_001256134.1.
DR RefSeq; NP_003882.1; NM_003891.2.
DR UniGene; Hs.1011; -.
DR PDB; 3F1S; X-ray; 2.30 A; B=125-400.
DR PDB; 3H5C; X-ray; 3.26 A; B=84-400.
DR PDBsum; 3F1S; -.
DR PDBsum; 3H5C; -.
DR ProteinModelPortal; P22891; -.
DR SMR; P22891; 46-85, 89-400.
DR STRING; 9606.ENSP00000364697; -.
DR DrugBank; DB00170; Menadione.
DR MEROPS; S01.979; -.
DR PhosphoSite; P22891; -.
DR UniCarbKB; P22891; -.
DR DMDM; 131092; -.
DR PaxDb; P22891; -.
DR PRIDE; P22891; -.
DR Ensembl; ENST00000342783; ENSP00000344458; ENSG00000126231.
DR Ensembl; ENST00000375547; ENSP00000364697; ENSG00000126231.
DR GeneID; 8858; -.
DR KEGG; hsa:8858; -.
DR UCSC; uc001vta.2; human.
DR CTD; 8858; -.
DR GeneCards; GC13P113812; -.
DR H-InvDB; HIX0037352; -.
DR HGNC; HGNC:9460; PROZ.
DR HPA; HPA016503; -.
DR MIM; 176895; gene.
DR neXtProt; NX_P22891; -.
DR PharmGKB; PA33813; -.
DR eggNOG; NOG145536; -.
DR HOGENOM; HOG000251821; -.
DR HOVERGEN; HBG013304; -.
DR OMA; WFLTGIL; -.
DR OrthoDB; EOG761BTN; -.
DR Reactome; REACT_17015; Metabolism of proteins.
DR EvolutionaryTrace; P22891; -.
DR GenomeRNAi; 8858; -.
DR NextBio; 33263; -.
DR PRO; PR:P22891; -.
DR ArrayExpress; P22891; -.
DR Bgee; P22891; -.
DR CleanEx; HS_PROZ; -.
DR Genevestigator; P22891; -.
DR GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
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; IEA:InterPro.
DR GO; GO:0007596; P:blood coagulation; IEA:UniProtKB-KW.
DR GO; GO:0017187; P:peptidyl-glutamic acid carboxylation; TAS:Reactome.
DR GO; GO:0043687; P:post-translational protein modification; TAS:Reactome.
DR GO; GO:0006508; P:proteolysis; TAS:Reactome.
DR Gene3D; 4.10.740.10; -; 1.
DR InterPro; IPR017857; Coagulation_fac_subgr_Gla_dom.
DR InterPro; IPR000742; EG-like_dom.
DR InterPro; IPR013032; EGF-like_CS.
DR InterPro; IPR000152; EGF-type_Asp/Asn_hydroxyl_site.
DR InterPro; IPR000294; GLA_domain.
DR InterPro; IPR012224; Pept_S1A_FX.
DR InterPro; IPR001254; Peptidase_S1.
DR InterPro; IPR009003; Trypsin-like_Pept_dom.
DR Pfam; PF00008; EGF; 1.
DR Pfam; PF00594; Gla; 1.
DR Pfam; PF00089; Trypsin; 1.
DR PIRSF; PIRSF001143; Factor_X; 1.
DR PRINTS; PR00001; GLABLOOD.
DR SMART; SM00181; EGF; 2.
DR SMART; SM00069; GLA; 1.
DR SMART; SM00020; Tryp_SPc; 1.
DR SUPFAM; SSF50494; SSF50494; 1.
DR SUPFAM; SSF57630; SSF57630; 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; PS00011; GLA_1; 1.
DR PROSITE; PS50998; GLA_2; 1.
DR PROSITE; PS50240; TRYPSIN_DOM; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Blood coagulation; Calcium;
KW Cleavage on pair of basic residues; Complete proteome;
KW Direct protein sequencing; Disulfide bond; EGF-like domain;
KW Gamma-carboxyglutamic acid; Glycoprotein; Hemostasis; Hydroxylation;
KW Polymorphism; Reference proteome; Repeat; Secreted;
KW Serine protease homolog; Signal.
FT SIGNAL 1 23
FT PROPEP 24 40
FT /FTId=PRO_0000028488.
FT CHAIN 41 400 Vitamin K-dependent protein Z.
FT /FTId=PRO_0000028489.
FT DOMAIN 41 86 Gla.
FT DOMAIN 87 123 EGF-like 1.
FT DOMAIN 125 166 EGF-like 2.
FT DOMAIN 175 400 Peptidase S1.
FT MOD_RES 47 47 4-carboxyglutamate.
FT MOD_RES 48 48 4-carboxyglutamate.
FT MOD_RES 51 51 4-carboxyglutamate.
FT MOD_RES 55 55 4-carboxyglutamate.
FT MOD_RES 57 57 4-carboxyglutamate.
FT MOD_RES 60 60 4-carboxyglutamate.
FT MOD_RES 61 61 4-carboxyglutamate.
FT MOD_RES 66 66 4-carboxyglutamate.
FT MOD_RES 67 67 4-carboxyglutamate.
FT MOD_RES 70 70 4-carboxyglutamate.
FT MOD_RES 73 73 4-carboxyglutamate.
FT MOD_RES 75 75 4-carboxyglutamate.
FT MOD_RES 80 80 4-carboxyglutamate.
FT MOD_RES 104 104 (3R)-3-hydroxyaspartate (By similarity).
FT CARBOHYD 93 93 O-linked (Glc...).
FT CARBOHYD 99 99 N-linked (GlcNAc...).
FT CARBOHYD 225 225 N-linked (GlcNAc...).
FT CARBOHYD 233 233 N-linked (GlcNAc...).
FT CARBOHYD 306 306 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 332 332 N-linked (GlcNAc...).
FT DISULFID 58 63 By similarity.
FT DISULFID 91 102
FT DISULFID 96 111
FT DISULFID 113 122
FT DISULFID 129 141
FT DISULFID 137 150
FT DISULFID 152 165
FT DISULFID 203 219
FT DISULFID 327 341
FT VAR_SEQ 24 24 V -> ATSLKERHGLHSDSACTGVQESL (in isoform
FT 2).
FT /FTId=VSP_005415.
FT VARIANT 70 70 E -> K (in dbSNP:rs3024778).
FT /FTId=VAR_013124.
FT VARIANT 295 295 R -> H (in dbSNP:rs3024772).
FT /FTId=VAR_013125.
FT TURN 97 99
FT STRAND 106 108
FT STRAND 114 116
FT STRAND 119 122
FT STRAND 126 128
FT STRAND 134 136
FT STRAND 138 140
FT STRAND 145 147
FT STRAND 149 151
FT STRAND 156 158
FT STRAND 165 167
FT STRAND 191 195
FT STRAND 197 199
FT STRAND 201 209
FT STRAND 212 215
FT HELIX 217 220
FT STRAND 227 230
FT STRAND 240 249
FT TURN 255 258
FT STRAND 263 269
FT TURN 273 276
FT HELIX 285 290
FT TURN 291 295
FT STRAND 298 302
FT STRAND 309 311
FT STRAND 315 322
FT HELIX 324 331
FT STRAND 339 343
FT HELIX 348 350
FT STRAND 356 360
FT STRAND 365 371
FT HELIX 376 378
FT STRAND 380 387
FT HELIX 388 391
FT HELIX 392 399
SQ SEQUENCE 400 AA; 44744 MW; 7EBD2DCC48860268 CRC64;
MAGCVPLLQG LVLVLALHRV EPSVFLPASK ANDVLVRWKR AGSYLLEELF EGNLEKECYE
EICVYEEARE VFENEVVTDE FWRRYKGGSP CISQPCLHNG SCQDSIWGYT CTCSPGYEGS
NCELAKNECH PERTDGCQHF CLPGQESYTC SCAQGYRLGE DHKQCVPHDQ CACGVLTSEK
RAPDLQDLPW QVKLTNSEGK DFCGGVIIRE NFVLTTAKCS LLHRNITVKT YFNRTSQDPL
MIKITHVHVH MRYDADAGEN DLSLLELEWP IQCPGAGLPV CTPEKDFAEH LLIPRTRGLL
SGWARNGTDL GNSLTTRPVT LVEGEECGQV LNVTVTTRTY CERSSVAAMH WMDGSVVTRE
HRGSWFLTGV LGSQPVGGQA HMVLVTKVSR YSLWFKQIMN
//
MIM
176895
*RECORD*
*FIELD* NO
176895
*FIELD* TI
*176895 PROTEIN Z; PROZ
;;PZ
*FIELD* TX
DESCRIPTION
Protein Z, a 62-kD vitamin K-dependent plasma glycoprotein synthesized
read moreby the liver, serves as a cofactor for the inhibition of coagulation
factor Xa (F10; 613872) by the protein Z-dependent protease inhibitor
(ZPI, SERPINA10; 605271). Protein Z circulates in the plasma in a
complex with ZPI (summary by Broze, 2001).
CLONING
Protein Z was originally isolated in bovine plasma by Prowse and Esnouf
(1977) and in human plasma by Broze and Miletich (1984). The bovine
protein Z molecule contains 13 gamma-carboxyglutamic (Gla) residues
(Hojrup et al., 1982) and 396 amino acid residues (Hojrup et al., 1985).
Ichinose et al. (1990) isolated a cDNA coding for human protein Z. They
found that it is synthesized with a prepro-leader sequence of 40 amino
acids. The mature protein contains 360 residues including a Gla domain
of 13 carboxyglutamic acid residues, 2 epidermal growth factor domains,
and a C-terminal region that is highly homologous to the catalytic
domain of serine proteases. Its structure is similar to that of factors
VII (613878), IX (300746), and X (613872), and protein C (PROC; 612283).
Human protein Z, however, contains an asp instead of ser and a lys
instead of his in the catalytic triad of the active site.
GENE STRUCTURE
Fujimaki et al. (1998) determined that the PROZ gene spans about 14 kb
and contains 9 exons, including one alternative exon.
MAPPING
Fujimaki et al. (1998) mapped the PROZ gene to chromosome 13q13.
GENE FUNCTION
Hogg and Stenflo (1991) showed that human protein Z bound thrombin (F2;
176930) with a 20-fold weaker affinity than bovine protein Z. Human
protein Z was also less effective than bovine protein Z in promoting the
association of thrombin with phospholipid vesicles. Bovine protein Z
that was cleaved by thrombin at arg365 bound thrombin with a 10-fold
weaker affinity than did native bovine protein Z. The data suggested
that the species difference in the interaction between protein Z and
thrombin can be explained by a difference in the COOH-terminal region of
bovine protein Z versus human protein Z.
Han et al. (1998) showed that PROZ forms a calcium ion-dependent complex
with activated factor X at phospholipid surfaces. This PROZ-factor Xa
interaction reduces the rate of factor Xa inhibition by antithrombin but
dramatically enhances the inhibition of factor Xa produced by a plasma
protein named PROZ-dependent protease inhibitor (ZPI; 605271).
MOLECULAR GENETICS
Vasse et al. (2001) analyzed plasma protein Z levels in 56 patients with
deep venous thrombosis, 169 patients with ischemic stroke, and 88
controls. There was no significant difference in mean protein Z
concentrations between the deep venous thrombosis group and the
controls, and 5% of individuals in both groups had protein Z deficiency.
In patients with ischemic stroke, however, protein Z levels were lower
than the normal range, and 33 of these patients (20%) had protein Z
deficiency.
Among 42 control individuals, Lichy et al. (2004) found that the A
allele of the intron F 79G-A polymorphism (dbSNP rs17882561) in the PROZ
gene was significantly associated with lower plasma protein Z levels (p
= 0.0032). The frequency of the A allele of this SNP was significantly
lower in 200 patients with onset of cerebral ischemia before age 50
years compared to controls (15.7% compared to 24.4%, odds ratio of
0.58), suggesting that the A allele is a protective genetic marker. The
stuey suggested that high levels of protein Z may represent a
prothrombotic condition. Lichy et al. (2004) stated that their findings
were consistent with a role of protein Z as an enhancer of thrombin
activity, but noted that the results of their study were contradictory
to those of other studies, such as Vasse et al. (2001).
Kemkes-Matthes et al. (2004) found that presence of a heterozygous or
homozygous arg225-to-his (R225H) substitution in exon 8 of the PROZ gene
was associated with a higher frequency of thromboembolic complications
in patients carrying the factor V Leiden mutation (612309.0001),
although plasma levels of protein Z were not different between those
with or without the R225H substitution. In a study of 134 carriers of
factor V Leiden, the R225H mutation was found in 11 (14.4%) of 76
patients with thromboembolic events and in only 3 (5.1%) of 58 patients
who did not have thromboembolic events. Rice et al. (2001) found the
R225H mutation in 4.5% of blood donors.
Santacroce et al. (2006) found that lower plasma levels of protein Z
were independently associated with the A allele of 3 different intronic
polymorphisms in the PROZ gene: -103G-A in intron A (dbSNP rs3024719);
-42G-A in intron C; and 79G-A (dbSNP rs17882561) in intron F. The
-103G-A and 79G-A polymorphisms were shown to be in strong linkage
disequilibrium. None of these polymorphisms was likely to have an effect
on gene expression and they may be in linkage disequilibrium with
another variant. The findings suggested that genetic factors may play a
role in the wide normal range of PROZ plasma concentrations.
ANIMAL MODEL
Yin et al. (2000) found that Proz-null mice had a normal phenotype with
no increase of bleeding or thrombosis. However, Proz deficiency
dramatically increased the severity of the prothrombotic phenotype of
factor V Leiden (see 612309) mice. These results suggested that PROZ
plays a physiologically important role in the regulation of coagulation
in certain circumstances.
*FIELD* AV
.0001
PROTEIN Z DEFICIENCY
PROZ, GLU30GLN
Souri et al. (2004) reported a patient with thrombophilia due to factor
V Leiden (188055) who had had 3 deep venous thrombotic events and 1
spontaneous miscarriage and who also had low levels of plasma protein Z
to about 15% of normal (614024). In addition to a heterozygous F5
mutation (612309.0001), she had a heterozygous G-to-C transversion in
exon 2 of the PROZ gene, resulting in a glu30-to-gln (E30Q) substitution
in 1 of the 13 highly conserved gamma-carboxylation sites. The mutation
was not found in 127 controls. In vitro functional expression studies
showed that the E30Q mutant protein was not released from synthesizing
cells. Coexpression of E30Q with the wildtype protein Z interfered with
the secretion of the wildtype protein, consistent with a
dominant-negative effect. The patient was also heterozygous for a 79G-A
polymorphism in intron 6, which had previously been associated with
lowered protein Z levels.
*FIELD* RF
1. Broze, G. J., Jr.: Protein Z-dependent regulation of coagulation. Thromb.
Haemost. 86: 8-13, 2001.
2. Broze, G. J., Jr.; Miletich, J. P.: Human protein Z. J. Clin.
Invest. 73: 933-938, 1984.
3. Fujimaki, K.; Yamazaki, T.; Taniwaki, M.; Ichinose, A.: The gene
for human protein Z is localized to chromosome 13 at band q34 and
is coded by eight regular exons and one alternative exon. Biochemistry 37:
6838-6846, 1998.
4. Han, X.; Fiehler, R.; Broze, G. J.: Isolation of a protein Z-dependent
plasma protease inhibitor. Proc. Nat. Acad. Sci. 95: 9250-9255,
1998.
5. Hogg, P. J.; Stenflo, J.: Interaction of human protein Z with
thrombin: evaluation of the species difference in the interaction
between bovine and human protein Z and thrombin. Biochem. Biophys.
Res. Commun. 178: 801-807, 1991.
6. Hojrup, P.; Jensen, M. S.; Petersen, T. E.: Amino acid sequence
of bovine protein Z: a vitamin K-dependent serine protease homolog. FEBS
Lett. 184: 333-338, 1985.
7. Hojrup, P.; Roepstorff, P.; Petersen, T. E.: Amino-acid sequence
of the vitamin-K-dependent part of protein Z. Europ. J. Biochem. 126:
343-348, 1982.
8. Ichinose, A.; Takeya, H.; Espling, E.; Iwanaga, S.; Kisiel, W.;
Davie, E. W.: Amino acid sequence of human protein Z, a vitamin dependent
plasma glycoprotein. Biochem. Biophys. Res. Commun. 172: 1139-1144,
1990.
9. Kemkes-Matthes, B.; Matthes, K. J.; Souri, M.; Koseki-Kuno, S.;
Ichinose, A.: R225H amino acid substitution of protein Z identified
in patients with factor V Leiden mutation. Brit. J. Haemat. 128:
248-252, 2004.
10. Lichy, C.; Kropp, S.; Dong-Si, T.; Genius, J.; Dolan, T.; Hampe,
T.; Stoll, F.; Reuner, K.; Grond-Ginsbach, C.; Grau, A.: A common
polymorphism of the protein Z gene is associated with protein Z plasma
levels and with risk of cerebral ischemia in the young. Stroke 35:
40-45, 2004.
11. Prowse, C. V.; Esnouf, M. P.: The isolation of a new warfarin-sensitive
protein from bovine plasma. Biochem. Soc. Trans. 5: 255-256, 1977.
12. Rice, G. I.; Futers, S.; Grant, P. J.: Identification of novel
polymorphisms within the protein Z gene, haplotype distribution and
linkage analysis. (Letter) Thromb. Haemost. 85: 1023-1024, 2001.
13. Santacroce, R.; Sarno, M.; Cappucci, F.; Sessa, F.; Colaizzo,
D.; Brancaccio, V.; Grandone, E.; Margaglione, M.: Low protein Z
levels and risk of occurrence of deep vein thrombosis. J. Thromb.
Haemost. 4: 2417-2422, 2006.
14. Souri, M.; Koseki-Kuno, S.; Iwata, H.; Kemkes-Matthes, B.; Ichinose,
A.: A naturally occurring E30Q mutation in the Gla domain of protein
Z causes its impaired secretion and subsequent deficiency. Blood 105:
3149-3154, 2004.
15. Vasse, M.; Guegan-Massardier, E.; Borg, J.-Y.; Woimant, F.; Soria,
C.: Frequency of protein Z deficiency in patients with ischaemic
stroke. (Letter) Lancet 357: 933-934, 2001.
16. Yin, Z.-F.; Huang, Z.-F.; Cui, J.; Fiehler, R.; Lasky, N.; Ginsburg,
D.; Broze, G. J., Jr.: Prothrombotic phenotype of protein Z deficiency. Proc.
Nat. Acad. Sci. 97: 6734-6738, 2000.
*FIELD* CN
Cassandra L. Kniffin - updated: 6/27/2011
Carol A. Bocchini - updated: 6/3/2011
Marla J. F. O'Neill - updated: 2/10/2005
Victor A. McKusick - updated: 9/15/2000
*FIELD* CD
Victor A. McKusick: 1/11/1991
*FIELD* ED
carol: 07/07/2011
ckniffin: 6/27/2011
carol: 6/22/2011
carol: 6/3/2011
carol: 4/11/2011
carol: 4/8/2011
carol: 10/21/2008
carol: 9/12/2008
wwang: 3/7/2005
wwang: 2/16/2005
terry: 2/10/2005
terry: 3/20/2001
carol: 9/15/2000
mark: 9/17/1995
supermim: 3/16/1992
carol: 2/25/1991
carol: 2/11/1991
carol: 1/14/1991
carol: 1/11/1991
*RECORD*
*FIELD* NO
176895
*FIELD* TI
*176895 PROTEIN Z; PROZ
;;PZ
*FIELD* TX
DESCRIPTION
Protein Z, a 62-kD vitamin K-dependent plasma glycoprotein synthesized
read moreby the liver, serves as a cofactor for the inhibition of coagulation
factor Xa (F10; 613872) by the protein Z-dependent protease inhibitor
(ZPI, SERPINA10; 605271). Protein Z circulates in the plasma in a
complex with ZPI (summary by Broze, 2001).
CLONING
Protein Z was originally isolated in bovine plasma by Prowse and Esnouf
(1977) and in human plasma by Broze and Miletich (1984). The bovine
protein Z molecule contains 13 gamma-carboxyglutamic (Gla) residues
(Hojrup et al., 1982) and 396 amino acid residues (Hojrup et al., 1985).
Ichinose et al. (1990) isolated a cDNA coding for human protein Z. They
found that it is synthesized with a prepro-leader sequence of 40 amino
acids. The mature protein contains 360 residues including a Gla domain
of 13 carboxyglutamic acid residues, 2 epidermal growth factor domains,
and a C-terminal region that is highly homologous to the catalytic
domain of serine proteases. Its structure is similar to that of factors
VII (613878), IX (300746), and X (613872), and protein C (PROC; 612283).
Human protein Z, however, contains an asp instead of ser and a lys
instead of his in the catalytic triad of the active site.
GENE STRUCTURE
Fujimaki et al. (1998) determined that the PROZ gene spans about 14 kb
and contains 9 exons, including one alternative exon.
MAPPING
Fujimaki et al. (1998) mapped the PROZ gene to chromosome 13q13.
GENE FUNCTION
Hogg and Stenflo (1991) showed that human protein Z bound thrombin (F2;
176930) with a 20-fold weaker affinity than bovine protein Z. Human
protein Z was also less effective than bovine protein Z in promoting the
association of thrombin with phospholipid vesicles. Bovine protein Z
that was cleaved by thrombin at arg365 bound thrombin with a 10-fold
weaker affinity than did native bovine protein Z. The data suggested
that the species difference in the interaction between protein Z and
thrombin can be explained by a difference in the COOH-terminal region of
bovine protein Z versus human protein Z.
Han et al. (1998) showed that PROZ forms a calcium ion-dependent complex
with activated factor X at phospholipid surfaces. This PROZ-factor Xa
interaction reduces the rate of factor Xa inhibition by antithrombin but
dramatically enhances the inhibition of factor Xa produced by a plasma
protein named PROZ-dependent protease inhibitor (ZPI; 605271).
MOLECULAR GENETICS
Vasse et al. (2001) analyzed plasma protein Z levels in 56 patients with
deep venous thrombosis, 169 patients with ischemic stroke, and 88
controls. There was no significant difference in mean protein Z
concentrations between the deep venous thrombosis group and the
controls, and 5% of individuals in both groups had protein Z deficiency.
In patients with ischemic stroke, however, protein Z levels were lower
than the normal range, and 33 of these patients (20%) had protein Z
deficiency.
Among 42 control individuals, Lichy et al. (2004) found that the A
allele of the intron F 79G-A polymorphism (dbSNP rs17882561) in the PROZ
gene was significantly associated with lower plasma protein Z levels (p
= 0.0032). The frequency of the A allele of this SNP was significantly
lower in 200 patients with onset of cerebral ischemia before age 50
years compared to controls (15.7% compared to 24.4%, odds ratio of
0.58), suggesting that the A allele is a protective genetic marker. The
stuey suggested that high levels of protein Z may represent a
prothrombotic condition. Lichy et al. (2004) stated that their findings
were consistent with a role of protein Z as an enhancer of thrombin
activity, but noted that the results of their study were contradictory
to those of other studies, such as Vasse et al. (2001).
Kemkes-Matthes et al. (2004) found that presence of a heterozygous or
homozygous arg225-to-his (R225H) substitution in exon 8 of the PROZ gene
was associated with a higher frequency of thromboembolic complications
in patients carrying the factor V Leiden mutation (612309.0001),
although plasma levels of protein Z were not different between those
with or without the R225H substitution. In a study of 134 carriers of
factor V Leiden, the R225H mutation was found in 11 (14.4%) of 76
patients with thromboembolic events and in only 3 (5.1%) of 58 patients
who did not have thromboembolic events. Rice et al. (2001) found the
R225H mutation in 4.5% of blood donors.
Santacroce et al. (2006) found that lower plasma levels of protein Z
were independently associated with the A allele of 3 different intronic
polymorphisms in the PROZ gene: -103G-A in intron A (dbSNP rs3024719);
-42G-A in intron C; and 79G-A (dbSNP rs17882561) in intron F. The
-103G-A and 79G-A polymorphisms were shown to be in strong linkage
disequilibrium. None of these polymorphisms was likely to have an effect
on gene expression and they may be in linkage disequilibrium with
another variant. The findings suggested that genetic factors may play a
role in the wide normal range of PROZ plasma concentrations.
ANIMAL MODEL
Yin et al. (2000) found that Proz-null mice had a normal phenotype with
no increase of bleeding or thrombosis. However, Proz deficiency
dramatically increased the severity of the prothrombotic phenotype of
factor V Leiden (see 612309) mice. These results suggested that PROZ
plays a physiologically important role in the regulation of coagulation
in certain circumstances.
*FIELD* AV
.0001
PROTEIN Z DEFICIENCY
PROZ, GLU30GLN
Souri et al. (2004) reported a patient with thrombophilia due to factor
V Leiden (188055) who had had 3 deep venous thrombotic events and 1
spontaneous miscarriage and who also had low levels of plasma protein Z
to about 15% of normal (614024). In addition to a heterozygous F5
mutation (612309.0001), she had a heterozygous G-to-C transversion in
exon 2 of the PROZ gene, resulting in a glu30-to-gln (E30Q) substitution
in 1 of the 13 highly conserved gamma-carboxylation sites. The mutation
was not found in 127 controls. In vitro functional expression studies
showed that the E30Q mutant protein was not released from synthesizing
cells. Coexpression of E30Q with the wildtype protein Z interfered with
the secretion of the wildtype protein, consistent with a
dominant-negative effect. The patient was also heterozygous for a 79G-A
polymorphism in intron 6, which had previously been associated with
lowered protein Z levels.
*FIELD* RF
1. Broze, G. J., Jr.: Protein Z-dependent regulation of coagulation. Thromb.
Haemost. 86: 8-13, 2001.
2. Broze, G. J., Jr.; Miletich, J. P.: Human protein Z. J. Clin.
Invest. 73: 933-938, 1984.
3. Fujimaki, K.; Yamazaki, T.; Taniwaki, M.; Ichinose, A.: The gene
for human protein Z is localized to chromosome 13 at band q34 and
is coded by eight regular exons and one alternative exon. Biochemistry 37:
6838-6846, 1998.
4. Han, X.; Fiehler, R.; Broze, G. J.: Isolation of a protein Z-dependent
plasma protease inhibitor. Proc. Nat. Acad. Sci. 95: 9250-9255,
1998.
5. Hogg, P. J.; Stenflo, J.: Interaction of human protein Z with
thrombin: evaluation of the species difference in the interaction
between bovine and human protein Z and thrombin. Biochem. Biophys.
Res. Commun. 178: 801-807, 1991.
6. Hojrup, P.; Jensen, M. S.; Petersen, T. E.: Amino acid sequence
of bovine protein Z: a vitamin K-dependent serine protease homolog. FEBS
Lett. 184: 333-338, 1985.
7. Hojrup, P.; Roepstorff, P.; Petersen, T. E.: Amino-acid sequence
of the vitamin-K-dependent part of protein Z. Europ. J. Biochem. 126:
343-348, 1982.
8. Ichinose, A.; Takeya, H.; Espling, E.; Iwanaga, S.; Kisiel, W.;
Davie, E. W.: Amino acid sequence of human protein Z, a vitamin dependent
plasma glycoprotein. Biochem. Biophys. Res. Commun. 172: 1139-1144,
1990.
9. Kemkes-Matthes, B.; Matthes, K. J.; Souri, M.; Koseki-Kuno, S.;
Ichinose, A.: R225H amino acid substitution of protein Z identified
in patients with factor V Leiden mutation. Brit. J. Haemat. 128:
248-252, 2004.
10. Lichy, C.; Kropp, S.; Dong-Si, T.; Genius, J.; Dolan, T.; Hampe,
T.; Stoll, F.; Reuner, K.; Grond-Ginsbach, C.; Grau, A.: A common
polymorphism of the protein Z gene is associated with protein Z plasma
levels and with risk of cerebral ischemia in the young. Stroke 35:
40-45, 2004.
11. Prowse, C. V.; Esnouf, M. P.: The isolation of a new warfarin-sensitive
protein from bovine plasma. Biochem. Soc. Trans. 5: 255-256, 1977.
12. Rice, G. I.; Futers, S.; Grant, P. J.: Identification of novel
polymorphisms within the protein Z gene, haplotype distribution and
linkage analysis. (Letter) Thromb. Haemost. 85: 1023-1024, 2001.
13. Santacroce, R.; Sarno, M.; Cappucci, F.; Sessa, F.; Colaizzo,
D.; Brancaccio, V.; Grandone, E.; Margaglione, M.: Low protein Z
levels and risk of occurrence of deep vein thrombosis. J. Thromb.
Haemost. 4: 2417-2422, 2006.
14. Souri, M.; Koseki-Kuno, S.; Iwata, H.; Kemkes-Matthes, B.; Ichinose,
A.: A naturally occurring E30Q mutation in the Gla domain of protein
Z causes its impaired secretion and subsequent deficiency. Blood 105:
3149-3154, 2004.
15. Vasse, M.; Guegan-Massardier, E.; Borg, J.-Y.; Woimant, F.; Soria,
C.: Frequency of protein Z deficiency in patients with ischaemic
stroke. (Letter) Lancet 357: 933-934, 2001.
16. Yin, Z.-F.; Huang, Z.-F.; Cui, J.; Fiehler, R.; Lasky, N.; Ginsburg,
D.; Broze, G. J., Jr.: Prothrombotic phenotype of protein Z deficiency. Proc.
Nat. Acad. Sci. 97: 6734-6738, 2000.
*FIELD* CN
Cassandra L. Kniffin - updated: 6/27/2011
Carol A. Bocchini - updated: 6/3/2011
Marla J. F. O'Neill - updated: 2/10/2005
Victor A. McKusick - updated: 9/15/2000
*FIELD* CD
Victor A. McKusick: 1/11/1991
*FIELD* ED
carol: 07/07/2011
ckniffin: 6/27/2011
carol: 6/22/2011
carol: 6/3/2011
carol: 4/11/2011
carol: 4/8/2011
carol: 10/21/2008
carol: 9/12/2008
wwang: 3/7/2005
wwang: 2/16/2005
terry: 2/10/2005
terry: 3/20/2001
carol: 9/15/2000
mark: 9/17/1995
supermim: 3/16/1992
carol: 2/25/1991
carol: 2/11/1991
carol: 1/14/1991
carol: 1/11/1991