SPIT1_HUMAN
ID SPIT1_HUMAN Reviewed; 529 AA.
AC O43278; Q7Z7D2;
DT 21-FEB-2001, integrated into UniProtKB/Swiss-Prot.
DT 15-MAR-2005, sequence version 2.
DT 03-AUG-2022, entry version 202.
DE RecName: Full=Kunitz-type protease inhibitor 1;
DE AltName: Full=Hepatocyte growth factor activator inhibitor type 1;
DE Short=HAI-1;
DE Flags: Precursor;
GN Name=SPINT1; Synonyms=HAI1; ORFNames=UNQ223/PRO256;
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] (ISOFORM 2).
RX PubMed=9045658; DOI=10.1074/jbc.272.10.6370;
RA Shimomura T., Denda K., Kitamura A., Kawaguchi T., Kito M., Kondo J.,
RA Kagaya S., Qin L., Takata H., Miyazawa K., Kitamura N.;
RT "Hepatocyte growth factor activator inhibitor, a novel Kunitz-type serine
RT protease inhibitor.";
RL J. Biol. Chem. 272:6370-6376(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Kirchhofer D., Peek M., Li W., Stamos J., Eigenbrot C., Kadkhodayan S.,
RA Eliott J.M., Corpuz R.T., Lazarus R.A., Moran P.;
RT "Tissue-expression, protease-specificity and Kunitz domain functions of
RT HAI-1B, a new splice variant of hepatocyte growth factor activator
RT inhibitor-1.";
RL Submitted (JUN-2003) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=12975309; DOI=10.1101/gr.1293003;
RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A.,
RA Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D.,
RA Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L.,
RA Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C.,
RA Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J.,
RA Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.;
RT "The secreted protein discovery initiative (SPDI), a large-scale effort to
RT identify novel human secreted and transmembrane proteins: a bioinformatics
RT assessment.";
RL Genome Res. 13:2265-2270(2003).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Colon, and Placenta;
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 PARTIAL PROTEIN SEQUENCE, AND CHARACTERIZATION.
RC TISSUE=Milk;
RX PubMed=10373425; DOI=10.1074/jbc.274.26.18237;
RA Lin C.Y., Anders J., Johnson M., Dickson R.B.;
RT "Purification and characterization of a complex containing matriptase and a
RT Kunitz-type serine protease inhibitor from human milk.";
RL J. Biol. Chem. 274:18237-18242(1999).
RN [7]
RP PROTEIN SEQUENCE OF 36-50.
RX PubMed=15340161; DOI=10.1110/ps.04682504;
RA Zhang Z., Henzel W.J.;
RT "Signal peptide prediction based on analysis of experimentally verified
RT cleavage sites.";
RL Protein Sci. 13:2819-2824(2004).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 245-303 IN COMPLEX WITH HGFAC, AND
RP DISULFIDE BONDS.
RX PubMed=15713485; DOI=10.1016/j.jmb.2004.12.048;
RA Shia S., Stamos J., Kirchhofer D., Fan B., Wu J., Corpuz R.T., Santell L.,
RA Lazarus R.A., Eigenbrot C.;
RT "Conformational lability in serine protease active sites: structures of
RT hepatocyte growth factor activator (HGFA) alone and with the inhibitory
RT domain from HGFA inhibitor-1B.";
RL J. Mol. Biol. 346:1335-1349(2005).
CC -!- FUNCTION: Inhibitor of HGF activator. Also acts as an inhibitor of
CC matriptase (ST14).
CC -!- SUBUNIT: Interacts with HGFAC. {ECO:0000269|PubMed:15713485}.
CC -!- INTERACTION:
CC O43278-2; Q08AM2: ADAM33; NbExp=3; IntAct=EBI-12078338, EBI-10225815;
CC O43278-2; Q8TD06: AGR3; NbExp=3; IntAct=EBI-12078338, EBI-3925742;
CC O43278-2; O75508: CLDN11; NbExp=3; IntAct=EBI-12078338, EBI-12820543;
CC O43278-2; Q9BXN2-6: CLEC7A; NbExp=3; IntAct=EBI-12078338, EBI-11989440;
CC O43278-2; Q92520: FAM3C; NbExp=3; IntAct=EBI-12078338, EBI-2876774;
CC O43278-2; Q8IUG1: KRTAP1-3; NbExp=3; IntAct=EBI-12078338, EBI-11749135;
CC O43278-2; P21145: MAL; NbExp=3; IntAct=EBI-12078338, EBI-3932027;
CC O43278-2; Q9NVC3: SLC38A7; NbExp=3; IntAct=EBI-12078338, EBI-10314552;
CC O43278-2; Q9NRQ5: SMCO4; NbExp=3; IntAct=EBI-12078338, EBI-8640191;
CC O43278-2; P02787: TF; NbExp=3; IntAct=EBI-12078338, EBI-714319;
CC O43278-2; Q9BVC6: TMEM109; NbExp=3; IntAct=EBI-12078338, EBI-1057733;
CC O43278-2; Q8WZ59: TMEM190; NbExp=3; IntAct=EBI-12078338, EBI-10278423;
CC O43278-2; Q5BJF2: TMEM97; NbExp=3; IntAct=EBI-12078338, EBI-12111910;
CC O43278-2; Q86UF1: TSPAN33; NbExp=3; IntAct=EBI-12078338, EBI-12045841;
CC O43278-2; Q9UHD9: UBQLN2; NbExp=3; IntAct=EBI-12078338, EBI-947187;
CC O43278-2; O75841: UPK1B; NbExp=3; IntAct=EBI-12078338, EBI-12237619;
CC O43278-2; O95183: VAMP5; NbExp=3; IntAct=EBI-12078338, EBI-10191195;
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=HAI-1B;
CC IsoId=O43278-1; Sequence=Displayed;
CC Name=2; Synonyms=HAI-1A;
CC IsoId=O43278-2; Sequence=VSP_013019;
CC -!- DOMAIN: This inhibitor contains two inhibitory domains.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/SPINT1ID44384ch15q15.html";
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DR EMBL; AB000095; BAA25014.1; -; mRNA.
DR EMBL; AY296715; AAP44001.1; -; mRNA.
DR EMBL; AY358969; AAQ89328.1; -; mRNA.
DR EMBL; BT007425; AAP36093.1; -; mRNA.
DR EMBL; BC004140; AAH04140.1; -; mRNA.
DR EMBL; BC018702; AAH18702.1; -; mRNA.
DR CCDS; CCDS10067.1; -. [O43278-1]
DR CCDS; CCDS45231.1; -. [O43278-2]
DR RefSeq; NP_001027539.1; NM_001032367.1. [O43278-2]
DR RefSeq; NP_003701.1; NM_003710.3. [O43278-2]
DR RefSeq; NP_857593.1; NM_181642.2. [O43278-1]
DR RefSeq; XP_006720720.1; XM_006720657.1. [O43278-1]
DR PDB; 1YC0; X-ray; 2.60 A; I=245-303.
DR PDB; 2MSX; NMR; -; A=47-152.
DR PDB; 4ISL; X-ray; 2.29 A; B=245-304.
DR PDB; 4ISN; X-ray; 2.45 A; B=245-307.
DR PDB; 4ISO; X-ray; 2.01 A; B=245-304.
DR PDB; 5EZD; X-ray; 2.10 A; A/B=168-303.
DR PDB; 5H7V; X-ray; 3.82 A; A=36-457.
DR PDBsum; 1YC0; -.
DR PDBsum; 2MSX; -.
DR PDBsum; 4ISL; -.
DR PDBsum; 4ISN; -.
DR PDBsum; 4ISO; -.
DR PDBsum; 5EZD; -.
DR PDBsum; 5H7V; -.
DR AlphaFoldDB; O43278; -.
DR BMRB; O43278; -.
DR SMR; O43278; -.
DR BioGRID; 112570; 125.
DR DIP; DIP-37949N; -.
DR IntAct; O43278; 24.
DR MINT; O43278; -.
DR STRING; 9606.ENSP00000342098; -.
DR MEROPS; I02.007; -.
DR MEROPS; I02.008; -.
DR GlyGen; O43278; 6 sites, 1 O-linked glycan (3 sites).
DR iPTMnet; O43278; -.
DR PhosphoSitePlus; O43278; -.
DR SwissPalm; O43278; -.
DR BioMuta; SPINT1; -.
DR EPD; O43278; -.
DR jPOST; O43278; -.
DR MassIVE; O43278; -.
DR MaxQB; O43278; -.
DR PaxDb; O43278; -.
DR PeptideAtlas; O43278; -.
DR PRIDE; O43278; -.
DR ProteomicsDB; 48846; -. [O43278-1]
DR ProteomicsDB; 48847; -. [O43278-2]
DR Antibodypedia; 1540; 460 antibodies from 33 providers.
DR DNASU; 6692; -.
DR Ensembl; ENST00000344051.8; ENSP00000342098.4; ENSG00000166145.15. [O43278-1]
DR Ensembl; ENST00000562057.6; ENSP00000457076.1; ENSG00000166145.15. [O43278-2]
DR GeneID; 6692; -.
DR KEGG; hsa:6692; -.
DR MANE-Select; ENST00000562057.6; ENSP00000457076.1; NM_003710.4; NP_003701.1. [O43278-2]
DR UCSC; uc001zna.4; human. [O43278-1]
DR CTD; 6692; -.
DR DisGeNET; 6692; -.
DR GeneCards; SPINT1; -.
DR HGNC; HGNC:11246; SPINT1.
DR HPA; ENSG00000166145; Tissue enhanced (esophagus).
DR MIM; 605123; gene.
DR neXtProt; NX_O43278; -.
DR OpenTargets; ENSG00000166145; -.
DR PharmGKB; PA36076; -.
DR VEuPathDB; HostDB:ENSG00000166145; -.
DR eggNOG; KOG4295; Eukaryota.
DR GeneTree; ENSGT00940000161683; -.
DR InParanoid; O43278; -.
DR OMA; ENTDWHL; -.
DR OrthoDB; 687721at2759; -.
DR PhylomeDB; O43278; -.
DR TreeFam; TF325867; -.
DR PathwayCommons; O43278; -.
DR Reactome; R-HSA-6806942; MET Receptor Activation.
DR Reactome; R-HSA-8852405; Signaling by MST1.
DR SignaLink; O43278; -.
DR BioGRID-ORCS; 6692; 32 hits in 1078 CRISPR screens.
DR ChiTaRS; SPINT1; human.
DR EvolutionaryTrace; O43278; -.
DR GeneWiki; SPINT1; -.
DR GenomeRNAi; 6692; -.
DR Pharos; O43278; Tbio.
DR PRO; PR:O43278; -.
DR Proteomes; UP000005640; Chromosome 15.
DR RNAct; O43278; protein.
DR Bgee; ENSG00000166145; Expressed in lower esophagus mucosa and 148 other tissues.
DR ExpressionAtlas; O43278; baseline and differential.
DR Genevisible; O43278; HS.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0005576; C:extracellular region; TAS:ProtInc.
DR GO; GO:0005615; C:extracellular space; HDA:UniProtKB.
DR GO; GO:0016020; C:membrane; TAS:ProtInc.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:0004867; F:serine-type endopeptidase inhibitor activity; IBA:GO_Central.
DR GO; GO:0060670; P:branching involved in labyrinthine layer morphogenesis; IEA:Ensembl.
DR GO; GO:0071773; P:cellular response to BMP stimulus; IEA:Ensembl.
DR GO; GO:0008544; P:epidermis development; IBA:GO_Central.
DR GO; GO:0060429; P:epithelium development; IBA:GO_Central.
DR GO; GO:0030198; P:extracellular matrix organization; IBA:GO_Central.
DR GO; GO:2000178; P:negative regulation of neural precursor cell proliferation; IEA:Ensembl.
DR GO; GO:0001843; P:neural tube closure; IEA:Ensembl.
DR GO; GO:0060674; P:placenta blood vessel development; IEA:Ensembl.
DR GO; GO:0045687; P:positive regulation of glial cell differentiation; IEA:Ensembl.
DR CDD; cd00109; KU; 2.
DR CDD; cd00112; LDLa; 1.
DR Gene3D; 2.60.40.10; -; 1.
DR Gene3D; 4.10.400.10; -; 1.
DR Gene3D; 4.10.410.10; -; 2.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR002223; Kunitz_BPTI.
DR InterPro; IPR036880; Kunitz_BPTI_sf.
DR InterPro; IPR036055; LDL_receptor-like_sf.
DR InterPro; IPR023415; LDLR_class-A_CS.
DR InterPro; IPR002172; LDrepeatLR_classA_rpt.
DR InterPro; IPR013980; MANSC_dom.
DR InterPro; IPR011106; MANSC_N.
DR InterPro; IPR020901; Prtase_inh_Kunz-CS.
DR InterPro; IPR042482; Spint1.
DR PANTHER; PTHR46750; PTHR46750; 1.
DR Pfam; PF00014; Kunitz_BPTI; 2.
DR Pfam; PF00057; Ldl_recept_a; 1.
DR Pfam; PF07502; MANEC; 1.
DR PRINTS; PR00759; BASICPTASE.
DR SMART; SM00131; KU; 2.
DR SMART; SM00192; LDLa; 1.
DR SMART; SM00765; MANEC; 1.
DR SUPFAM; SSF57362; SSF57362; 2.
DR SUPFAM; SSF57424; SSF57424; 1.
DR PROSITE; PS00280; BPTI_KUNITZ_1; 2.
DR PROSITE; PS50279; BPTI_KUNITZ_2; 2.
DR PROSITE; PS01209; LDLRA_1; 1.
DR PROSITE; PS50068; LDLRA_2; 1.
DR PROSITE; PS50986; MANSC; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Direct protein sequencing;
KW Disulfide bond; Glycoprotein; Protease inhibitor; Reference proteome;
KW Repeat; Secreted; Serine protease inhibitor; Signal.
FT SIGNAL 1..35
FT /evidence="ECO:0000269|PubMed:15340161"
FT CHAIN 36..529
FT /note="Kunitz-type protease inhibitor 1"
FT /id="PRO_0000016883"
FT DOMAIN 57..140
FT /note="MANSC"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00341"
FT DOMAIN 250..300
FT /note="BPTI/Kunitz inhibitor 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00031"
FT DOMAIN 334..370
FT /note="LDL-receptor class A"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00124"
FT DOMAIN 391..441
FT /note="BPTI/Kunitz inhibitor 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00031"
FT SITE 260..261
FT /note="Reactive bond"
FT /evidence="ECO:0000250"
FT SITE 401..402
FT /note="Reactive bond"
FT /evidence="ECO:0000250"
FT CARBOHYD 66
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 235
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 523
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 250..300
FT /evidence="ECO:0000269|PubMed:15713485"
FT DISULFID 259..283
FT /evidence="ECO:0000269|PubMed:15713485"
FT DISULFID 275..296
FT /evidence="ECO:0000269|PubMed:15713485"
FT DISULFID 335..347
FT /evidence="ECO:0000250"
FT DISULFID 342..360
FT /evidence="ECO:0000250"
FT DISULFID 354..369
FT /evidence="ECO:0000250"
FT DISULFID 391..441
FT /evidence="ECO:0000250"
FT DISULFID 400..424
FT /evidence="ECO:0000250"
FT DISULFID 416..437
FT /evidence="ECO:0000250"
FT VAR_SEQ 306..321
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:9045658"
FT /id="VSP_013019"
FT VARIANT 123
FT /note="Y -> C (in dbSNP:rs11549915)"
FT /id="VAR_050065"
FT VARIANT 142
FT /note="T -> R (in dbSNP:rs12323939)"
FT /id="VAR_050066"
FT VARIANT 337
FT /note="P -> L (in dbSNP:rs7165897)"
FT /id="VAR_050067"
FT CONFLICT 469
FT /note="A -> T (in Ref. 2 and 3)"
FT /evidence="ECO:0000305"
FT HELIX 50..53
FT /evidence="ECO:0007829|PDB:2MSX"
FT STRAND 54..56
FT /evidence="ECO:0007829|PDB:2MSX"
FT STRAND 61..63
FT /evidence="ECO:0007829|PDB:2MSX"
FT HELIX 66..69
FT /evidence="ECO:0007829|PDB:2MSX"
FT TURN 70..72
FT /evidence="ECO:0007829|PDB:2MSX"
FT STRAND 75..77
FT /evidence="ECO:0007829|PDB:2MSX"
FT HELIX 84..93
FT /evidence="ECO:0007829|PDB:2MSX"
FT STRAND 99..104
FT /evidence="ECO:0007829|PDB:2MSX"
FT STRAND 106..108
FT /evidence="ECO:0007829|PDB:2MSX"
FT STRAND 113..119
FT /evidence="ECO:0007829|PDB:2MSX"
FT STRAND 131..133
FT /evidence="ECO:0007829|PDB:2MSX"
FT STRAND 135..142
FT /evidence="ECO:0007829|PDB:2MSX"
FT TURN 143..145
FT /evidence="ECO:0007829|PDB:2MSX"
FT HELIX 146..149
FT /evidence="ECO:0007829|PDB:2MSX"
FT TURN 150..152
FT /evidence="ECO:0007829|PDB:2MSX"
FT STRAND 169..173
FT /evidence="ECO:0007829|PDB:5EZD"
FT STRAND 177..180
FT /evidence="ECO:0007829|PDB:5EZD"
FT STRAND 190..196
FT /evidence="ECO:0007829|PDB:5EZD"
FT STRAND 199..201
FT /evidence="ECO:0007829|PDB:5EZD"
FT STRAND 209..212
FT /evidence="ECO:0007829|PDB:5EZD"
FT STRAND 215..222
FT /evidence="ECO:0007829|PDB:5EZD"
FT STRAND 234..240
FT /evidence="ECO:0007829|PDB:5EZD"
FT HELIX 246..250
FT /evidence="ECO:0007829|PDB:4ISO"
FT STRAND 263..268
FT /evidence="ECO:0007829|PDB:4ISO"
FT TURN 270..272
FT /evidence="ECO:0007829|PDB:4ISO"
FT STRAND 273..280
FT /evidence="ECO:0007829|PDB:4ISO"
FT STRAND 282..284
FT /evidence="ECO:0007829|PDB:4ISO"
FT STRAND 290..292
FT /evidence="ECO:0007829|PDB:4ISO"
FT HELIX 293..300
FT /evidence="ECO:0007829|PDB:4ISO"
SQ SEQUENCE 529 AA; 58398 MW; A87F286C23C73422 CRC64;
MAPARTMARA RLAPAGIPAV ALWLLCTLGL QGTQAGPPPA PPGLPAGADC LNSFTAGVPG
FVLDTNASVS NGATFLESPT VRRGWDCVRA CCTTQNCNLA LVELQPDRGE DAIAACFLIN
CLYEQNFVCK FAPREGFINY LTREVYRSYR QLRTQGFGGS GIPKAWAGID LKVQPQEPLV
LKDVENTDWR LLRGDTDVRV ERKDPNQVEL WGLKEGTYLF QLTVTSSDHP EDTANVTVTV
LSTKQTEDYC LASNKVGRCR GSFPRWYYDP TEQICKSFVY GGCLGNKNNY LREEECILAC
RGVQGGPLRG SSGAQATFPQ GPSMERRHPV CSGTCQPTQF RCSNGCCIDS FLECDDTPNC
PDASDEAACE KYTSGFDELQ RIHFPSDKGH CVDLPDTGLC KESIPRWYYN PFSEHCARFT
YGGCYGNKNN FEEEQQCLES CRGISKKDVF GLRREIPIPS TGSVEMAVAV FLVICIVVVV
AILGYCFFKN QRKDFHGHHH HPPPTPASST VSTTEDTEHL VYNHTTRPL
