EPPI_HUMAN
ID EPPI_HUMAN Reviewed; 133 AA.
AC O95925; A6PVD6; Q86TP9; Q96SD7; Q9HD30;
DT 04-MAY-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-1999, sequence version 1.
DT 03-AUG-2022, entry version 178.
DE RecName: Full=Eppin;
DE AltName: Full=Cancer/testis antigen 71;
DE Short=CT71;
DE AltName: Full=Epididymal protease inhibitor;
DE AltName: Full=Protease inhibitor WAP7;
DE AltName: Full=Serine protease inhibitor-like with Kunitz and WAP domains 1;
DE AltName: Full=WAP four-disulfide core domain protein 7;
DE Flags: Precursor;
GN Name=EPPIN; Synonyms=SPINLW1, WAP7, WFDC7;
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] (ISOFORMS 1 AND 2), SUBUNIT, AND TISSUE
RP SPECIFICITY.
RC TISSUE=Epididymis, and Testis;
RX PubMed=11404006; DOI=10.1016/s0378-1119(01)00462-0;
RA Richardson R.T., Sivashanmugam P., Hall S.H., Hamil K.G., Moore P.A.,
RA Ruben S.M., French F.S., O'Rand M.G.;
RT "Cloning and sequencing of human eppin: a novel family of protease
RT inhibitors expressed in the epididymis and testis.";
RL Gene 270:93-102(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Stavrides G.S., Huckle E.J., Deloukas P.;
RL Submitted (SEP-1999) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Testis;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
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 [6]
RP FUNCTION.
RX PubMed=15229136; DOI=10.1095/biolreprod.104.031567;
RA Yenugu S., Richardson R.T., Sivashanmugam P., Wang Z., O'rand M.G.,
RA French F.S., Hall S.H.;
RT "Antimicrobial activity of human EPPIN, an androgen-regulated, sperm-bound
RT protein with a whey acidic protein motif.";
RL Biol. Reprod. 71:1484-1490(2004).
RN [7]
RP INTERACTION WITH SEMG1, SUBCELLULAR LOCATION, AND SUBUNIT.
RX PubMed=15590901; DOI=10.1095/biolreprod.104.036483;
RA Wang Z., Widgren E.E., Sivashanmugam P., O'Rand M.G., Richardson R.T.;
RT "Association of eppin with semenogelin on human spermatozoa.";
RL Biol. Reprod. 72:1064-1070(2005).
RN [8]
RP IDENTIFICATION IN A COMPLEX WITH LTF AND CLU, AND IDENTIFICATION BY MASS
RP SPECTROMETRY.
RX PubMed=17567961; DOI=10.1095/biolreprod.107.060194;
RA Wang Z., Widgren E.E., Richardson R.T., O'Rand M.G.;
RT "Characterization of an eppin protein complex from human semen and
RT spermatozoa.";
RL Biol. Reprod. 77:476-484(2007).
RN [9]
RP FUNCTION ON KLK3 ACTIVITY, AND MUTAGENESIS OF LEU-87.
RX PubMed=17644992;
RA Wang Z., Widgren E.E., Richardson R.T., Orand M.G.;
RT "Eppin: a molecular strategy for male contraception.";
RL Soc. Reprod. Fertil. Suppl. 65:535-542(2007).
RN [10]
RP DOMAIN.
RX PubMed=18331357; DOI=10.1111/j.1742-4658.2008.06333.x;
RA McCrudden M.T., Dafforn T.R., Houston D.F., Turkington P.T., Timson D.J.;
RT "Functional domains of the human epididymal protease inhibitor, eppin.";
RL FEBS J. 275:1742-1750(2008).
RN [11]
RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RX PubMed=21461566; DOI=10.3892/mmr.2010.403;
RA Long Y., Gu A., Yang H., Ji G., Han X., Song L., Wang S., Wang X.;
RT "Distribution of Eppin in mouse and human testis.";
RL Mol. Med. Report. 4:71-75(2011).
RN [12]
RP INTERACTION WITH LTF AND SEMG1, MUTAGENESIS OF CYS-102; TYR-107; CYS-110;
RP PHE-117; CYS-123 AND CYS-127, AND PUTATIVE CONTRACEPTIVE TARGET.
RX PubMed=22699487; DOI=10.1095/biolreprod.112.101832;
RA Silva E.J., Hamil K.G., Richardson R.T., O'Rand M.G.;
RT "Characterization of EPPIN's semenogelin I binding Site: a contraceptive
RT drug target.";
RL Biol. Reprod. 87:56-56(2012).
CC -!- FUNCTION: Serine protease inhibitor that plays an essential role in
CC male reproduction and fertility. Modulates the hydrolysis of SEMG1 by
CC KLK3/PSA (a serine protease), provides antimicrobial protection for
CC spermatozoa in the ejaculate coagulum, and binds SEMG1 thereby
CC inhibiting sperm motility. {ECO:0000269|PubMed:15229136,
CC ECO:0000269|PubMed:17644992}.
CC -!- SUBUNIT: Monomer. Homodimer. Homomultimers. Interacts with SEMG1 (via
CC 164-283 AA). Interacts with LTF. Found in a complex with LTF, CLU,
CC EPPIN and SEMG1. {ECO:0000269|PubMed:11404006,
CC ECO:0000269|PubMed:15590901, ECO:0000269|PubMed:17567961,
CC ECO:0000269|PubMed:22699487}.
CC -!- SUBCELLULAR LOCATION: [Isoform 1]: Secreted. Cell surface. Note=Bound
CC to the surface of testicular and on the head and tail of ejaculate
CC spermatozoa.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=O95925-1; Sequence=Displayed;
CC Name=2; Synonyms=Eppin-2;
CC IsoId=O95925-2; Sequence=VSP_006755;
CC Name=3;
CC IsoId=O95925-3; Sequence=VSP_043679;
CC -!- TISSUE SPECIFICITY: In testis, expressed and secreted by Sertoli cells,
CC appearing on the surface of testicular and ejaculate spermatozoa.
CC Expressed in the spermatogonia and the earliest preleptotene
CC spermatocytes. In the epididymis, is expressed and secreted by
CC epithelial cells and covers the surface of epididymal spermatozoa and
CC ciliated epithelial cells (at protein level). Expressed specifically in
CC epididymis and testis. Isoform 2 is expressed only in the epididymis.
CC Weak expression is detected in myoid cells as well as spermatogenic
CC cells. {ECO:0000269|PubMed:11404006, ECO:0000269|PubMed:21461566}.
CC -!- DOMAIN: The BPTI/Kunitz inhibitor domain is required for elastase
CC inhibitory activity. BPTI/Kunitz inhibitor and WAP domains are involved
CC in the protein antibacterial activity. {ECO:0000269|PubMed:18331357}.
CC -!- MISCELLANEOUS: Might be used as a target for male contraception.
CC {ECO:0000305|PubMed:22699487}.
CC -!- MISCELLANEOUS: [Isoform 2]: Lacks a cleavable signal sequence.
CC {ECO:0000305}.
CC -!- MISCELLANEOUS: [Isoform 3]: Based on a readthrough transcript which may
CC produce a EPPIN-WFDC6 fusion protein. {ECO:0000305}.
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DR EMBL; AF286368; AAG00546.1; -; mRNA.
DR EMBL; AF286369; AAG00547.1; -; mRNA.
DR EMBL; AF286370; AAG00548.1; -; mRNA.
DR EMBL; AL118493; CAB56343.1; -; mRNA.
DR EMBL; AK301937; BAG63357.1; -; mRNA.
DR EMBL; AL031663; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC044829; AAH44829.2; -; mRNA.
DR EMBL; BC053369; AAH53369.1; -; mRNA.
DR CCDS; CCDS13359.1; -. [O95925-1]
DR RefSeq; NP_001185915.1; NM_001198986.1. [O95925-3]
DR RefSeq; NP_001289790.1; NM_001302861.1.
DR RefSeq; NP_065131.1; NM_020398.3. [O95925-1]
DR AlphaFoldDB; O95925; -.
DR SMR; O95925; -.
DR BioGRID; 121383; 53.
DR IntAct; O95925; 3.
DR STRING; 9606.ENSP00000361746; -.
DR MEROPS; I02.058; -.
DR MEROPS; I17.953; -.
DR BioMuta; EPPIN; -.
DR MassIVE; O95925; -.
DR PaxDb; O95925; -.
DR PeptideAtlas; O95925; -.
DR PRIDE; O95925; -.
DR ProteomicsDB; 51127; -. [O95925-1]
DR ProteomicsDB; 51128; -. [O95925-2]
DR ProteomicsDB; 51129; -. [O95925-3]
DR Antibodypedia; 34909; 96 antibodies from 19 providers.
DR Antibodypedia; 76905; 16 antibodies from 2 providers.
DR DNASU; 57119; -.
DR Ensembl; ENST00000336443.3; ENSP00000338114.3; ENSG00000101448.14. [O95925-2]
DR Ensembl; ENST00000354280.9; ENSP00000361746.4; ENSG00000101448.14. [O95925-1]
DR Ensembl; ENST00000504988.1; ENSP00000424176.1; ENSG00000249139.2. [O95925-3]
DR GeneID; 100526773; -.
DR GeneID; 57119; -.
DR KEGG; hsa:100526773; -.
DR KEGG; hsa:57119; -.
DR MANE-Select; ENST00000354280.9; ENSP00000361746.4; NM_020398.4; NP_065131.1.
DR UCSC; uc002xou.4; human. [O95925-1]
DR CTD; 100526773; -.
DR CTD; 57119; -.
DR DisGeNET; 100526773; -.
DR DisGeNET; 57119; -.
DR GeneCards; EPPIN; -.
DR GeneCards; EPPIN-WFDC6; -.
DR HGNC; HGNC:15932; EPPIN.
DR HGNC; HGNC:38825; EPPIN-WFDC6.
DR HPA; ENSG00000101448; Group enriched (epididymis, testis).
DR HPA; ENSG00000249139; Group enriched (epididymis, testis).
DR MIM; 609031; gene.
DR neXtProt; NX_O95925; -.
DR OpenTargets; ENSG00000101448; -.
DR OpenTargets; ENSG00000249139; -.
DR PharmGKB; PA38054; -.
DR VEuPathDB; HostDB:ENSG00000101448; -.
DR VEuPathDB; HostDB:ENSG00000249139; -.
DR eggNOG; KOG4295; Eukaryota.
DR GeneTree; ENSGT00940000156753; -.
DR HOGENOM; CLU_127181_0_0_1; -.
DR InParanoid; O95925; -.
DR OMA; ERNQCAN; -.
DR OrthoDB; 1474897at2759; -.
DR PhylomeDB; O95925; -.
DR TreeFam; TF342459; -.
DR PathwayCommons; O95925; -.
DR Reactome; R-HSA-6803157; Antimicrobial peptides.
DR SignaLink; O95925; -.
DR BioGRID-ORCS; 100526773; 11 hits in 958 CRISPR screens.
DR BioGRID-ORCS; 57119; 7 hits in 966 CRISPR screens.
DR GeneWiki; SPINLW1; -.
DR Pharos; O95925; Tbio.
DR PRO; PR:O95925; -.
DR Proteomes; UP000005640; Chromosome 20.
DR RNAct; O95925; protein.
DR Bgee; ENSG00000101448; Expressed in right testis and 71 other tissues.
DR ExpressionAtlas; O95925; baseline and differential.
DR Genevisible; O95925; HS.
DR GO; GO:0001669; C:acrosomal vesicle; IEA:Ensembl.
DR GO; GO:0009986; C:cell surface; IDA:UniProtKB.
DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB.
DR GO; GO:0032991; C:protein-containing complex; IDA:UniProtKB.
DR GO; GO:0097524; C:sperm plasma membrane; TAS:Reactome.
DR GO; GO:0004867; F:serine-type endopeptidase inhibitor activity; IEA:UniProtKB-KW.
DR GO; GO:0042742; P:defense response to bacterium; IDA:UniProtKB.
DR GO; GO:0090281; P:negative regulation of calcium ion import; IMP:UniProtKB.
DR GO; GO:1901318; P:negative regulation of flagellated sperm motility; IMP:UniProtKB.
DR GO; GO:0010466; P:negative regulation of peptidase activity; IDA:UniProtKB.
DR CDD; cd00109; KU; 1.
DR Gene3D; 4.10.410.10; -; 1.
DR Gene3D; 4.10.75.10; -; 1.
DR InterPro; IPR036645; Elafin-like_sf.
DR InterPro; IPR002223; Kunitz_BPTI.
DR InterPro; IPR036880; Kunitz_BPTI_sf.
DR InterPro; IPR020901; Prtase_inh_Kunz-CS.
DR InterPro; IPR008197; WAP_dom.
DR Pfam; PF00014; Kunitz_BPTI; 1.
DR Pfam; PF00095; WAP; 1.
DR PRINTS; PR00759; BASICPTASE.
DR SMART; SM00131; KU; 1.
DR SMART; SM00217; WAP; 1.
DR SUPFAM; SSF57256; SSF57256; 1.
DR SUPFAM; SSF57362; SSF57362; 1.
DR PROSITE; PS00280; BPTI_KUNITZ_1; 1.
DR PROSITE; PS50279; BPTI_KUNITZ_2; 1.
DR PROSITE; PS51390; WAP; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Antimicrobial; Disulfide bond; Protease inhibitor;
KW Reference proteome; Secreted; Serine protease inhibitor; Signal.
FT SIGNAL 1..21
FT /evidence="ECO:0000255"
FT CHAIN 22..133
FT /note="Eppin"
FT /id="PRO_0000041378"
FT DOMAIN 26..73
FT /note="WAP"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00722"
FT DOMAIN 77..127
FT /note="BPTI/Kunitz inhibitor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00031"
FT REGION 102..133
FT /note="Interaction with SEMG1"
FT REGION 117..133
FT /note="Interaction with LTF"
FT /evidence="ECO:0000269|PubMed:22699487"
FT DISULFID 33..61
FT /evidence="ECO:0000250"
FT DISULFID 40..65
FT /evidence="ECO:0000250"
FT DISULFID 48..60
FT /evidence="ECO:0000250"
FT DISULFID 54..69
FT /evidence="ECO:0000250"
FT DISULFID 77..127
FT /evidence="ECO:0000250"
FT DISULFID 86..110
FT /evidence="ECO:0000250"
FT DISULFID 102..123
FT /evidence="ECO:0000250"
FT VAR_SEQ 1..31
FT /note="MGSSGLLSLLVLFVLLANVQGPGLTDWLFPR -> MLSKAHGCKTALSLG
FT (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:11404006"
FT /id="VSP_006755"
FT VAR_SEQ 131..133
FT /note="RFP -> QPCPKIKVECEVEEIDQCTKPRDCPENMKCCPFSRGKKCLDFRKA
FT SLST (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_043679"
FT VARIANT 92
FT /note="H -> R (in dbSNP:rs2231838)"
FT /id="VAR_024696"
FT VARIANT 128
FT /note="K -> T (in dbSNP:rs2231839)"
FT /id="VAR_052950"
FT MUTAGEN 87
FT /note="L->G: Loss of effect on KLK3 activity."
FT /evidence="ECO:0000269|PubMed:17644992"
FT MUTAGEN 102
FT /note="C->A: Reduces the binding to SEMG1 by 45%."
FT /evidence="ECO:0000269|PubMed:22699487"
FT MUTAGEN 107
FT /note="Y->A: Reduces the binding to SEMG1 by 68%."
FT /evidence="ECO:0000269|PubMed:22699487"
FT MUTAGEN 110
FT /note="C->A: Does not affect the binding of SEMG1 or LTF.
FT Does not affect the binding of SEMG1; when associated with
FT A-123 and A-127."
FT /evidence="ECO:0000269|PubMed:22699487"
FT MUTAGEN 117
FT /note="F->A: Reduces the binding to SEMG1 by 68% and to LTF
FT by 73%."
FT /evidence="ECO:0000269|PubMed:22699487"
FT MUTAGEN 123
FT /note="C->A: Does not affect the binding of SEMG1 or LTF.
FT Does not affect the binding of SEMG1; when associated with
FT A-110 and A-127."
FT /evidence="ECO:0000269|PubMed:22699487"
FT MUTAGEN 127
FT /note="C->A: Does not affect the binding of SEMG1 or LTF.
FT Does not affect the binding of SEMG1; when associated with
FT A-110 and A-123."
FT /evidence="ECO:0000269|PubMed:22699487"
SQ SEQUENCE 133 AA; 15284 MW; F7831B203366D9DC CRC64;
MGSSGLLSLL VLFVLLANVQ GPGLTDWLFP RRCPKIREEC EFQERDVCTK DRQCQDNKKC
CVFSCGKKCL DLKQDVCEMP KETGPCLAYF LHWWYDKKDN TCSMFVYGGC QGNNNNFQSK
ANCLNTCKNK RFP
