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}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; 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 //