ID ISK1_MOUSE Reviewed; 80 AA. AC P09036; Q5M9M3; DT 01-NOV-1988, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1988, sequence version 1. DT 27-MAR-2024, entry version 163. DE RecName: Full=Serine protease inhibitor Kazal-type 1 {ECO:0000312|MGI:MGI:106202}; DE AltName: Full=P12 {ECO:0000303|PubMed:3428272}; DE AltName: Full=Prostatic secretory glycoprotein {ECO:0000303|PubMed:3428272}; DE AltName: Full=Serine protease inhibitor Kazal-type 3 {ECO:0000303|PubMed:16083722}; DE Flags: Precursor; GN Name=Spink1 {ECO:0000312|MGI:MGI:106202}; GN Synonyms=Spink3 {ECO:0000303|PubMed:22228629}; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND INDUCTION. RC STRAIN=C57BL/6J; RX PubMed=3428272; DOI=10.1002/j.1460-2075.1987.tb02705.x; RA Mills J.S., Needham M., Parker M.G.; RT "A secretory protease inhibitor requires androgens for its expression in RT male sex accessory tissues but is expressed constitutively in pancreas."; RL EMBO J. 6:3711-3717(1987). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC STRAIN=C57BL/6J; TISSUE=Pancreas; RX PubMed=16141072; DOI=10.1126/science.1112014; RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J., RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.; RT "The transcriptional landscape of the mammalian genome."; RL Science 309:1559-1563(2005). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Kidney; 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 [4] RP PROTEIN SEQUENCE OF 43-47; 49-61 AND 63-72, AND SUBCELLULAR LOCATION. RX PubMed=1929395; DOI=10.1016/0003-9861(91)90540-y; RA Lai M.-L., Chen S.-W., Chen Y.-H.; RT "Purification and characterization of a trypsin inhibitor from mouse RT seminal vesicle secretion."; RL Arch. Biochem. Biophys. 290:265-271(1991). RN [5] RP FUNCTION, TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE. RX PubMed=9828198; DOI=10.1095/biolreprod59.6.1498; RA Chen L.-Y., Lin Y.-H., Lai M.-L., Chen Y.-H.; RT "Developmental profile of a caltrin-like protease inhibitor, P12, in mouse RT seminal vesicle and characterization of its binding sites on sperm RT surface."; RL Biol. Reprod. 59:1498-1505(1998). RN [6] RP FUNCTION, AND MUTAGENESIS OF ARG-42; TYR-44; ASP-45; ARG-66; LYS-67 AND RP ARG-68. RX PubMed=14645103; DOI=10.1095/biolreprod.103.020552; RA Luo C.W., Lin H.J., Gopinath S.C., Chen Y.H.; RT "Distinction of sperm-binding site and reactive site for trypsin inhibition RT on p12 secreted from the accessory sex glands of male mice."; RL Biol. Reprod. 70:965-971(2004). RN [7] RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=16083722; DOI=10.1016/j.gastro.2005.05.057; RA Ohmuraya M., Hirota M., Araki M., Mizushima N., Matsui M., Mizumoto T., RA Haruna K., Kume S., Takeya M., Ogawa M., Araki K., Yamamura K.; RT "Autophagic cell death of pancreatic acinar cells in serine protease RT inhibitor Kazal type 3-deficient mice."; RL Gastroenterology 129:696-705(2005). RN [8] RP FUNCTION. RX PubMed=22228629; DOI=10.1530/rep-11-0107; RA Zalazar L., Saez Lancellotti T.E., Clementi M., Lombardo C., Lamattina L., RA De Castro R., Fornes M.W., Cesari A.; RT "SPINK3 modulates mouse sperm physiology through the reduction of nitric RT oxide level independently of its trypsin inhibitory activity."; RL Reproduction 143:281-295(2012). CC -!- FUNCTION: Serine protease inhibitor which exhibits anti-trypsin CC activity (PubMed:3428272, PubMed:14645103, PubMed:22228629). In the CC pancreas, protects against trypsin-catalyzed premature activation of CC zymogens (PubMed:16083722). {ECO:0000269|PubMed:14645103, CC ECO:0000269|PubMed:16083722, ECO:0000269|PubMed:22228629, CC ECO:0000269|PubMed:3428272}. CC -!- FUNCTION: In the male reproductive tract, binds to sperm heads where it CC modulates sperm capacitance by inhibiting calcium uptake and nitrogen CC oxide (NO) production (PubMed:9828198, PubMed:14645103, CC PubMed:16083722, PubMed:22228629). {ECO:0000269|PubMed:14645103, CC ECO:0000269|PubMed:16083722, ECO:0000269|PubMed:22228629, CC ECO:0000269|PubMed:9828198}. CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:1929395}. CC -!- TISSUE SPECIFICITY: In the genital tract, expressed only in male CC accessory glands including seminal vesicle, coagulating gland and CC prostate. {ECO:0000269|PubMed:9828198}. CC -!- DEVELOPMENTAL STAGE: In the seminal vesicle, not expressed during CC prepubertal stages; expression coincides with maturation. CC {ECO:0000269|PubMed:9828198}. CC -!- INDUCTION: By androgens in adult male sex accessory glands. Expressed CC constitutively in pancreas. {ECO:0000269|PubMed:3428272}. CC -!- DISRUPTION PHENOTYPE: Lethal with no survival past two weeks of age. CC Animals are small and show severe, progressive degeneration of CC pancreatic tissue associated with autophagic cell death. CC {ECO:0000269|PubMed:16083722}. 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; X06342; CAA29648.1; -; mRNA. DR EMBL; AK007841; BAB25298.1; -; mRNA. DR EMBL; AK007985; BAB25389.1; -; mRNA. DR EMBL; BC086887; AAH86887.1; -; mRNA. DR CCDS; CCDS37803.1; -. DR PIR; S01498; S01498. DR RefSeq; NP_033284.1; NM_009258.5. DR AlphaFoldDB; P09036; -. DR SMR; P09036; -. DR BioGRID; 203452; 1. DR STRING; 10090.ENSMUSP00000025381; -. DR MEROPS; I01.011; -. DR PhosphoSitePlus; P09036; -. DR PaxDb; 10090-ENSMUSP00000025381; -. DR PeptideAtlas; P09036; -. DR ProteomicsDB; 269509; -. DR Antibodypedia; 27654; 312 antibodies from 32 providers. DR DNASU; 20730; -. DR Ensembl; ENSMUST00000025381.4; ENSMUSP00000025381.3; ENSMUSG00000024503.4. DR GeneID; 20730; -. DR KEGG; mmu:20730; -. DR UCSC; uc008eul.2; mouse. DR AGR; MGI:106202; -. DR CTD; 6690; -. DR MGI; MGI:106202; Spink1. DR VEuPathDB; HostDB:ENSMUSG00000024503; -. DR eggNOG; KOG3649; Eukaryota. DR GeneTree; ENSGT00530000064228; -. DR HOGENOM; CLU_169765_2_1_1; -. DR InParanoid; P09036; -. DR OMA; REAKCNN; -. DR OrthoDB; 2920086at2759; -. DR PhylomeDB; P09036; -. DR BioGRID-ORCS; 20730; 4 hits in 79 CRISPR screens. DR ChiTaRS; Spink1; mouse. DR PRO; PR:P09036; -. DR Proteomes; UP000000589; Chromosome 18. DR RNAct; P09036; Protein. DR Bgee; ENSMUSG00000024503; Expressed in prostate gland ventral lobe and 81 other cell types or tissues. DR GO; GO:0005615; C:extracellular space; IDA:MGI. DR GO; GO:0030414; F:peptidase inhibitor activity; IDA:MGI. DR GO; GO:0004867; F:serine-type endopeptidase inhibitor activity; IDA:MGI. DR GO; GO:0090281; P:negative regulation of calcium ion import; IDA:MGI. DR GO; GO:0010751; P:negative regulation of nitric oxide mediated signal transduction; IDA:MGI. DR GO; GO:0050732; P:negative regulation of peptidyl-tyrosine phosphorylation; IDA:MGI. DR GO; GO:0007263; P:nitric oxide mediated signal transduction; IDA:MGI. DR GO; GO:0060046; P:regulation of acrosome reaction; IDA:MGI. DR GO; GO:2001256; P:regulation of store-operated calcium entry; IDA:MGI. DR GO; GO:0048240; P:sperm capacitation; IDA:MGI. DR CDD; cd01327; KAZAL_PSTI; 1. DR Gene3D; 3.30.60.30; -; 1. DR InterPro; IPR002350; Kazal_dom. DR InterPro; IPR036058; Kazal_dom_sf. DR InterPro; IPR001239; Prot_inh_Kazal-m. DR PANTHER; PTHR21312; SERINE PROTEASE INHIBITOR; 1. DR PANTHER; PTHR21312:SF27; SERINE PROTEASE INHIBITOR KAZAL-TYPE 1; 1. DR Pfam; PF00050; Kazal_1; 1. DR PRINTS; PR00290; KAZALINHBTR. 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; P09036; MM. PE 1: Evidence at protein level; KW Direct protein sequencing; Disulfide bond; Protease inhibitor; KW Reference proteome; Secreted; Serine protease inhibitor; Signal. FT SIGNAL 1..23 FT /evidence="ECO:0000255" FT CHAIN 24..80 FT /note="Serine protease inhibitor Kazal-type 1" FT /id="PRO_0000016568" FT DOMAIN 27..80 FT /note="Kazal-like" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798" FT SITE 42..43 FT /note="Reactive bond for trypsin" FT /evidence="ECO:0000269|PubMed:14645103, FT ECO:0000269|PubMed:1929395" FT SITE 44..45 FT /note="Necessary for sperm binding" FT /evidence="ECO:0000269|PubMed:9828198" FT DISULFID 33..62 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798" FT DISULFID 40..59 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798" FT DISULFID 48..80 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798" FT MUTAGEN 42 FT /note="R->L: Abolishes trypsin inhibitor activity. No FT effect on sperm binding." FT /evidence="ECO:0000269|PubMed:14645103" FT MUTAGEN 44 FT /note="Y->V: Severely impairs sperm binding. No effect on FT trypsin inhibitor activity." FT /evidence="ECO:0000269|PubMed:14645103" FT MUTAGEN 45 FT /note="D->G: Fails to bind sperm. No effect on trypsin FT inhibitor activity." FT /evidence="ECO:0000269|PubMed:14645103" FT MUTAGEN 66 FT /note="R->G: No effect on trypsin inhibitor activity or FT sperm binding." FT /evidence="ECO:0000269|PubMed:14645103" FT MUTAGEN 67 FT /note="K->S: No effect on trypsin inhibitor activity or FT sperm binding." FT /evidence="ECO:0000269|PubMed:14645103" FT MUTAGEN 68 FT /note="R->T: No effect on trypsin inhibitor activity or FT sperm binding." FT /evidence="ECO:0000269|PubMed:14645103" SQ SEQUENCE 80 AA; 8488 MW; 4DC1F2EC4804CCA6 CRC64; MKVAVIFLLS ALALLSLAGN TFSAKVTGKE ASCHDAVAGC PRIYDPVCGT DGITYANECV LCFENRKRIE PVLIRKGGPC //