CLCA1_MOUSE
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 03-AUG-2022, entry version 149.
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 GlyGen; Q9D7Z6; 6 sites.
DR iPTMnet; Q9D7Z6; -.
DR PhosphoSitePlus; Q9D7Z6; -.
DR MaxQB; Q9D7Z6; -.
DR PaxDb; Q9D7Z6; -.
DR PeptideAtlas; Q9D7Z6; -.
DR PRIDE; Q9D7Z6; -.
DR ProteomicsDB; 283571; -.
DR Antibodypedia; 33585; 216 antibodies from 31 providers.
DR DNASU; 23844; -.
DR Ensembl; ENSMUST00000029919; ENSMUSP00000029919; ENSMUSG00000028255.
DR GeneID; 23844; -.
DR KEGG; mmu:23844; -.
DR UCSC; uc008rqf.2; mouse.
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; IPQQNGA; -.
DR OrthoDB; 685640at2759; -.
DR PhylomeDB; Q9D7Z6; -.
DR TreeFam; TF328396; -.
DR Reactome; R-MMU-2672351; Stimuli-sensing channels.
DR BioGRID-ORCS; 23844; 5 hits in 71 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 tissues.
DR Genevisible; Q9D7Z6; MM.
DR GO; GO:0005615; C:extracellular space; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IDA:MGI.
DR GO; GO:0005887; C:integral component of plasma membrane; IBA:GO_Central.
DR GO; GO:0005902; C:microvillus; IDA:MGI.
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 Gene3D; 2.60.40.10; -; 1.
DR Gene3D; 3.40.50.410; -; 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 Pfam; PF08434; CLCA; 1.
DR Pfam; PF13519; VWA_2; 1.
DR SMART; SM00327; VWA; 1.
DR SUPFAM; SSF53300; SSF53300; 1.
DR TIGRFAMs; TIGR00868; hCaCC; 1.
DR PROSITE; PS50234; VWFA; 1.
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
