ISK2_HUMAN
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 03-AUG-2022, entry version 174.
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.
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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 PaxDb; P20155; -.
DR PeptideAtlas; P20155; -.
DR PRIDE; P20155; -.
DR ProteomicsDB; 53731; -.
DR Antibodypedia; 12523; 47 antibodies from 18 providers.
DR DNASU; 6691; -.
DR Ensembl; ENST00000248701.8; ENSP00000248701.4; ENSG00000128040.12.
DR GeneID; 6691; -.
DR KEGG; hsa:6691; -.
DR UCSC; uc003hcg.3; human.
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 PhylomeDB; P20155; -.
DR PathwayCommons; P20155; -.
DR SignaLink; P20155; -.
DR BioGRID-ORCS; 6691; 12 hits in 1070 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 107 other tissues.
DR ExpressionAtlas; P20155; baseline and differential.
DR Genevisible; P20155; HS.
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:1900004; P:negative regulation of serine-type endopeptidase activity; IBA:GO_Central.
DR GO; GO:0007286; P:spermatid development; IMP:UniProtKB.
DR InterPro; IPR002350; Kazal_dom.
DR InterPro; IPR036058; Kazal_dom_sf.
DR InterPro; IPR042167; SPINK2.
DR PANTHER; PTHR47608; PTHR47608; 1.
DR Pfam; PF00050; Kazal_1; 1.
DR SMART; SM00280; KAZAL; 1.
DR SUPFAM; SSF100895; SSF100895; 1.
DR PROSITE; PS00282; KAZAL_1; 1.
DR PROSITE; PS51465; KAZAL_2; 1.
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
