ID   CLCA1_MOUSE             Reviewed;         913 AA.
AC   Q9D7Z6; O88826; Q8R049;
DT   20-MAY-2008, integrated into UniProtKB/Swiss-Prot.
DT   01-DEC-2001, sequence version 2.
DT   27-MAR-2024, entry version 158.
DE   RecName: Full=Calcium-activated chloride channel regulator 1;
DE            EC=3.4.-.- {ECO:0000250|UniProtKB:A8K7I4};
DE   AltName: Full=Calcium-activated chloride channel family member 3;
DE            Short=mCLCA3;
DE   AltName: Full=Protein gob-5;
DE   Flags: Precursor;
GN   Name=Clca1; Synonyms=Clca3, Gob5;
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], AND TISSUE SPECIFICITY.
RC   TISSUE=Intestine;
RX   PubMed=10049711; DOI=10.1006/bbrc.1999.0168;
RA   Komiya T., Tanigawa Y., Hirohashi S.;
RT   "Cloning and identification of the gene gob-5, which is expressed in
RT   intestinal goblet cells in mice.";
RL   Biochem. Biophys. Res. Commun. 255:347-351(1999).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND INDUCTION.
RX   PubMed=11694454; DOI=10.1165/ajrcmb.25.4.4578;
RA   Zhou Y., Dong Q., Louahed J., Dragwa C., Savio D., Huang M., Weiss C.,
RA   Tomer Y., McLane M.P., Nicolaides N.C., Levitt R.C.;
RT   "Characterization of a calcium-activated chloride channel as a shared
RT   target of Th2 cytokine pathways and its potential involvement in asthma.";
RL   Am. J. Respir. Cell Mol. Biol. 25:486-491(2001).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   STRAIN=C57BL/6J; TISSUE=Colon, and Stomach;
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   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   STRAIN=FVB/N; TISSUE=Colon;
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   [5]
RP   FUNCTION, AND TISSUE SPECIFICITY.
RX   PubMed=11296262; DOI=10.1073/pnas.081510898;
RA   Nakanishi A., Morita S., Iwashita H., Sagiya Y., Ashida Y., Shirafuji H.,
RA   Fujisawa Y., Nishimura O., Fujino M.;
RT   "Role of gob-5 in mucus overproduction and airway hyperresponsiveness in
RT   asthma.";
RL   Proc. Natl. Acad. Sci. U.S.A. 98:5175-5180(2001).
RN   [6]
RP   SUBCELLULAR LOCATION, TISSUE SPECIFICITY, PROTEOLYTIC PROCESSING, AND
RP   GLYCOSYLATION.
RX   PubMed=12019299; DOI=10.1177/002215540205000609;
RA   Leverkoehne I., Gruber A.D.;
RT   "The murine mCLCA3 (alias gob-5) protein is located in the mucin granule
RT   membranes of intestinal, respiratory, and uterine goblet cells.";
RL   J. Histochem. Cytochem. 50:829-838(2002).
RN   [7]
RP   INDUCTION.
RX   PubMed=16251409; DOI=10.1016/s0002-9440(10)61212-6;
RA   Sabo-Attwood T., Ramos-Nino M., Bond J., Butnor K.J., Heintz N.,
RA   Gruber A.D., Steele C., Taatjes D.J., Vacek P., Mossman B.T.;
RT   "Gene expression profiles reveal increased mClca3 (Gob5) expression and
RT   mucin production in a murine model of asbestos-induced fibrogenesis.";
RL   Am. J. Pathol. 167:1243-1256(2005).
RN   [8]
RP   SUBCELLULAR LOCATION.
RX   PubMed=15919655; DOI=10.1074/jbc.m504654200;
RA   Gibson A., Lewis A.P., Affleck K., Aitken A.J., Meldrum E., Thompson N.;
RT   "hCLCA1 and mCLCA3 are secreted non-integral membrane proteins and
RT   therefore are not ion channels.";
RL   J. Biol. Chem. 280:27205-27212(2005).
RN   [9]
RP   INDUCTION.
RX   PubMed=16099848; DOI=10.1074/mcp.m500098-mcp200;
RA   Brouillard F., Bensalem N., Hinzpeter A., Tondelier D., Trudel S.,
RA   Gruber A.D., Ollero M., Edelman A.;
RT   "Blue native/SDS-PAGE analysis reveals reduced expression of the mClCA3
RT   protein in cystic fibrosis knock-out mice.";
RL   Mol. Cell. Proteomics 4:1762-1775(2005).
RN   [10]
RP   FUNCTION, AND DISRUPTION PHENOTYPE.
RX   PubMed=16645179; DOI=10.1165/rcmb.2005-0451oc;
RA   Long A.J., Sypek J.P., Askew R., Fish S.C., Mason L.E., Williams C.M.M.,
RA   Goldman S.J.;
RT   "Gob-5 contributes to goblet cell hyperplasia and modulates pulmonary
RT   tissue inflammation.";
RL   Am. J. Respir. Cell Mol. Biol. 35:357-365(2006).
RN   [11]
RP   SUBCELLULAR LOCATION, GLYCOSYLATION, AND PROCESSING.
RX   PubMed=16895902; DOI=10.1074/jbc.m606489200;
RA   Mundhenk L., Alfalah M., Elble R.C., Pauli B.U., Naim H.Y., Gruber A.D.;
RT   "Both cleavage products of the mCLCA3 protein are secreted soluble
RT   proteins.";
RL   J. Biol. Chem. 281:30072-30080(2006).
CC   -!- FUNCTION: May be involved in mediating calcium-activated chloride
CC       conductance. May play critical roles in goblet cell metaplasia, mucus
CC       hypersecretion, cystic fibrosis and AHR. May be involved in the
CC       regulation of mucus production and/or secretion by goblet cells.
CC       Involved in the regulation of tissue inflammation in the innate immune
CC       response. May play a role as a tumor suppressor. Induces MUC5AC.
CC       {ECO:0000269|PubMed:11296262, ECO:0000269|PubMed:11694454,
CC       ECO:0000269|PubMed:16645179}.
CC   -!- SUBCELLULAR LOCATION: Secreted, extracellular space
CC       {ECO:0000269|PubMed:12019299, ECO:0000269|PubMed:15919655,
CC       ECO:0000269|PubMed:16895902}. Note=The 75 kDa N-terminal and a 35 kDa
CC       C-terminal products are fully secreted into extracellular environment
CC       as a soluble complex of two glycoproteins.
CC   -!- TISSUE SPECIFICITY: Exclusively expressed in the digestive and
CC       respiratory tracts and in the uterus (at protein level). Expressed in
CC       small intestine, colon, stomach, and uterus and slightly expressed in
CC       trachea tissue. Exclusively expressed in the mucin granule membranes of
CC       gastrointestinal, respiratory, and uterine goblet cells and other
CC       mucin-producing cells. In the colon, expressed in the surface mucous
CC       cells. In the stomach highly expressed in the surface epithelium in the
CC       pylorus. Strongly expressed in the airway epithelium of lung tissues
CC       associated with airway hyperresponsiveness (AHR).
CC       {ECO:0000269|PubMed:10049711, ECO:0000269|PubMed:11296262,
CC       ECO:0000269|PubMed:12019299}.
CC   -!- INDUCTION: By IL3, IL4 and IL9 in the lung. Increases in the
CC       bronchiolar epithelium of asbestos-induced fibrogenesis. Decreases in
CC       cystic fibrosis knockout mice. {ECO:0000269|PubMed:11694454,
CC       ECO:0000269|PubMed:16099848, ECO:0000269|PubMed:16251409}.
CC   -!- DOMAIN: The metalloprotease region is responsible for autoproteolytic
CC       processing. It can also cross-cleave other CLCA substrates.
CC       {ECO:0000250|UniProtKB:A8K7I4}.
CC   -!- PTM: The 110 kDa translation product is autoproteolytically cleaved by
CC       the metalloprotease domain in the endoplasmic reticulum into a 75 kDa
CC       N-terminal and a 35 kDa C-terminal products that remain physically
CC       associated with each other. The cleavage is necessary for calcium-
CC       activated chloride channel (CaCC) activation activity.
CC       {ECO:0000250|UniProtKB:A8K7I4, ECO:0000269|PubMed:12019299}.
CC   -!- PTM: Glycosylated. {ECO:0000269|PubMed:12019299,
CC       ECO:0000269|PubMed:16895902}.
CC   -!- DISRUPTION PHENOTYPE: Mice exhibit significantly increased
CC       bronchoalveolar lavage (BAL) inflammation consisted predominantly of
CC       neutrophils; have decreased goblet cell hyperplasia as well as
CC       decreased mucus production; have decreased airway hypersensitivity
CC       after cholinergic provocation with methacholine.
CC       {ECO:0000269|PubMed:16645179}.
CC   -!- SIMILARITY: Belongs to the CLCR family. {ECO:0000305}.
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DR   EMBL; AB017156; BAA33743.1; -; mRNA.
DR   EMBL; AK008659; BAB25815.2; -; mRNA.
DR   EMBL; AK136476; BAE22995.1; -; mRNA.
DR   EMBL; BC028343; AAH28343.1; -; mRNA.
DR   EMBL; BC116318; AAI16319.1; -; mRNA.
DR   EMBL; BC116319; AAI16320.1; -; mRNA.
DR   CCDS; CCDS17889.1; -.
DR   PIR; JG0168; JG0168.
DR   RefSeq; NP_059502.1; NM_017474.2.
DR   AlphaFoldDB; Q9D7Z6; -.
DR   SMR; Q9D7Z6; -.
DR   BioGRID; 204754; 5.
DR   IntAct; Q9D7Z6; 1.
DR   MINT; Q9D7Z6; -.
DR   STRING; 10090.ENSMUSP00000029919; -.
DR   MEROPS; M87.001; -.
DR   GlyCosmos; Q9D7Z6; 6 sites, No reported glycans.
DR   GlyGen; Q9D7Z6; 6 sites.
DR   iPTMnet; Q9D7Z6; -.
DR   PhosphoSitePlus; Q9D7Z6; -.
DR   MaxQB; Q9D7Z6; -.
DR   PaxDb; 10090-ENSMUSP00000029919; -.
DR   PeptideAtlas; Q9D7Z6; -.
DR   ProteomicsDB; 283571; -.
DR   Antibodypedia; 33585; 239 antibodies from 31 providers.
DR   DNASU; 23844; -.
DR   Ensembl; ENSMUST00000029919.7; ENSMUSP00000029919.6; ENSMUSG00000028255.7.
DR   GeneID; 23844; -.
DR   KEGG; mmu:23844; -.
DR   UCSC; uc008rqf.2; mouse.
DR   AGR; MGI:1346342; -.
DR   CTD; 1179; -.
DR   MGI; MGI:1346342; Clca1.
DR   VEuPathDB; HostDB:ENSMUSG00000028255; -.
DR   eggNOG; ENOG502QRRD; Eukaryota.
DR   GeneTree; ENSGT00940000154682; -.
DR   HOGENOM; CLU_005812_0_1_1; -.
DR   InParanoid; Q9D7Z6; -.
DR   OMA; QERVFVH; -.
DR   OrthoDB; 5479609at2759; -.
DR   PhylomeDB; Q9D7Z6; -.
DR   TreeFam; TF328396; -.
DR   Reactome; R-MMU-2672351; Stimuli-sensing channels.
DR   BioGRID-ORCS; 23844; 5 hits in 76 CRISPR screens.
DR   ChiTaRS; Clca1; mouse.
DR   PRO; PR:Q9D7Z6; -.
DR   Proteomes; UP000000589; Chromosome 3.
DR   RNAct; Q9D7Z6; Protein.
DR   Bgee; ENSMUSG00000028255; Expressed in left colon and 70 other cell types or tissues.
DR   GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR   GO; GO:0016020; C:membrane; IDA:MGI.
DR   GO; GO:0005902; C:microvillus; IDA:MGI.
DR   GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR   GO; GO:0030141; C:secretory granule; IDA:MGI.
DR   GO; GO:0042589; C:zymogen granule membrane; ISO:MGI.
DR   GO; GO:0005254; F:chloride channel activity; ISA:MGI.
DR   GO; GO:0005229; F:intracellular calcium activated chloride channel activity; IBA:GO_Central.
DR   GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR   GO; GO:0008237; F:metallopeptidase activity; IEA:UniProtKB-KW.
DR   GO; GO:0006816; P:calcium ion transport; IEA:UniProtKB-KW.
DR   GO; GO:0071456; P:cellular response to hypoxia; IEA:Ensembl.
DR   GO; GO:0006821; P:chloride transport; ISA:MGI.
DR   GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR   CDD; cd00198; vWFA; 1.
DR   Gene3D; 2.60.40.10; Immunoglobulins; 1.
DR   Gene3D; 3.40.50.410; von Willebrand factor, type A domain; 1.
DR   InterPro; IPR004727; CLCA_chordata.
DR   InterPro; IPR013642; CLCA_N.
DR   InterPro; IPR013783; Ig-like_fold.
DR   InterPro; IPR002035; VWF_A.
DR   InterPro; IPR036465; vWFA_dom_sf.
DR   NCBIfam; NF041940; choice_anch_X; 1.
DR   NCBIfam; TIGR00868; hCaCC; 1.
DR   PANTHER; PTHR10579; CALCIUM-ACTIVATED CHLORIDE CHANNEL REGULATOR; 1.
DR   PANTHER; PTHR10579:SF52; CALCIUM-ACTIVATED CHLORIDE CHANNEL REGULATOR 1; 1.
DR   Pfam; PF08434; CLCA; 1.
DR   Pfam; PF13519; VWA_2; 1.
DR   SMART; SM00327; VWA; 1.
DR   SUPFAM; SSF53300; vWA-like; 1.
DR   PROSITE; PS50234; VWFA; 1.
DR   Genevisible; Q9D7Z6; MM.
PE   1: Evidence at protein level;
KW   Autocatalytic cleavage; Calcium; Calcium transport; Chloride; Glycoprotein;
KW   Hydrolase; Ion transport; Metal-binding; Metalloprotease; Protease;
KW   Reference proteome; Secreted; Signal; Transport; Zinc.
FT   SIGNAL          1..21
FT                   /evidence="ECO:0000255"
FT   CHAIN           22..913
FT                   /note="Calcium-activated chloride channel regulator 1"
FT                   /id="PRO_0000333692"
FT   DOMAIN          307..476
FT                   /note="VWFA"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00219"
FT   REGION          46..199
FT                   /note="Metalloprotease domain"
FT                   /evidence="ECO:0000250|UniProtKB:A8K7I4"
FT   ACT_SITE        157
FT                   /evidence="ECO:0000250|UniProtKB:A8K7I4"
FT   BINDING         156
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000250|UniProtKB:A8K7I4"
FT   BINDING         160
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000250|UniProtKB:A8K7I4"
FT   BINDING         167
FT                   /ligand="Zn(2+)"
FT                   /ligand_id="ChEBI:CHEBI:29105"
FT                   /ligand_note="catalytic"
FT                   /evidence="ECO:0000250|UniProtKB:A8K7I4"
FT   SITE            695..696
FT                   /note="Cleavage; by autolysis"
FT                   /evidence="ECO:0000250|UniProtKB:A8K7I4"
FT   CARBOHYD        504
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        770
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        804
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        810
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        836
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        887
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CONFLICT        469
FT                   /note="L -> F (in Ref. 4; AAH28343)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   913 AA;  100071 MW;  A7FA2F9E1089806D CRC64;
     MESLKSPVFL LILHLLEGVL SESLIQLNNN GYEGIVIAID HDVPEDEALI QHIKDMVTQA
     SPYLFEATGK RFYFKNVAIL IPESWKAKPE YTRPKLETFK NADVLVSTTS PLGNDEPYTE
     HIGACGEKGI RIHLTPDFLA GKKLTQYGPQ DRTFVHEWAH FRWGVFNEYN NDEKFYLSKG
     KPQAVRCSAA ITGKNQVRRC QGGSCITNGK CVIDRVTGLY KDNCVFVPDP HQNEKASIMF
     NQNINSVVEF CTEKNHNQEA PNDQNQRCNL RSTWEVIQES EDFKQTTPMT AQPPAPTFSL
     LQIGQRIVCL VLDKSGSMLN DDRLNRMNQA SRLFLLQTVE QGSWVGMVTF DSAAYVQSEL
     KQLNSGADRD LLIKHLPTVS AGGTSICSGL RTAFTVIKKK YPTDGSEIVL LTDGEDNTIS
     SCFDLVKQSG AIIHTVALGP AAAKELEQLS KMTGGLQTYS SDQVQNNGLV DAFAALSSGN
     AAIAQHSIQL ESRGVNLQNN QWMNGSVIVD SSVGKDTLFL ITWTTHPPTI FIWDPSGVEQ
     NGFILDTTTK VAYLQVPGTA KVGFWKYSIQ ASSQTLTLTV TSRAASATLP PITVTPVVNK
     NTGKFPSPVT VYASIRQGAS PILRASVTAL IESVNGKTVT LELLDNGAGA DATKNDGVYS
     RFFTAFDANG RYSVKIWALG GVTSDRQRAA PPKNRAMYID GWIEDGEVRM NPPRPETSYV
     QDKQLCFSRT SSGGSFVATN VPAAAPIPDL FPPCQITDLK ASIQGQNLVN LTWTAPGDDY
     DHGRASNYII RMSTSIVDLR DHFNTSLQVN TTGLIPKEAS SEEIFEFELG GNTFGNGTDI
     FIAIQAVDKS NLKSEISNIA RVSVFIPAQE PPIPEDSTPP CPDISINSTI PGIHVLKIMW
     KWLGEMQVTL GLH
//