ISK1_HUMAN
ID ISK1_HUMAN Reviewed; 79 AA.
AC P00995;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT 01-JUL-1989, sequence version 2.
DT 03-AUG-2022, entry version 210.
DE RecName: Full=Serine protease inhibitor Kazal-type 1 {ECO:0000312|HGNC:HGNC:11244};
DE AltName: Full=Pancreatic secretory trypsin inhibitor {ECO:0000303|PubMed:3501289};
DE AltName: Full=Tumor-associated trypsin inhibitor;
DE Short=TATI;
DE Flags: Precursor;
GN Name=SPINK1; Synonyms=PSTI;
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 [GENOMIC DNA].
RX PubMed=3501289; DOI=10.1016/0006-291x(87)90415-3;
RA Horii A., Kobayashi T., Tomita N., Yamamoto T., Fukushige S., Murotsu T.,
RA Ogawa M., Mori T., Matsubara K.;
RT "Primary structure of human pancreatic secretory trypsin inhibitor (PSTI)
RT gene.";
RL Biochem. Biophys. Res. Commun. 149:635-641(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=3877508; DOI=10.1016/0006-291x(85)91176-3;
RA Yamamoto T., Nakamura Y., Nishide T., Emi M., Ogawa M., Mori T.,
RA Matsubara K.;
RT "Molecular cloning and nucleotide sequence of human pancreatic secretory
RT trypsin inhibitor (PSTI) cDNA.";
RL Biochem. Biophys. Res. Commun. 132:605-612(1985).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2961612; DOI=10.1016/0014-5793(87)81141-9;
RA Tomita N., Horii A., Yamamoto T., Ogawa M., Mori T., Matsubara K.;
RT "Expression of pancreatic secretory trypsin inhibitor gene in neoplastic
RT tissues.";
RL FEBS Lett. 225:113-119(1987).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS PCTT PRO-14 AND SER-34, AND
RP VARIANT SER-55.
RX PubMed=10835640; DOI=10.1038/76088;
RA Witt H., Luck W., Hennies H.C., Classen M., Kage A., Lass U., Landt O.,
RA Becker M.;
RT "Mutations in the gene encoding the serine protease inhibitor, Kazal type 1
RT are associated with chronic pancreatitis.";
RL Nat. Genet. 25:213-216(2000).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Pancreas, and Spleen;
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 PROTEIN SEQUENCE OF 24-79.
RX PubMed=843082; DOI=10.1016/0003-9861(77)90103-5;
RA Bartelt D.C., Shapanka R., Greene L.J.;
RT "The primary structure of the human pancreatic secretory trypsin inhibitor.
RT Amino acid sequence of the reduced S-aminoethylated protein.";
RL Arch. Biochem. Biophys. 179:189-199(1977).
RN [7]
RP PROTEIN SEQUENCE OF 24-46, FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=7142173; DOI=10.1016/s0021-9258(18)33505-1;
RA Huhtala M.-L., Pesonen K., Kalkkinen N., Stenman U.-H.;
RT "Purification and characterization of a tumor-associated trypsin inhibitor
RT from the urine of a patient with ovarian cancer.";
RL J. Biol. Chem. 257:13713-13716(1982).
RN [8]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS).
RX PubMed=1613792; DOI=10.1016/0022-2836(92)90107-u;
RA Hecht H.-J., Szardenings M., Collins J., Schomburg D.;
RT "Three-dimensional structure of a recombinant variant of human pancreatic
RT secretory trypsin inhibitor (Kazal type).";
RL J. Mol. Biol. 225:1095-1103(1992).
RN [9]
RP STRUCTURE BY NMR OF MUTANT LEU-41/ARG-44.
RX PubMed=8433367; DOI=10.1006/jmbi.1993.1073;
RA Klaus W., Schomburg D.;
RT "Solution structure of a variant of human pancreatic secretory trypsin
RT inhibitor determined by nuclear magnetic resonance spectroscopy.";
RL J. Mol. Biol. 229:695-706(1993).
RN [10]
RP VARIANT PCTT SER-34, AND VARIANT SER-55.
RX PubMed=10691414; DOI=10.1136/jmg.37.1.67;
RA Chen J.-M., Mercier B., Audrezet M.-P., Ferec C.;
RT "Mutational analysis of the human pancreatic secretory trypsin inhibitor
RT (PSTI) gene in hereditary and sporadic chronic pancreatitis.";
RL J. Med. Genet. 37:67-69(2000).
RN [11]
RP VARIANT TCP SER-34, AND INVOLVEMENT IN FIBROCALCULOUS PANCREATIC DIABETES.
RX PubMed=12187509; DOI=10.1086/342731;
RA Hassan Z., Mohan V., Ali L., Allotey R., Barakat K., Faruque M.O.,
RA Deepa R., McDermott M.F., Jackson A.E., Cassell P., Curtis D.,
RA Gelding S.V., Vijayaravaghan S., Gyr N., Whitcomb D.C., Azad Khan A.K.,
RA Hitman G.A.;
RT "SPINK1 is a susceptibility gene for fibrocalculous pancreatic diabetes in
RT subjects from the Indian subcontinent.";
RL Am. J. Hum. Genet. 71:964-968(2002).
RN [12]
RP VARIANT TCP SER-34, AND VARIANT SER-55.
RX PubMed=12011155; DOI=10.1136/jmg.39.5.347;
RA Chandak G.R., Idris M.M., Reddy D.N., Bhaskar S., Sriram P.V.J., Singh L.;
RT "Mutations in the pancreatic secretory trypsin inhibitor gene (PSTI/SPINK1)
RT rather than the cationic trypsinogen gene (PRSS1) are significantly
RT associated with tropical calcific pancreatitis.";
RL J. Med. Genet. 39:347-351(2002).
RN [13]
RP VARIANT PCTT PHE-12.
RX PubMed=12974284; DOI=10.1007/s00439-003-0996-3;
RA Deybach J.-C.D., Phung L., Lamoril J., Bouizegarene P., Levy P.,
RA Deybach J.-C., Ruszniewski P.;
RT "Gene symbol: Spink1-Omim 167790. Disease: hereditary pancreatitis.";
RL Hum. Genet. 113:369-369(2003).
RN [14]
RP VARIANT PCTT SER-34, AND VARIANT SER-55.
RX PubMed=18617776; DOI=10.1097/meg.0b013e3282f5728c;
RA O'Reilly D.A., Witt H., Rahman S.H., Schulz H.U., Sargen K., Kage A.,
RA Cartmell M.T., Landt O., Larvin M., Demaine A.G., McMahon M.J., Becker M.,
RA Kingsnorth A.N.;
RT "The SPINK1 N34S variant is associated with acute pancreatitis.";
RL Eur. J. Gastroenterol. Hepatol. 20:726-731(2008).
RN [15]
RP VARIANT PCTT SER-34.
RX PubMed=19888199; DOI=10.1038/ajg.2009.630;
RA Aoun E., Muddana V., Papachristou G.I., Whitcomb D.C.;
RT "SPINK1 N34S is strongly associated with recurrent acute pancreatitis but
RT is not a risk factor for the first or sentinel acute pancreatitis event.";
RL Am. J. Gastroenterol. 105:446-451(2010).
CC -!- FUNCTION: Serine protease inhibitor which exhibits anti-trypsin
CC activity (PubMed:7142173). In the pancreas, protects against trypsin-
CC catalyzed premature activation of zymogens (By similarity).
CC {ECO:0000250|UniProtKB:P09036, ECO:0000269|PubMed:7142173}.
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. {ECO:0000250|UniProtKB:P09036}.
CC -!- INTERACTION:
CC P00995; Q12797-6: ASPH; NbExp=3; IntAct=EBI-8054204, EBI-12092171;
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:7142173}.
CC -!- DISEASE: Pancreatitis, hereditary (PCTT) [MIM:167800]: A disease
CC characterized by pancreas inflammation, permanent destruction of the
CC pancreatic parenchyma, maldigestion, and severe abdominal pain attacks.
CC {ECO:0000269|PubMed:10691414, ECO:0000269|PubMed:10835640,
CC ECO:0000269|PubMed:12974284, ECO:0000269|PubMed:18617776,
CC ECO:0000269|PubMed:19888199}. Note=Disease susceptibility is associated
CC with variants affecting the gene represented in this entry.
CC -!- DISEASE: Tropical calcific pancreatitis (TCP) [MIM:608189]: Idiopathic,
CC juvenile, nonalcoholic form of chronic pancreatitis widely prevalent in
CC several tropical countries. It can be associated with fibrocalculous
CC pancreatic diabetes (FCPD) depending on both environmental and genetic
CC factors. TCP differs from alcoholic pancreatitis by a much younger age
CC of onset, pancreatic calcification, a high incidence of insulin
CC dependent but ketosis resistant diabetes mellitus, and an exceptionally
CC high incidence of pancreatic cancer. {ECO:0000269|PubMed:12011155,
CC ECO:0000269|PubMed:12187509}. Note=Disease susceptibility is associated
CC with variants affecting the gene represented in this entry.
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DR EMBL; M20530; AAA36522.1; -; Genomic_DNA.
DR EMBL; M22971; AAA36522.1; JOINED; Genomic_DNA.
DR EMBL; M20528; AAA36522.1; JOINED; Genomic_DNA.
DR EMBL; M20529; AAA36522.1; JOINED; Genomic_DNA.
DR EMBL; Y00705; CAA68697.1; -; mRNA.
DR EMBL; M11949; AAA36521.1; -; mRNA.
DR EMBL; AF286028; AAG00531.1; -; Genomic_DNA.
DR EMBL; BC025790; AAH25790.1; -; mRNA.
DR CCDS; CCDS4286.1; -.
DR PIR; A27484; TIHUA.
DR RefSeq; NP_003113.2; NM_003122.4.
DR PDB; 1CGI; X-ray; 2.30 A; I=24-79.
DR PDB; 1CGJ; X-ray; 2.30 A; I=24-79.
DR PDB; 1HPT; X-ray; 2.30 A; A=24-79.
DR PDB; 7QE8; X-ray; 2.90 A; C/D=24-79.
DR PDB; 7QE9; X-ray; 2.10 A; C/D=24-79.
DR PDBsum; 1CGI; -.
DR PDBsum; 1CGJ; -.
DR PDBsum; 1HPT; -.
DR PDBsum; 7QE8; -.
DR PDBsum; 7QE9; -.
DR AlphaFoldDB; P00995; -.
DR SMR; P00995; -.
DR BioGRID; 112568; 8.
DR IntAct; P00995; 1.
DR MINT; P00995; -.
DR STRING; 9606.ENSP00000296695; -.
DR MEROPS; I01.011; -.
DR iPTMnet; P00995; -.
DR PhosphoSitePlus; P00995; -.
DR BioMuta; SPINK1; -.
DR DMDM; 124856; -.
DR jPOST; P00995; -.
DR MassIVE; P00995; -.
DR MaxQB; P00995; -.
DR PaxDb; P00995; -.
DR PeptideAtlas; P00995; -.
DR PRIDE; P00995; -.
DR ProteomicsDB; 51298; -.
DR Antibodypedia; 27654; 281 antibodies from 32 providers.
DR DNASU; 6690; -.
DR Ensembl; ENST00000296695.10; ENSP00000296695.5; ENSG00000164266.11.
DR GeneID; 6690; -.
DR KEGG; hsa:6690; -.
DR MANE-Select; ENST00000296695.10; ENSP00000296695.5; NM_001379610.1; NP_001366539.1.
DR UCSC; uc003los.3; human.
DR CTD; 6690; -.
DR DisGeNET; 6690; -.
DR GeneCards; SPINK1; -.
DR GeneReviews; SPINK1; -.
DR HGNC; HGNC:11244; SPINK1.
DR HPA; ENSG00000164266; Tissue enriched (pancreas).
DR MalaCards; SPINK1; -.
DR MIM; 167790; gene.
DR MIM; 167800; phenotype.
DR MIM; 608189; phenotype.
DR neXtProt; NX_P00995; -.
DR OpenTargets; ENSG00000164266; -.
DR Orphanet; 676; Hereditary chronic pancreatitis.
DR Orphanet; 64740; NON RARE IN EUROPE: Recurrent acute pancreatitis.
DR Orphanet; 103918; Tropical pancreatitis.
DR PharmGKB; PA36074; -.
DR VEuPathDB; HostDB:ENSG00000164266; -.
DR eggNOG; KOG3649; Eukaryota.
DR GeneTree; ENSGT00530000064228; -.
DR InParanoid; P00995; -.
DR OMA; EPSCENF; -.
DR OrthoDB; 1591004at2759; -.
DR PhylomeDB; P00995; -.
DR PathwayCommons; P00995; -.
DR SignaLink; P00995; -.
DR BioGRID-ORCS; 6690; 10 hits in 1065 CRISPR screens.
DR ChiTaRS; SPINK1; human.
DR EvolutionaryTrace; P00995; -.
DR GeneWiki; SPINK1; -.
DR GenomeRNAi; 6690; -.
DR Pharos; P00995; Tbio.
DR PRO; PR:P00995; -.
DR Proteomes; UP000005640; Chromosome 5.
DR RNAct; P00995; protein.
DR Bgee; ENSG00000164266; Expressed in body of pancreas and 122 other tissues.
DR ExpressionAtlas; P00995; baseline and differential.
DR Genevisible; P00995; HS.
DR GO; GO:0005737; C:cytoplasm; IEA:Ensembl.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
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:0071375; P:cellular response to peptide hormone stimulus; IEA:Ensembl.
DR GO; GO:0090281; P:negative regulation of calcium ion import; IEA:Ensembl.
DR GO; GO:0010751; P:negative regulation of nitric oxide mediated signal transduction; IEA:Ensembl.
DR GO; GO:0050732; P:negative regulation of peptidyl-tyrosine phosphorylation; IEA:Ensembl.
DR GO; GO:1900004; P:negative regulation of serine-type endopeptidase activity; IEA:Ensembl.
DR GO; GO:0007263; P:nitric oxide mediated signal transduction; IEA:Ensembl.
DR GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; IEA:Ensembl.
DR GO; GO:0007204; P:positive regulation of cytosolic calcium ion concentration; IEA:Ensembl.
DR GO; GO:0050679; P:positive regulation of epithelial cell proliferation; IEA:Ensembl.
DR GO; GO:0090187; P:positive regulation of pancreatic juice secretion; IEA:Ensembl.
DR GO; GO:0090277; P:positive regulation of peptide hormone secretion; IEA:Ensembl.
DR GO; GO:0060046; P:regulation of acrosome reaction; IEA:Ensembl.
DR GO; GO:2001256; P:regulation of store-operated calcium entry; IEA:Ensembl.
DR GO; GO:0045471; P:response to ethanol; IEA:Ensembl.
DR GO; GO:0031667; P:response to nutrient levels; IEA:Ensembl.
DR GO; GO:0048240; P:sperm capacitation; IEA:Ensembl.
DR InterPro; IPR002350; Kazal_dom.
DR InterPro; IPR036058; Kazal_dom_sf.
DR InterPro; IPR001239; Prot_inh_Kazal-m.
DR Pfam; PF00050; Kazal_1; 1.
DR PRINTS; PR00290; KAZALINHBTR.
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; Direct protein sequencing; Disease variant; Disulfide bond;
KW Protease inhibitor; Reference proteome; Secreted;
KW Serine protease inhibitor; Signal.
FT SIGNAL 1..23
FT /evidence="ECO:0000269|PubMed:7142173,
FT ECO:0000269|PubMed:843082"
FT CHAIN 24..79
FT /note="Serine protease inhibitor Kazal-type 1"
FT /id="PRO_0000016557"
FT DOMAIN 26..79
FT /note="Kazal-like"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00798"
FT SITE 41..42
FT /note="Reactive bond for trypsin"
FT /evidence="ECO:0000250|UniProtKB:P09036,
FT ECO:0000255|PROSITE-ProRule:PRU00798"
FT SITE 43..44
FT /note="Necessary for sperm binding"
FT /evidence="ECO:0000250|UniProtKB:P09036"
FT DISULFID 32..61
FT DISULFID 39..58
FT DISULFID 47..79
FT VARIANT 12
FT /note="L -> F (in PCTT; benign variant; dbSNP:rs35877720)"
FT /evidence="ECO:0000269|PubMed:12974284"
FT /id="VAR_032011"
FT VARIANT 14
FT /note="L -> P (in PCTT; dbSNP:rs104893939)"
FT /evidence="ECO:0000269|PubMed:10835640"
FT /id="VAR_011688"
FT VARIANT 34
FT /note="N -> S (in PCTT and TCP; associated with disease
FT susceptibility; risk factor also for acute pancreatitis;
FT may confer susceptibility to fibrocalculous pancreatic
FT diabetes; dbSNP:rs17107315)"
FT /evidence="ECO:0000269|PubMed:10691414,
FT ECO:0000269|PubMed:10835640, ECO:0000269|PubMed:12011155,
FT ECO:0000269|PubMed:12187509"
FT /id="VAR_011689"
FT VARIANT 55
FT /note="P -> S (in dbSNP:rs111966833)"
FT /evidence="ECO:0000269|PubMed:10691414,
FT ECO:0000269|PubMed:10835640, ECO:0000269|PubMed:12011155,
FT ECO:0000269|PubMed:18617776"
FT /id="VAR_011690"
FT VARIANT 67
FT /note="R -> H (in dbSNP:rs35523678)"
FT /id="VAR_032012"
FT CONFLICT 44
FT /note="D -> N (in Ref. 6; AA sequence and 7; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 52
FT /note="N -> D (in Ref. 6; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 64
FT /note="N -> G (in Ref. 3; CAA68697)"
FT /evidence="ECO:0000305"
FT STRAND 26..28
FT /evidence="ECO:0007829|PDB:1HPT"
FT STRAND 37..40
FT /evidence="ECO:0007829|PDB:1CGI"
FT STRAND 46..48
FT /evidence="ECO:0007829|PDB:1CGI"
FT STRAND 53..56
FT /evidence="ECO:0007829|PDB:1CGI"
FT HELIX 57..67
FT /evidence="ECO:0007829|PDB:1CGI"
FT STRAND 73..77
FT /evidence="ECO:0007829|PDB:1CGI"
SQ SEQUENCE 79 AA; 8507 MW; 3583C8196952EB3A CRC64;
MKVTGIFLLS ALALLSLSGN TGADSLGREA KCYNELNGCT KIYDPVCGTD GNTYPNECVL
CFENRKRQTS ILIQKSGPC
