SPIT2_HUMAN
ID SPIT2_HUMAN Reviewed; 252 AA.
AC O43291; A8K667; B4DLU1; O00271; O14895; Q5TZQ3; Q969E0;
DT 21-FEB-2001, integrated into UniProtKB/Swiss-Prot.
DT 21-FEB-2001, sequence version 2.
DT 03-AUG-2022, entry version 194.
DE RecName: Full=Kunitz-type protease inhibitor 2;
DE AltName: Full=Hepatocyte growth factor activator inhibitor type 2;
DE Short=HAI-2;
DE AltName: Full=Placental bikunin;
DE Flags: Precursor;
GN Name=SPINT2; Synonyms=HAI2, KOP;
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 1).
RX PubMed=9346890; DOI=10.1074/jbc.272.44.27558;
RA Kawaguchi T., Qin L., Shimomura T., Kondo J., Matsumoto K., Denda K.,
RA Kitamura N.;
RT "Purification and cloning of hepatocyte growth factor activator inhibitor
RT type 2, a Kunitz-type serine protease inhibitor.";
RL J. Biol. Chem. 272:27558-27564(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND PROTEIN SEQUENCE OF 28-74.
RC TISSUE=Placenta;
RX PubMed=9115294; DOI=10.1074/jbc.272.18.12202;
RA Marlor C.W., Delaria K.A., Davis G., Muller D.K., Greve J.M.,
RA Tamburini P.P.;
RT "Identification and cloning of human placental bikunin, a novel serine
RT protease inhibitor containing two Kunitz domains.";
RL J. Biol. Chem. 272:12202-12208(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Pancreatic cancer;
RX PubMed=9434156; DOI=10.1016/s0167-4781(97)00129-2;
RA Mueller-Pillasch F., Wallrapp C., Bartels K., Varga G., Friess H.,
RA Buechler M., Adler G., Gress T.M.;
RT "Cloning of a new Kunitz-type protease inhibitor with a putative
RT transmembrane domain overexpressed in pancreatic cancer.";
RL Biochim. Biophys. Acta 1395:88-95(1998).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Placenta;
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] (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 (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E.,
RA Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A.,
RA Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S.,
RA Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A.,
RA Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J.,
RA Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M.,
RA Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W.,
RA Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V.,
RA Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D.,
RA McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I.,
RA Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L.,
RA Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A.,
RA She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J.,
RA Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [7]
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 [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT LEU-200.
RC TISSUE=Colon, and Ovary;
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 [9]
RP PROTEIN SEQUENCE OF 28-42.
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 [10]
RP VARIANT DIAR3 CYS-163, AND CHARACTERIZATION OF VARIANT DIAR3 CYS-163.
RX PubMed=19185281; DOI=10.1016/j.ajhg.2009.01.004;
RA Heinz-Erian P., Mueller T., Krabichler B., Schranz M., Becker C.,
RA Rueschendorf F., Nuernberg P., Rossier B., Vujic M., Booth I.W.,
RA Holmberg C., Wijmenga C., Grigelioniene G., Kneepkens C.M.F., Rosipal S.,
RA Mistrik M., Kappler M., Michaud L., Doczy L.-C., Siu V.M., Krantz M.,
RA Zoller H., Utermann G., Janecke A.R.;
RT "Mutations in SPINT2 cause a syndromic form of congenital sodium
RT diarrhea.";
RL Am. J. Hum. Genet. 84:188-196(2009).
CC -!- FUNCTION: Inhibitor of HGF activator. Also inhibits plasmin, plasma and
CC tissue kallikrein, and factor XIa.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000305}; Single-pass type I
CC membrane protein {ECO:0000305}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=O43291-1; Sequence=Displayed;
CC Name=2;
CC IsoId=O43291-2; Sequence=VSP_043680;
CC -!- TISSUE SPECIFICITY: Expressed in placenta, kidney, pancreas, prostate,
CC testis, thymus, and trachea.
CC -!- DOMAIN: This inhibitor contains two inhibitory domains.
CC -!- DISEASE: Diarrhea 3, secretory sodium, congenital, with or without
CC other congenital anomalies (DIAR3) [MIM:270420]: A disease
CC characterized by life-threatening secretory diarrhea, severe metabolic
CC acidosis and hyponatremia. Hyponatremia is secondary to extraordinarily
CC high fecal sodium loss, with low or normal excretion of urinary sodium,
CC in the absence of infectious, autoimmune and endocrine causes.
CC {ECO:0000269|PubMed:19185281}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
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DR EMBL; AB006534; BAA25024.1; -; mRNA.
DR EMBL; U78095; AAC02781.1; -; mRNA.
DR EMBL; AF027205; AAB84031.1; -; mRNA.
DR EMBL; AK291532; BAF84221.1; -; mRNA.
DR EMBL; AK297154; BAG59653.1; -; mRNA.
DR EMBL; BT020115; AAV38918.1; -; mRNA.
DR EMBL; BT020116; AAV38919.1; -; mRNA.
DR EMBL; BT020117; AAV38920.1; -; mRNA.
DR EMBL; AC011479; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471126; EAW56766.1; -; Genomic_DNA.
DR EMBL; CH471126; EAW56767.1; -; Genomic_DNA.
DR EMBL; BC001668; AAH01668.1; -; mRNA.
DR EMBL; BC007705; AAH07705.1; -; mRNA.
DR EMBL; BC011951; AAH11951.1; -; mRNA.
DR EMBL; BC011955; AAH11955.1; -; mRNA.
DR EMBL; BC012868; AAH12868.1; -; mRNA.
DR CCDS; CCDS12510.1; -. [O43291-1]
DR CCDS; CCDS54261.1; -. [O43291-2]
DR RefSeq; NP_001159575.1; NM_001166103.1. [O43291-2]
DR RefSeq; NP_066925.1; NM_021102.3. [O43291-1]
DR PDB; 4U32; X-ray; 1.65 A; X=34-88.
DR PDBsum; 4U32; -.
DR AlphaFoldDB; O43291; -.
DR SMR; O43291; -.
DR BioGRID; 115896; 148.
DR IntAct; O43291; 77.
DR MINT; O43291; -.
DR STRING; 9606.ENSP00000301244; -.
DR MEROPS; I02.009; -.
DR MEROPS; I02.010; -.
DR GlyGen; O43291; 3 sites, 1 O-linked glycan (1 site).
DR iPTMnet; O43291; -.
DR PhosphoSitePlus; O43291; -.
DR BioMuta; SPINT2; -.
DR EPD; O43291; -.
DR jPOST; O43291; -.
DR MassIVE; O43291; -.
DR MaxQB; O43291; -.
DR PaxDb; O43291; -.
DR PeptideAtlas; O43291; -.
DR PRIDE; O43291; -.
DR ProteomicsDB; 48859; -. [O43291-1]
DR ProteomicsDB; 48860; -. [O43291-2]
DR Antibodypedia; 2598; 399 antibodies from 33 providers.
DR DNASU; 10653; -.
DR Ensembl; ENST00000301244.12; ENSP00000301244.5; ENSG00000167642.13. [O43291-1]
DR Ensembl; ENST00000454580.7; ENSP00000389788.2; ENSG00000167642.13. [O43291-2]
DR GeneID; 10653; -.
DR KEGG; hsa:10653; -.
DR MANE-Select; ENST00000301244.12; ENSP00000301244.5; NM_021102.4; NP_066925.1.
DR UCSC; uc002ohr.2; human. [O43291-1]
DR CTD; 10653; -.
DR DisGeNET; 10653; -.
DR GeneCards; SPINT2; -.
DR HGNC; HGNC:11247; SPINT2.
DR HPA; ENSG00000167642; Low tissue specificity.
DR MalaCards; SPINT2; -.
DR MIM; 270420; phenotype.
DR MIM; 605124; gene.
DR neXtProt; NX_O43291; -.
DR OpenTargets; ENSG00000167642; -.
DR Orphanet; 563708; Syndromic congenital sodium diarrhea.
DR PharmGKB; PA36077; -.
DR VEuPathDB; HostDB:ENSG00000167642; -.
DR eggNOG; KOG4295; Eukaryota.
DR GeneTree; ENSGT00940000160348; -.
DR HOGENOM; CLU_140751_0_0_1; -.
DR InParanoid; O43291; -.
DR OMA; KEECMHR; -.
DR OrthoDB; 1282068at2759; -.
DR PhylomeDB; O43291; -.
DR TreeFam; TF326553; -.
DR PathwayCommons; O43291; -.
DR Reactome; R-HSA-6806942; MET Receptor Activation.
DR Reactome; R-HSA-8852405; Signaling by MST1.
DR SignaLink; O43291; -.
DR BioGRID-ORCS; 10653; 24 hits in 1071 CRISPR screens.
DR ChiTaRS; SPINT2; human.
DR GeneWiki; SPINT2; -.
DR GenomeRNAi; 10653; -.
DR Pharos; O43291; Tbio.
DR PRO; PR:O43291; -.
DR Proteomes; UP000005640; Chromosome 19.
DR RNAct; O43291; protein.
DR Bgee; ENSG00000167642; Expressed in type B pancreatic cell and 197 other tissues.
DR ExpressionAtlas; O43291; baseline and differential.
DR Genevisible; O43291; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:HGNC-UCL.
DR GO; GO:0005576; C:extracellular region; TAS:ProtInc.
DR GO; GO:0016021; C:integral component of membrane; TAS:ProtInc.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:0004866; F:endopeptidase inhibitor activity; TAS:ProtInc.
DR GO; GO:0004867; F:serine-type endopeptidase inhibitor activity; IDA:UniProtKB.
DR GO; GO:0071711; P:basement membrane organization; IEA:Ensembl.
DR GO; GO:0071773; P:cellular response to BMP stimulus; IEA:Ensembl.
DR GO; GO:0060672; P:epithelial cell morphogenesis involved in placental branching; IEA:Ensembl.
DR GO; GO:0007163; P:establishment or maintenance of cell polarity; IEA:Ensembl.
DR GO; GO:2000146; P:negative regulation of cell motility; IDA:MGI.
DR GO; GO:0022408; P:negative regulation of cell-cell adhesion; IDA:MGI.
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 CDD; cd00109; KU; 2.
DR Gene3D; 4.10.410.10; -; 2.
DR InterPro; IPR002223; Kunitz_BPTI.
DR InterPro; IPR036880; Kunitz_BPTI_sf.
DR InterPro; IPR020901; Prtase_inh_Kunz-CS.
DR Pfam; PF00014; Kunitz_BPTI; 2.
DR PRINTS; PR00759; BASICPTASE.
DR SMART; SM00131; KU; 2.
DR SUPFAM; SSF57362; SSF57362; 2.
DR PROSITE; PS00280; BPTI_KUNITZ_1; 2.
DR PROSITE; PS50279; BPTI_KUNITZ_2; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Direct protein sequencing;
KW Disease variant; Disulfide bond; Glycoprotein; Membrane;
KW Protease inhibitor; Reference proteome; Repeat; Serine protease inhibitor;
KW Signal; Transmembrane; Transmembrane helix.
FT SIGNAL 1..27
FT /evidence="ECO:0000269|PubMed:15340161,
FT ECO:0000269|PubMed:9115294"
FT CHAIN 28..252
FT /note="Kunitz-type protease inhibitor 2"
FT /id="PRO_0000016885"
FT TOPO_DOM 28..197
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 198..218
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 219..252
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 38..88
FT /note="BPTI/Kunitz inhibitor 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00031"
FT DOMAIN 133..183
FT /note="BPTI/Kunitz inhibitor 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00031"
FT REGION 100..122
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 48..49
FT /note="Reactive bond"
FT /evidence="ECO:0000250"
FT SITE 143..144
FT /note="Reactive bond"
FT /evidence="ECO:0000250"
FT CARBOHYD 57
FT /note="N-linked (GlcNAc...) asparagine"
FT CARBOHYD 94
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 38..88
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00031"
FT DISULFID 47..71
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00031"
FT DISULFID 63..84
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00031"
FT DISULFID 133..183
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00031"
FT DISULFID 142..166
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00031"
FT DISULFID 158..179
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00031"
FT VAR_SEQ 36..92
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_043680"
FT VARIANT 163
FT /note="Y -> C (in DIAR3; has a significantly reduced
FT ability to inhibit trypsin compared to wild-type;
FT dbSNP:rs121908403)"
FT /evidence="ECO:0000269|PubMed:19185281"
FT /id="VAR_058718"
FT VARIANT 200
FT /note="V -> L (in dbSNP:rs11548457)"
FT /evidence="ECO:0000269|PubMed:15489334"
FT /id="VAR_012482"
FT CONFLICT 3
FT /note="Q -> H (in Ref. 3; AAB84031)"
FT /evidence="ECO:0000305"
FT CONFLICT 11
FT /note="R -> P (in Ref. 1; BAA25024)"
FT /evidence="ECO:0000305"
FT CONFLICT 53
FT /note="R -> K (in Ref. 3; AAB84031)"
FT /evidence="ECO:0000305"
FT CONFLICT 240
FT /note="D -> H (in Ref. 3; AAB84031)"
FT /evidence="ECO:0000305"
FT TURN 36..38
FT /evidence="ECO:0007829|PDB:4U32"
FT STRAND 51..57
FT /evidence="ECO:0007829|PDB:4U32"
FT TURN 58..61
FT /evidence="ECO:0007829|PDB:4U32"
FT STRAND 62..68
FT /evidence="ECO:0007829|PDB:4U32"
FT STRAND 70..72
FT /evidence="ECO:0007829|PDB:4U32"
FT STRAND 78..80
FT /evidence="ECO:0007829|PDB:4U32"
FT HELIX 81..87
FT /evidence="ECO:0007829|PDB:4U32"
SQ SEQUENCE 252 AA; 28228 MW; A7D3360C0EECAB2B CRC64;
MAQLCGLRRS RAFLALLGSL LLSGVLAADR ERSIHDFCLV SKVVGRCRAS MPRWWYNVTD
GSCQLFVYGG CDGNSNNYLT KEECLKKCAT VTENATGDLA TSRNAADSSV PSAPRRQDSE
DHSSDMFNYE EYCTANAVTG PCRASFPRWY FDVERNSCNN FIYGGCRGNK NSYRSEEACM
LRCFRQQENP PLPLGSKVVV LAGLFVMVLI LFLGASMVYL IRVARRNQER ALRTVWSSGD
DKEQLVKNTY VL
