ID ISK2_HUMAN Reviewed; 84 AA. AC P20155; Q6FGH2; DT 01-FEB-1991, integrated into UniProtKB/Swiss-Prot. DT 01-DEC-1992, sequence version 2. DT 24-JAN-2024, entry version 180. DE RecName: Full=Serine protease inhibitor Kazal-type 2; DE AltName: Full=Acrosin-trypsin inhibitor; DE AltName: Full=Epididymis tissue protein Li 172; DE AltName: Full=HUSI-II; DE Flags: Precursor; GN Name=SPINK2; 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]. RX PubMed=1704312; DOI=10.1016/0014-5793(91)80099-o; RA Moeritz A., Lilja H., Fink E.; RT "Molecular cloning and sequence analysis of the cDNA encoding the human RT acrosin-trypsin inhibitor (HUSI-II)."; RL FEBS Lett. 278:127-130(1991). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=8428671; DOI=10.1016/0378-1119(93)90138-s; RA Moeritz A., Grzeschik K.H., Wingender E., Fink E.; RT "Organization and sequence of the gene encoding the human acrosin-trypsin RT inhibitor (HUSI-II)."; RL Gene 123:277-281(1993). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY. RC TISSUE=Epididymis; RX PubMed=20736409; DOI=10.1074/mcp.m110.001719; RA Li J., Liu F., Wang H., Liu X., Liu J., Li N., Wan F., Wang W., Zhang C., RA Jin S., Liu J., Zhu P., Liu Y.; RT "Systematic mapping and functional analysis of a family of human epididymal RT secretory sperm-located proteins."; RL Mol. Cell. Proteomics 9:2517-2528(2010). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. 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 [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. 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 [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 (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. 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 [8] RP PROTEIN SEQUENCE OF 24-84, AND PYROGLUTAMATE FORMATION AT GLN-24. RC TISSUE=Semen; RX PubMed=2226783; DOI=10.1016/0014-5793(90)81273-q; RA Fink E., Hehlein-Fink C., Eulitz M.; RT "Amino acid sequence elucidation of human acrosin-trypsin inhibitor (HUSI- RT II) reveals that Kazal-type proteinase inhibitors are structurally related RT to beta-subunits of glycoprotein hormones."; RL FEBS Lett. 270:222-224(1990). RN [9] RP STRUCTURE BY NMR OF 23-84, FUNCTION, MUTAGENESIS OF PRO-45; ARG-46; HIS-47 RP AND PHE-48, IDENTIFICATION BY MASS SPECTROMETRY, AND DISULFIDE BONDS. RX PubMed=19422058; DOI=10.1002/prot.22432; RA Chen T., Lee T.-R., Liang W.-G., Chang W.-S., Lyu P.-C.; RT "Identification of trypsin-inhibitory site and structure determination of RT human SPINK2 serine proteinase inhibitor."; RL Proteins 77:209-219(2009). RN [10] RP FUNCTION, SUBCELLULAR LOCATION, AND INVOLVEMENT IN SPGF29. RX PubMed=28554943; DOI=10.15252/emmm.201607461; RA Kherraf Z.E., Christou-Kent M., Karaouzene T., Amiri-Yekta A., Martinez G., RA Vargas A.S., Lambert E., Borel C., Dorphin B., Aknin-Seifer I., RA Mitchell M.J., Metzler-Guillemain C., Escoffier J., Nef S., Grepillat M., RA Thierry-Mieg N., Satre V., Bailly M., Boitrelle F., Pernet-Gallay K., RA Hennebicq S., Faure J., Bottari S.P., Coutton C., Ray P.F., Arnoult C.; RT "SPINK2 deficiency causes infertility by inducing sperm defects in RT heterozygotes and azoospermia in homozygotes."; RL EMBO Mol. Med. 9:1132-1149(2017). CC -!- FUNCTION: As a strong inhibitor of acrosin, it is required for normal CC spermiogenesis. It probably hinders premature activation of proacrosin CC and other proteases, thus preventing the cascade of events leading to CC spermiogenesis defects (PubMed:28554943). May be involved in the CC regulation of serine protease-dependent germ cell apoptosis (By CC similarity). It also inhibits trypsin. {ECO:0000250|UniProtKB:Q8BMY7, CC ECO:0000269|PubMed:19422058, ECO:0000269|PubMed:28554943}. CC -!- INTERACTION: CC P20155; Q6UY14-3: ADAMTSL4; NbExp=3; IntAct=EBI-10200479, EBI-10173507; CC P20155; P28799: GRN; NbExp=3; IntAct=EBI-10200479, EBI-747754; CC P20155; Q9Y5K2: KLK4; NbExp=4; IntAct=EBI-10200479, EBI-10224152; CC P20155; P26371: KRTAP5-9; NbExp=3; IntAct=EBI-10200479, EBI-3958099; CC P20155; Q7Z3S9: NOTCH2NLA; NbExp=3; IntAct=EBI-10200479, EBI-945833; CC P20155; P49788: RARRES1; NbExp=5; IntAct=EBI-10200479, EBI-25504187; CC P20155; O76024: WFS1; NbExp=3; IntAct=EBI-10200479, EBI-720609; CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000305}. Cytoplasmic vesicle, CC secretory vesicle, acrosome {ECO:0000269|PubMed:28554943}. CC -!- TISSUE SPECIFICITY: Expressed in epididymis (at protein level). CC {ECO:0000269|PubMed:20736409}. CC -!- DISEASE: Spermatogenic failure 29 (SPGF29) [MIM:618091]: An autosomal CC recessive infertility disorder caused by spermatogenesis defects that CC result in non-obstructive azoospermia or oligozoospermia. When CC produced, spermatozoa are immotile and have abnormal morphology, CC primarily defects of the acrosome and head-neck junction. CC {ECO:0000269|PubMed:28554943}. Note=The disease is caused by variants CC affecting the gene represented in this entry. 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; M91438; AAB59431.1; -; Genomic_DNA. DR EMBL; X57655; CAB37834.1; -; mRNA. DR EMBL; M84967; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; GU727622; ADU87624.1; -; mRNA. DR EMBL; AK312222; BAG35155.1; -; mRNA. DR EMBL; CR542135; CAG46932.1; -; mRNA. DR EMBL; CH471057; EAX05513.1; -; Genomic_DNA. DR EMBL; BC022514; AAH22514.1; -; mRNA. DR CCDS; CCDS3508.1; -. DR PIR; JU0152; JU0152. DR RefSeq; NP_001258650.1; NM_001271721.1. DR RefSeq; NP_001258651.1; NM_001271722.1. DR RefSeq; NP_066937.1; NM_021114.3. DR PDB; 2JXD; NMR; -; A=23-84. DR PDB; 6KBR; X-ray; 2.00 A; C=23-84. DR PDBsum; 2JXD; -. DR PDBsum; 6KBR; -. DR AlphaFoldDB; P20155; -. DR BMRB; P20155; -. DR SMR; P20155; -. DR BioGRID; 112569; 30. DR IntAct; P20155; 29. DR MEROPS; I01.012; -. DR iPTMnet; P20155; -. DR PhosphoSitePlus; P20155; -. DR BioMuta; SPINK2; -. DR DMDM; 123985; -. DR jPOST; P20155; -. DR MassIVE; P20155; -. DR PeptideAtlas; P20155; -. DR ProteomicsDB; 53731; -. DR Antibodypedia; 12523; 59 antibodies from 18 providers. DR DNASU; 6691; -. DR Ensembl; ENST00000248701.8; ENSP00000248701.4; ENSG00000128040.13. DR GeneID; 6691; -. DR KEGG; hsa:6691; -. DR UCSC; uc003hcg.3; human. DR AGR; HGNC:11245; -. DR CTD; 6691; -. DR DisGeNET; 6691; -. DR GeneCards; SPINK2; -. DR HGNC; HGNC:11245; SPINK2. DR HPA; ENSG00000128040; Tissue enriched (epididymis). DR MalaCards; SPINK2; -. DR MIM; 605753; gene. DR MIM; 618091; phenotype. DR neXtProt; NX_P20155; -. DR OpenTargets; ENSG00000128040; -. DR PharmGKB; PA36075; -. DR VEuPathDB; HostDB:ENSG00000128040; -. DR GeneTree; ENSGT00530000064285; -. DR HOGENOM; CLU_169765_2_0_1; -. DR InParanoid; P20155; -. DR OrthoDB; 4736384at2759; -. DR PhylomeDB; P20155; -. DR PathwayCommons; P20155; -. DR SignaLink; P20155; -. DR BioGRID-ORCS; 6691; 12 hits in 1145 CRISPR screens. DR EvolutionaryTrace; P20155; -. DR GeneWiki; SPINK2; -. DR GenomeRNAi; 6691; -. DR Pharos; P20155; Tdark. DR PRO; PR:P20155; -. DR Proteomes; UP000005640; Chromosome 4. DR RNAct; P20155; Protein. DR Bgee; ENSG00000128040; Expressed in corpus epididymis and 109 other cell types or tissues. DR ExpressionAtlas; P20155; baseline and differential. DR GO; GO:0001669; C:acrosomal vesicle; IDA:UniProtKB. DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell. DR GO; GO:0004866; F:endopeptidase inhibitor activity; TAS:ProtInc. DR GO; GO:0004867; F:serine-type endopeptidase inhibitor activity; IEA:UniProtKB-KW. DR GO; GO:0001675; P:acrosome assembly; ISS:UniProtKB. DR GO; GO:0007286; P:spermatid development; IMP:UniProtKB. DR Gene3D; 3.30.60.30; -; 1. DR InterPro; IPR002350; Kazal_dom. DR InterPro; IPR036058; Kazal_dom_sf. DR InterPro; IPR042167; SPINK2. DR PANTHER; PTHR47608:SF1; SERINE PROTEASE INHIBITOR KAZAL-TYPE 2; 1. DR PANTHER; PTHR47608; SERINE PROTEASE INHIBITOR KAZAL-TYPE 2, SPINK2; 1. DR Pfam; PF00050; Kazal_1; 1. DR SMART; SM00280; KAZAL; 1. DR SUPFAM; SSF100895; Kazal-type serine protease inhibitors; 1. DR PROSITE; PS00282; KAZAL_1; 1. DR PROSITE; PS51465; KAZAL_2; 1. DR Genevisible; P20155; HS. PE 1: Evidence at protein level; KW 3D-structure; Cytoplasmic vesicle; Direct protein sequencing; KW Disulfide bond; Protease inhibitor; Pyrrolidone carboxylic acid; KW Reference proteome; Secreted; Serine protease inhibitor; Signal. FT SIGNAL 1..23 FT /evidence="ECO:0000269|PubMed:2226783" FT CHAIN 24..84 FT /note="Serine protease inhibitor Kazal-type 2" FT /id="PRO_0000016561" FT DOMAIN 30..84 FT /note="Kazal-like" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798" FT SITE 46..47 FT /note="Reactive bond" FT MOD_RES 24 FT /note="Pyrrolidone carboxylic acid" FT /evidence="ECO:0000269|PubMed:2226783" FT DISULFID 36..66 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798, FT ECO:0000269|PubMed:19422058" FT DISULFID 44..63 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798, FT ECO:0000269|PubMed:19422058" FT DISULFID 52..84 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798, FT ECO:0000269|PubMed:19422058" FT MUTAGEN 45 FT /note="P->A: No effect on inhibitory activity towards FT trypsin." FT /evidence="ECO:0000269|PubMed:19422058" FT MUTAGEN 46 FT /note="R->A: Loss of inhibitory activity towards trypsin." FT /evidence="ECO:0000269|PubMed:19422058" FT MUTAGEN 47 FT /note="H->A: Reduces inhibitory activity towards trypsin." FT /evidence="ECO:0000269|PubMed:19422058" FT MUTAGEN 48 FT /note="F->A: Reduces inhibitory activity towards trypsin." FT /evidence="ECO:0000269|PubMed:19422058" FT STRAND 27..32 FT /evidence="ECO:0007829|PDB:2JXD" FT HELIX 36..38 FT /evidence="ECO:0007829|PDB:6KBR" FT STRAND 51..53 FT /evidence="ECO:0007829|PDB:6KBR" FT STRAND 58..61 FT /evidence="ECO:0007829|PDB:6KBR" FT HELIX 62..72 FT /evidence="ECO:0007829|PDB:6KBR" FT STRAND 73..75 FT /evidence="ECO:0007829|PDB:2JXD" FT STRAND 78..83 FT /evidence="ECO:0007829|PDB:6KBR" SQ SEQUENCE 84 AA; 9291 MW; E1DE1792BFB1BB85 CRC64; MALSVLRLAL LLLAVTFAAS LIPQFGLFSK YRTPNCSQYR LPGCPRHFNP VCGSDMSTYA NECTLCMKIR EGGHNIKIIR NGPC //