WFDC2_HUMAN
ID WFDC2_HUMAN Reviewed; 124 AA.
AC Q14508; A2A2A5; A2A2A6; A6PVD5; Q6IB27; Q8WXV9; Q8WXW0; Q8WXW1; Q8WXW2;
AC Q96KJ1;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2002, sequence version 2.
DT 03-AUG-2022, entry version 188.
DE RecName: Full=WAP four-disulfide core domain protein 2;
DE AltName: Full=Epididymal secretory protein E4;
DE AltName: Full=Major epididymis-specific protein E4;
DE AltName: Full=Putative protease inhibitor WAP5;
DE Flags: Precursor;
GN Name=WFDC2; Synonyms=HE4, WAP5;
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).
RC TISSUE=Epididymis;
RX PubMed=1686187; DOI=10.1095/biolreprod45.2.350;
RA Kirchhoff C., Habben L., Ivell R., Krull N.;
RT "A major human epididymis-specific cDNA encodes a protein with sequence
RT homology to extracellular proteinase inhibitors.";
RL Biol. Reprod. 45:350-357(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 3; 4 AND 5).
RX PubMed=11965550; DOI=10.1038/sj.onc.1205363;
RA Bingle L., Singleton V., Bingle C.D.;
RT "The putative ovarian tumour marker gene HE4 (WFDC2), is expressed in
RT normal tissues and undergoes complex alternative splicing to yield multiple
RT protein isoforms.";
RL Oncogene 21:2768-2773(2002).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=12839961;
RA Hellstrom I., Raycraft J., Hayden-Ledbetter M., Ledbetter J.A.,
RA Schummer M., McIntosh M., Drescher C., Urban N., Hellstrom K.E.;
RT "The HE4 (WFDC2) protein is a biomarker for ovarian carcinoma.";
RL Cancer Res. 63:3695-3700(2003).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=11780052; DOI=10.1038/414865a;
RA Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R.,
RA Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L.,
RA Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P.,
RA Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J., Buck D., Burrill W.D.,
RA Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G.,
RA Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E.,
RA Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D.,
RA Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P.,
RA Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E.,
RA Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J.,
RA Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D.,
RA Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S.,
RA Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D.,
RA Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A.,
RA Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T.,
RA Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I.,
RA Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M.,
RA Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D.,
RA Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M.,
RA Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A.,
RA Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L.,
RA Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L.,
RA Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 20.";
RL Nature 414:865-871(2001).
RN [6]
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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
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 [8]
RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=15781627; DOI=10.1158/0008-5472.can-04-3924;
RA Drapkin R., von Horsten H.H., Lin Y., Mok S.C., Crum C.P., Welch W.R.,
RA Hecht J.L.;
RT "Human epididymis protein 4 (HE4) is a secreted glycoprotein that is
RT overexpressed by serous and endometrioid ovarian carcinomas.";
RL Cancer Res. 65:2162-2169(2005).
RN [9]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-44.
RC TISSUE=Saliva;
RX PubMed=16740002; DOI=10.1021/pr050492k;
RA Ramachandran P., Boontheung P., Xie Y., Sondej M., Wong D.T., Loo J.A.;
RT "Identification of N-linked glycoproteins in human saliva by glycoprotein
RT capture and mass spectrometry.";
RL J. Proteome Res. 5:1493-1503(2006).
RN [10]
RP FUNCTION, SUBUNIT, GLYCOSYLATION AT ASN-44, AND SUBCELLULAR LOCATION.
RC TISSUE=Seminal plasma;
RX PubMed=23139753; DOI=10.1371/journal.pone.0047672;
RA Chhikara N., Saraswat M., Tomar A.K., Dey S., Singh S., Yadav S.;
RT "Human epididymis protein-4 (HE-4): a novel cross-class protease
RT inhibitor.";
RL PLoS ONE 7:E47672-E47672(2012).
CC -!- FUNCTION: Broad range protease inhibitor.
CC {ECO:0000269|PubMed:23139753}.
CC -!- SUBUNIT: Homotrimer; disulfide-linked. {ECO:0000269|PubMed:23139753}.
CC -!- INTERACTION:
CC Q14508; P07355: ANXA2; NbExp=36; IntAct=EBI-723529, EBI-352622;
CC Q14508; Q3SXY8: ARL13B; NbExp=3; IntAct=EBI-723529, EBI-11343438;
CC Q14508; P11912: CD79A; NbExp=3; IntAct=EBI-723529, EBI-7797864;
CC Q14508; O75208: COQ9; NbExp=3; IntAct=EBI-723529, EBI-724524;
CC Q14508; Q7Z7G2: CPLX4; NbExp=3; IntAct=EBI-723529, EBI-18013275;
CC Q14508; Q96BA8: CREB3L1; NbExp=3; IntAct=EBI-723529, EBI-6942903;
CC Q14508; P00387: CYB5R3; NbExp=3; IntAct=EBI-723529, EBI-1046040;
CC Q14508; Q5JX71: FAM209A; NbExp=3; IntAct=EBI-723529, EBI-18304435;
CC Q14508; Q9Y680: FKBP7; NbExp=3; IntAct=EBI-723529, EBI-3918971;
CC Q14508; Q5T7V8: GORAB; NbExp=3; IntAct=EBI-723529, EBI-3917143;
CC Q14508; Q96RD7: PANX1; NbExp=3; IntAct=EBI-723529, EBI-7037612;
CC Q14508; A1A5C7-2: SLC22A23; NbExp=3; IntAct=EBI-723529, EBI-12081840;
CC Q14508; P27105: STOM; NbExp=3; IntAct=EBI-723529, EBI-1211440;
CC Q14508; Q9Y320: TMX2; NbExp=3; IntAct=EBI-723529, EBI-6447886;
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:15781627,
CC ECO:0000269|PubMed:23139753}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=5;
CC Comment=Additional isoforms seem to exist.;
CC Name=1;
CC IsoId=Q14508-1; Sequence=Displayed;
CC Name=2; Synonyms=HE4-V3;
CC IsoId=Q14508-2; Sequence=VSP_007666, VSP_007667;
CC Name=3; Synonyms=HE4-V2;
CC IsoId=Q14508-3; Sequence=VSP_007668;
CC Name=4; Synonyms=HE4-V1;
CC IsoId=Q14508-4; Sequence=VSP_007669, VSP_007671;
CC Name=5; Synonyms=HE4-V4;
CC IsoId=Q14508-5; Sequence=VSP_007670, VSP_007672;
CC -!- TISSUE SPECIFICITY: Expressed in a number of normal tissues, including
CC male reproductive system, regions of the respiratory tract and
CC nasopharynx. Highly expressed in a number of tumors cells lines, such
CC ovarian, colon, breast, lung and renal cells lines. Initially described
CC as being exclusively transcribed in the epididymis.
CC {ECO:0000269|PubMed:15781627}.
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DR EMBL; X63187; CAA44869.1; -; mRNA.
DR EMBL; AF330259; AAL37485.1; -; mRNA.
DR EMBL; AF330260; AAL37486.1; -; mRNA.
DR EMBL; AF330261; AAL37487.1; -; mRNA.
DR EMBL; AF330262; AAL37488.1; -; mRNA.
DR EMBL; AY212888; AAO52683.1; -; mRNA.
DR EMBL; CR456977; CAG33258.1; -; mRNA.
DR EMBL; AL031663; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471077; EAW75836.1; -; Genomic_DNA.
DR EMBL; CH471077; EAW75837.1; -; Genomic_DNA.
DR EMBL; CH471077; EAW75839.1; -; Genomic_DNA.
DR EMBL; BC046106; AAH46106.1; -; mRNA.
DR CCDS; CCDS35501.1; -. [Q14508-1]
DR PIR; S25454; S25454.
DR RefSeq; NP_006094.3; NM_006103.3. [Q14508-1]
DR AlphaFoldDB; Q14508; -.
DR SMR; Q14508; -.
DR BioGRID; 115677; 28.
DR IntAct; Q14508; 32.
DR STRING; 9606.ENSP00000361761; -.
DR MEROPS; I17.004; -.
DR GlyConnect; 1902; 26 N-Linked glycans (1 site), 3 O-Linked glycans (2 sites).
DR GlyGen; Q14508; 2 sites, 35 N-linked glycans (1 site), 2 O-linked glycans (1 site).
DR iPTMnet; Q14508; -.
DR BioMuta; WFDC2; -.
DR DMDM; 20141958; -.
DR EPD; Q14508; -.
DR jPOST; Q14508; -.
DR MassIVE; Q14508; -.
DR MaxQB; Q14508; -.
DR PaxDb; Q14508; -.
DR PeptideAtlas; Q14508; -.
DR PRIDE; Q14508; -.
DR ProteomicsDB; 60010; -. [Q14508-1]
DR ProteomicsDB; 60011; -. [Q14508-2]
DR ProteomicsDB; 60012; -. [Q14508-3]
DR ProteomicsDB; 60013; -. [Q14508-4]
DR ProteomicsDB; 60014; -. [Q14508-5]
DR ABCD; Q14508; 3 sequenced antibodies.
DR Antibodypedia; 27648; 648 antibodies from 43 providers.
DR CPTC; Q14508; 2 antibodies.
DR DNASU; 10406; -.
DR Ensembl; ENST00000217425.9; ENSP00000217425.5; ENSG00000101443.18. [Q14508-5]
DR Ensembl; ENST00000339946.7; ENSP00000340215.3; ENSG00000101443.18. [Q14508-3]
DR Ensembl; ENST00000342873.7; ENSP00000342890.3; ENSG00000101443.18. [Q14508-2]
DR Ensembl; ENST00000372676.8; ENSP00000361761.3; ENSG00000101443.18. [Q14508-1]
DR GeneID; 10406; -.
DR KEGG; hsa:10406; -.
DR MANE-Select; ENST00000372676.8; ENSP00000361761.3; NM_006103.4; NP_006094.3.
DR UCSC; uc002xoo.4; human. [Q14508-1]
DR CTD; 10406; -.
DR DisGeNET; 10406; -.
DR GeneCards; WFDC2; -.
DR HGNC; HGNC:15939; WFDC2.
DR HPA; ENSG00000101443; Tissue enhanced (cervix, salivary gland).
DR MIM; 617548; gene.
DR neXtProt; NX_Q14508; -.
DR OpenTargets; ENSG00000101443; -.
DR PharmGKB; PA38059; -.
DR VEuPathDB; HostDB:ENSG00000101443; -.
DR eggNOG; ENOG502SA8J; Eukaryota.
DR GeneTree; ENSGT00730000111410; -.
DR HOGENOM; CLU_105901_3_0_1; -.
DR InParanoid; Q14508; -.
DR OMA; NEKQGSC; -.
DR OrthoDB; 1409658at2759; -.
DR PhylomeDB; Q14508; -.
DR PathwayCommons; Q14508; -.
DR SignaLink; Q14508; -.
DR BioGRID-ORCS; 10406; 11 hits in 1061 CRISPR screens.
DR ChiTaRS; WFDC2; human.
DR GeneWiki; WFDC2; -.
DR GenomeRNAi; 10406; -.
DR Pharos; Q14508; Tbio.
DR PRO; PR:Q14508; -.
DR Proteomes; UP000005640; Chromosome 20.
DR RNAct; Q14508; protein.
DR Bgee; ENSG00000101443; Expressed in olfactory segment of nasal mucosa and 143 other tissues.
DR ExpressionAtlas; Q14508; baseline and differential.
DR Genevisible; Q14508; HS.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0005615; C:extracellular space; IBA:GO_Central.
DR GO; GO:0019828; F:aspartic-type endopeptidase inhibitor activity; IDA:CACAO.
DR GO; GO:0004869; F:cysteine-type endopeptidase inhibitor activity; IEA:UniProtKB-KW.
DR GO; GO:0004866; F:endopeptidase inhibitor activity; TAS:ProtInc.
DR GO; GO:0004867; F:serine-type endopeptidase inhibitor activity; IDA:CACAO.
DR GO; GO:0019731; P:antibacterial humoral response; IBA:GO_Central.
DR GO; GO:0045087; P:innate immune response; IBA:GO_Central.
DR GO; GO:0006508; P:proteolysis; TAS:ProtInc.
DR GO; GO:0007283; P:spermatogenesis; TAS:ProtInc.
DR Gene3D; 4.10.75.10; -; 2.
DR InterPro; IPR036645; Elafin-like_sf.
DR InterPro; IPR008197; WAP_dom.
DR Pfam; PF00095; WAP; 2.
DR PRINTS; PR00003; 4DISULPHCORE.
DR SMART; SM00217; WAP; 2.
DR SUPFAM; SSF57256; SSF57256; 2.
DR PROSITE; PS51390; WAP; 2.
PE 1: Evidence at protein level;
KW Alternative splicing; Aspartic protease inhibitor; Disulfide bond;
KW Glycoprotein; Protease inhibitor; Reference proteome; Repeat; Secreted;
KW Serine protease inhibitor; Signal; Thiol protease inhibitor.
FT SIGNAL 1..30
FT /evidence="ECO:0000255"
FT CHAIN 31..124
FT /note="WAP four-disulfide core domain protein 2"
FT /id="PRO_0000041370"
FT DOMAIN 31..73
FT /note="WAP 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00722"
FT DOMAIN 74..123
FT /note="WAP 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00722"
FT CARBOHYD 44
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:16740002,
FT ECO:0000269|PubMed:23139753"
FT DISULFID 36..62
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00722"
FT DISULFID 45..66
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00722"
FT DISULFID 49..61
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00722"
FT DISULFID 55..70
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00722"
FT DISULFID 80..110
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00722"
FT DISULFID 93..114
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00722"
FT DISULFID 97..109
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00722"
FT DISULFID 103..119
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00722"
FT VAR_SEQ 2..23
FT /note="PACRLGPLAAALLLSLLLFGFT -> LQVQVNLPVSPLPTYPYSFFYP (in
FT isoform 2)"
FT /evidence="ECO:0000303|PubMed:11965550"
FT /id="VSP_007666"
FT VAR_SEQ 24..74
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:11965550"
FT /id="VSP_007667"
FT VAR_SEQ 27..74
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:11965550"
FT /id="VSP_007668"
FT VAR_SEQ 71..79
FT /note="SLPNDKEGS -> LLCPNGQLAE (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:11965550"
FT /id="VSP_007669"
FT VAR_SEQ 75..102
FT /note="DKEGSCPQVNINFPQLGLCRDQCQVDSQ -> ALFHWHLKTRRLWEISGPRP
FT RRPTWDSS (in isoform 5)"
FT /evidence="ECO:0000303|PubMed:11965550"
FT /id="VSP_007670"
FT VAR_SEQ 80..124
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:11965550"
FT /id="VSP_007671"
FT VAR_SEQ 103..124
FT /note="Missing (in isoform 5)"
FT /evidence="ECO:0000303|PubMed:11965550"
FT /id="VSP_007672"
FT CONFLICT 71..72
FT /note="SL -> LLC (in Ref. 1; CAA44869 and 2; AAL37485)"
FT /evidence="ECO:0000305"
FT CONFLICT 101
FT /note="S -> T (in Ref. 1; CAA44869)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 124 AA; 12993 MW; 9536B00B385259AD CRC64;
MPACRLGPLA AALLLSLLLF GFTLVSGTGA EKTGVCPELQ ADQNCTQECV SDSECADNLK
CCSAGCATFC SLPNDKEGSC PQVNINFPQL GLCRDQCQVD SQCPGQMKCC RNGCGKVSCV
TPNF
