Entry euk: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   15-MAR-2017, entry version 178.
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;
OC   Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC   Catarrhini; Hominidae; 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.,
RA   Murotsu T., Ogawa M., Mori T., Matsubara K.;
RT   "Primary structure of human pancreatic secretory trypsin inhibitor
RT   (PSTI) 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
RT   secretory 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
RT   neoplastic tissues.";
RL   FEBS Lett. 225:113-119(1987).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS PCTT PRO-14 AND SER-34,
RP   AND VARIANT SER-55.
RX   PubMed=10835640; DOI=10.1038/76088;
RA   Witt H., Luck W., Hennies H.C., Classen M., Kage A., Lass U.,
RA   Landt O., Becker M.;
RT   "Mutations in the gene encoding the serine protease inhibitor, Kazal
RT   type 1 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
RT   project: 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
RT   inhibitor. Amino acid sequence of the reduced S-aminoethylated
RT   protein.";
RL   Arch. Biochem. Biophys. 179:189-199(1977).
RN   [7]
RP   PROTEIN SEQUENCE OF 24-46, FUNCTION, AND SUBCELLULAR LOCATION.
RX   PubMed=7142173;
RA   Huhtala M.-L., Pesonen K., Kalkkinen N., Stenman U.-H.;
RT   "Purification and characterization of a tumor-associated trypsin
RT   inhibitor 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
RT   pancreatic 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
RT   inhibitor (PSTI) gene in hereditary and sporadic chronic
RT   pancreatitis.";
RL   J. Med. Genet. 37:67-69(2000).
RN   [11]
RP   VARIANT TCP SER-34, AND INVOLVEMENT IN FIBROCALCULOUS PANCREATIC
RP   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.,
RA   Azad Khan A.K., Hitman G.A.;
RT   "SPINK1 is a susceptibility gene for fibrocalculous pancreatic
RT   diabetes in 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.,
RA   Singh L.;
RT   "Mutations in the pancreatic secretory trypsin inhibitor gene
RT   (PSTI/SPINK1) rather than the cationic trypsinogen gene (PRSS1) are
RT   significantly 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.,
RA   Becker M., 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
RT   but is not a risk factor for the first or sentinel acute pancreatitis
RT   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
CC       trypsin-catalyzed premature activation of zymogens (By
CC       similarity). {ECO:0000250|UniProtKB:P09036,
CC       ECO:0000269|PubMed:7142173}.
CC   -!- FUNCTION: In the male reproductive tract, binds to sperm heads
CC       where it modulates sperm capacitance by inhibiting calcium uptake
CC       and nitrogen oxide (NO) production.
CC       {ECO:0000250|UniProtKB:P09036}.
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
CC       the pancreatic parenchyma, maldigestion, and severe abdominal pain
CC       attacks. {ECO:0000269|PubMed:10691414,
CC       ECO:0000269|PubMed:10835640, ECO:0000269|PubMed:12974284,
CC       ECO:0000269|PubMed:18617776, ECO:0000269|PubMed:19888199}.
CC       Note=Disease susceptibility is associated with variations
CC       affecting the gene represented in this entry.
CC   -!- DISEASE: Tropical calcific pancreatitis (TCP) [MIM:608189]:
CC       Idiopathic, juvenile, nonalcoholic form of chronic pancreatitis
CC       widely prevalent in several tropical countries. It can be
CC       associated with fibrocalculous pancreatic diabetes (FCPD)
CC       depending on both environmental and genetic factors. TCP differs
CC       from alcoholic pancreatitis by a much younger age of onset,
CC       pancreatic calcification, a high incidence of insulin dependent
CC       but ketosis resistant diabetes mellitus, and an exceptionally high
CC       incidence of pancreatic cancer. {ECO:0000269|PubMed:12011155,
CC       ECO:0000269|PubMed:12187509}. Note=Disease susceptibility is
CC       associated with variations affecting the gene represented in this
CC       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   UniGene; Hs.407856; -.
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   PDBsum; 1CGI; -.
DR   PDBsum; 1CGJ; -.
DR   PDBsum; 1HPT; -.
DR   ProteinModelPortal; P00995; -.
DR   SMR; P00995; -.
DR   BioGrid; 112568; 1.
DR   MINT; MINT-1504272; -.
DR   STRING; 9606.ENSP00000296695; -.
DR   MEROPS; I01.011; -.
DR   iPTMnet; P00995; -.
DR   PhosphoSitePlus; P00995; -.
DR   BioMuta; SPINK1; -.
DR   DMDM; 124856; -.
DR   MaxQB; P00995; -.
DR   PaxDb; P00995; -.
DR   PeptideAtlas; P00995; -.
DR   PRIDE; P00995; -.
DR   DNASU; 6690; -.
DR   Ensembl; ENST00000296695; ENSP00000296695; ENSG00000164266.
DR   GeneID; 6690; -.
DR   KEGG; hsa:6690; -.
DR   UCSC; uc003los.3; human.
DR   CTD; 6690; -.
DR   DisGeNET; 6690; -.
DR   GeneCards; SPINK1; -.
DR   HGNC; HGNC:11244; SPINK1.
DR   HPA; CAB026366; -.
DR   HPA; HPA027498; -.
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; 103918; Tropical pancreatitis.
DR   PharmGKB; PA36074; -.
DR   eggNOG; KOG3649; Eukaryota.
DR   eggNOG; ENOG410YC3T; LUCA.
DR   GeneTree; ENSGT00530000064228; -.
DR   HOGENOM; HOG000090244; -.
DR   HOVERGEN; HBG006182; -.
DR   InParanoid; P00995; -.
DR   OMA; CTKIYNP; -.
DR   OrthoDB; EOG091G14HG; -.
DR   PhylomeDB; P00995; -.
DR   ChiTaRS; SPINK1; human.
DR   EvolutionaryTrace; P00995; -.
DR   GeneWiki; SPINK1; -.
DR   GenomeRNAi; 6690; -.
DR   PMAP-CutDB; P00995; -.
DR   PRO; PR:P00995; -.
DR   Proteomes; UP000005640; Chromosome 5.
DR   Bgee; ENSG00000164266; -.
DR   CleanEx; HS_SPINK1; -.
DR   ExpressionAtlas; P00995; baseline and differential.
DR   Genevisible; P00995; HS.
DR   GO; GO:0001669; C:acrosomal vesicle; IBA:GO_Central.
DR   GO; GO:0070062; C:extracellular exosome; IDA:UniProtKB.
DR   GO; GO:0005615; C:extracellular space; IBA:GO_Central.
DR   GO; GO:0004866; F:endopeptidase inhibitor activity; TAS:ProtInc.
DR   GO; GO:0004867; F:serine-type endopeptidase inhibitor activity; IBA:GO_Central.
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; IBA:GO_Central.
DR   GO; GO:0060046; P:regulation of acrosome reaction; IBA:GO_Central.
DR   GO; GO:2001256; P:regulation of store-operated calcium entry; IEA:Ensembl.
DR   InterPro; IPR002350; Kazal_dom.
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; Complete proteome; Direct protein sequencing;
KW   Disease mutation; Disulfide bond; Polymorphism; Protease inhibitor;
KW   Reference proteome; Secreted; Serine protease inhibitor; Signal.
FT   SIGNAL        1     23       {ECO:0000269|PubMed:7142173,
FT                                ECO:0000269|PubMed:843082}.
FT   CHAIN        24     79       Serine protease inhibitor Kazal-type 1.
FT                                /FTId=PRO_0000016557.
FT   DOMAIN       26     79       Kazal-like. {ECO:0000255|PROSITE-
FT                                ProRule:PRU00798}.
FT   SITE         41     42       Reactive bond for trypsin.
FT                                {ECO:0000250|UniProtKB:P09036,
FT                                ECO:0000255|PROSITE-ProRule:PRU00798}.
FT   SITE         43     44       Necessary for sperm binding.
FT                                {ECO:0000250|UniProtKB:P09036}.
FT   DISULFID     32     61
FT   DISULFID     39     58
FT   DISULFID     47     79
FT   VARIANT      12     12       L -> F (in PCTT; dbSNP:rs35877720).
FT                                {ECO:0000269|PubMed:12974284}.
FT                                /FTId=VAR_032011.
FT   VARIANT      14     14       L -> P (in PCTT; dbSNP:rs104893939).
FT                                {ECO:0000269|PubMed:10835640}.
FT                                /FTId=VAR_011688.
FT   VARIANT      34     34       N -> S (in PCTT and TCP; associated with
FT                                disease susceptibility; risk factor also
FT                                for acute pancreatitis; may confer
FT                                susceptibility to fibrocalculous
FT                                pancreatic diabetes; dbSNP:rs17107315).
FT                                {ECO:0000269|PubMed:10691414,
FT                                ECO:0000269|PubMed:10835640,
FT                                ECO:0000269|PubMed:12011155,
FT                                ECO:0000269|PubMed:12187509}.
FT                                /FTId=VAR_011689.
FT   VARIANT      55     55       P -> S (in dbSNP:rs111966833).
FT                                {ECO:0000269|PubMed:10691414,
FT                                ECO:0000269|PubMed:10835640,
FT                                ECO:0000269|PubMed:12011155,
FT                                ECO:0000269|PubMed:18617776}.
FT                                /FTId=VAR_011690.
FT   VARIANT      67     67       R -> H (in dbSNP:rs35523678).
FT                                /FTId=VAR_032012.
FT   CONFLICT     44     44       D -> N (in Ref. 6; AA sequence and 7; AA
FT                                sequence). {ECO:0000305}.
FT   CONFLICT     52     52       N -> D (in Ref. 6; AA sequence).
FT                                {ECO:0000305}.
FT   CONFLICT     64     64       N -> G (in Ref. 3; CAA68697).
FT                                {ECO:0000305}.
FT   STRAND       26     28       {ECO:0000244|PDB:1HPT}.
FT   STRAND       37     40       {ECO:0000244|PDB:1CGI}.
FT   STRAND       46     48       {ECO:0000244|PDB:1CGI}.
FT   STRAND       53     56       {ECO:0000244|PDB:1CGI}.
FT   HELIX        57     67       {ECO:0000244|PDB:1CGI}.
FT   STRAND       73     77       {ECO:0000244|PDB:1CGI}.
CC   --------------------------------------------------------------------------
CC   The following FT lines are automated annotations from the MyHits database.
CC   --------------------------------------------------------------------------
FT   MYHIT        26     79       iprf:KAZAL_2 [T]
FT   MYHIT        39     61       ipat:KAZAL_1 [T]
FT   MYHIT        32     79       ipfam:Kazal_1 [T]
FT   MYHIT        31     79       ismart:KAZAL [T]
SQ   SEQUENCE   79 AA;  8507 MW;  3583C8196952EB3A CRC64;
     MKVTGIFLLS ALALLSLSGN TGADSLGREA KCYNELNGCT KIYDPVCGTD GNTYPNECVL
     CFENRKRQTS ILIQKSGPC
//