CLCN2_MOUSE
ID CLCN2_MOUSE Reviewed; 908 AA.
AC Q9R0A1; Q0VBC2; Q9WUJ9;
DT 21-FEB-2001, integrated into UniProtKB/Swiss-Prot.
DT 27-JUL-2011, sequence version 2.
DT 03-AUG-2022, entry version 170.
DE RecName: Full=Chloride channel protein 2;
DE Short=ClC-2;
GN Name=Clcn2; Synonyms=Clc2;
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].
RC STRAIN=C57BL/6J; TISSUE=Duodenal mucosa;
RX PubMed=10524221; DOI=10.1016/s0167-4781(99)00110-4;
RA Joo N.S., Clarke L.L., Han B.H., Forte L.R., Kim H.D.;
RT "Cloning of ClC-2 chloride channel from murine duodenum and its presence in
RT CFTR knockout mice.";
RL Biochim. Biophys. Acta 1446:431-437(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=FVB/N;
RA Hathaway J.K., Rice W.R., Wert S., Whitsett J.A.;
RT "CFTR and ClC-2 expression levels in the fetal mouse lung.";
RL Submitted (MAR-1999) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
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 PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-28, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Spleen, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [6]
RP TISSUE SPECIFICITY.
RX PubMed=29403011; DOI=10.1038/s41588-018-0048-5;
RA Scholl U.I., Stoelting G., Schewe J., Thiel A., Tan H., Nelson-Williams C.,
RA Vichot A.A., Jin S.C., Loring E., Untiet V., Yoo T., Choi J., Xu S., Wu A.,
RA Kirchner M., Mertins P., Rump L.C., Onder A.M., Gamble C., McKenney D.,
RA Lash R.W., Jones D.P., Chune G., Gagliardi P., Choi M., Gordon R.,
RA Stowasser M., Fahlke C., Lifton R.P.;
RT "CLCN2 chloride channel mutations in familial hyperaldosteronism type II.";
RL Nat. Genet. 50:349-354(2018).
RN [7]
RP TISSUE SPECIFICITY, AND DISRUPTION PHENOTYPE.
RX PubMed=29403012; DOI=10.1038/s41588-018-0053-8;
RA Fernandes-Rosa F.L., Daniil G., Orozco I.J., Goeppner C., El Zein R.,
RA Jain V., Boulkroun S., Jeunemaitre X., Amar L., Lefebvre H.,
RA Schwarzmayr T., Strom T.M., Jentsch T.J., Zennaro M.C.;
RT "A gain-of-function mutation in the CLCN2 chloride channel gene causes
RT primary aldosteronism.";
RL Nat. Genet. 50:355-361(2018).
CC -!- FUNCTION: Voltage-gated chloride channel. Chloride channels have
CC several functions including the regulation of cell volume, membrane
CC potential stabilization, signal transduction and transepithelial
CC transport (By similarity). Involved in the regulation of aldosterone
CC production. The opening of CLCN2 channels at hyperpolarized membrane
CC potentials in the glomerulosa causes cell membrane depolarization,
CC activation of voltage-gated Ca2+ channels and increased expression of
CC aldosterone synthase, the rate-limiting enzyme for aldosterone
CC biosynthesis (By similarity). {ECO:0000250|UniProtKB:P35525,
CC ECO:0000250|UniProtKB:P51788}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:P35525};
CC Multi-pass membrane protein.
CC -!- TISSUE SPECIFICITY: Expressed in the adrenal gland and brain.
CC {ECO:0000269|PubMed:29403011, ECO:0000269|PubMed:29403012}.
CC -!- PTM: Phosphorylated. Activated by dephosphorylation.
CC {ECO:0000250|UniProtKB:P35525}.
CC -!- DISRUPTION PHENOTYPE: Hyperpolarization-activated chloride currents are
CC absent in glomerulosa cells of knockout mice.
CC {ECO:0000269|PubMed:29403012}.
CC -!- MISCELLANEOUS: The CLC channel family contains both chloride channels
CC and proton-coupled anion transporters that exchange chloride or another
CC anion for protons. The absence of conserved gating glutamate residues
CC is typical for family members that function as channels (By
CC similarity). {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the chloride channel (TC 2.A.49) family. ClC-
CC 2/CLCN2 subfamily. {ECO:0000305}.
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DR EMBL; AF097415; AAD50604.1; -; mRNA.
DR EMBL; AF139724; AAD26466.1; -; mRNA.
DR EMBL; AC087898; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CT010490; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC120699; AAI20700.1; -; mRNA.
DR EMBL; BC137625; AAI37626.1; -; mRNA.
DR CCDS; CCDS28057.1; -.
DR RefSeq; NP_034030.2; NM_009900.2.
DR AlphaFoldDB; Q9R0A1; -.
DR SMR; Q9R0A1; -.
DR BioGRID; 198735; 1.
DR STRING; 10090.ENSMUSP00000007207; -.
DR GlyConnect; 2209; 1 N-Linked glycan (1 site).
DR GlyGen; Q9R0A1; 1 site, 1 N-linked glycan (1 site).
DR iPTMnet; Q9R0A1; -.
DR PhosphoSitePlus; Q9R0A1; -.
DR SwissPalm; Q9R0A1; -.
DR MaxQB; Q9R0A1; -.
DR PaxDb; Q9R0A1; -.
DR PRIDE; Q9R0A1; -.
DR ProteomicsDB; 285479; -.
DR Antibodypedia; 2994; 311 antibodies from 36 providers.
DR DNASU; 12724; -.
DR Ensembl; ENSMUST00000007207; ENSMUSP00000007207; ENSMUSG00000022843.
DR GeneID; 12724; -.
DR KEGG; mmu:12724; -.
DR UCSC; uc012ada.1; mouse.
DR CTD; 1181; -.
DR MGI; MGI:105061; Clcn2.
DR VEuPathDB; HostDB:ENSMUSG00000022843; -.
DR eggNOG; KOG0476; Eukaryota.
DR GeneTree; ENSGT00940000155439; -.
DR HOGENOM; CLU_006904_0_1_1; -.
DR InParanoid; Q9R0A1; -.
DR OMA; ACFMFNN; -.
DR OrthoDB; 1131873at2759; -.
DR PhylomeDB; Q9R0A1; -.
DR TreeFam; TF300522; -.
DR Reactome; R-MMU-2672351; Stimuli-sensing channels.
DR BioGRID-ORCS; 12724; 0 hits in 74 CRISPR screens.
DR PRO; PR:Q9R0A1; -.
DR Proteomes; UP000000589; Chromosome 16.
DR RNAct; Q9R0A1; protein.
DR Bgee; ENSMUSG00000022843; Expressed in dorsal pancreas and 209 other tissues.
DR ExpressionAtlas; Q9R0A1; baseline and differential.
DR Genevisible; Q9R0A1; MM.
DR GO; GO:0034707; C:chloride channel complex; IEA:UniProtKB-KW.
DR GO; GO:0030425; C:dendrite; ISO:MGI.
DR GO; GO:0005887; C:integral component of plasma membrane; IBA:GO_Central.
DR GO; GO:0043204; C:perikaryon; ISO:MGI.
DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR GO; GO:0005247; F:voltage-gated chloride channel activity; IMP:MGI.
DR GO; GO:0090425; P:acinar cell differentiation; IMP:MGI.
DR GO; GO:0060689; P:cell differentiation involved in salivary gland development; IMP:MGI.
DR GO; GO:0006821; P:chloride transport; ISO:MGI.
DR GO; GO:0030324; P:lung development; ISO:MGI.
DR GO; GO:0032347; P:regulation of aldosterone biosynthetic process; ISS:UniProtKB.
DR GO; GO:0034765; P:regulation of ion transmembrane transport; IEA:UniProtKB-KW.
DR GO; GO:0060041; P:retina development in camera-type eye; IMP:MGI.
DR Gene3D; 3.10.580.10; -; 2.
DR InterPro; IPR046342; CBS_dom_sf.
DR InterPro; IPR002244; Cl-channel-2.
DR InterPro; IPR014743; Cl-channel_core.
DR InterPro; IPR001807; Cl-channel_volt-gated.
DR Pfam; PF00654; Voltage_CLC; 1.
DR PRINTS; PR00762; CLCHANNEL.
DR PRINTS; PR01113; CLCHANNEL2.
DR SUPFAM; SSF54631; SSF54631; 1.
DR SUPFAM; SSF81340; SSF81340; 1.
DR PROSITE; PS51371; CBS; 2.
PE 1: Evidence at protein level;
KW CBS domain; Cell membrane; Chloride; Chloride channel; Ion channel;
KW Ion transport; Membrane; Phosphoprotein; Reference proteome; Repeat;
KW Transmembrane; Transmembrane helix; Transport; Voltage-gated channel.
FT CHAIN 1..908
FT /note="Chloride channel protein 2"
FT /id="PRO_0000094434"
FT TOPO_DOM 1..95
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250"
FT TRANSMEM 96..129
FT /note="Helical"
FT /evidence="ECO:0000250"
FT TRANSMEM 138..163
FT /note="Helical"
FT /evidence="ECO:0000250"
FT INTRAMEM 172..179
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 188..206
FT /note="Helical"
FT /evidence="ECO:0000250"
FT TRANSMEM 213..231
FT /note="Helical"
FT /evidence="ECO:0000250"
FT INTRAMEM 247..259
FT /note="Helical"
FT /evidence="ECO:0000250"
FT INTRAMEM 263..271
FT /note="Helical"
FT /evidence="ECO:0000250"
FT TRANSMEM 283..303
FT /note="Helical"
FT /evidence="ECO:0000250"
FT TRANSMEM 329..357
FT /note="Helical"
FT /evidence="ECO:0000250"
FT TRANSMEM 366..385
FT /note="Helical"
FT /evidence="ECO:0000250"
FT TRANSMEM 437..457
FT /note="Helical"
FT /evidence="ECO:0000250"
FT TRANSMEM 465..488
FT /note="Helical"
FT /evidence="ECO:0000250"
FT INTRAMEM 505..519
FT /note="Helical"
FT /evidence="ECO:0000250"
FT INTRAMEM 520..521
FT /note="Note=Loop between two helices"
FT /evidence="ECO:0000250"
FT INTRAMEM 522..533
FT /note="Helical"
FT /evidence="ECO:0000250"
FT INTRAMEM 534..538
FT /note="Note=Loop between two helices"
FT /evidence="ECO:0000250"
FT TRANSMEM 539..556
FT /note="Helical"
FT /evidence="ECO:0000250"
FT TOPO_DOM 557..908
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250"
FT DOMAIN 592..650
FT /note="CBS 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00703"
FT DOMAIN 800..860
FT /note="CBS 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00703"
FT REGION 653..722
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 866..908
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 169..173
FT /note="Selectivity filter part_1"
FT /evidence="ECO:0000250"
FT MOTIF 211..215
FT /note="Selectivity filter part_2"
FT /evidence="ECO:0000250"
FT MOTIF 465..469
FT /note="Selectivity filter part_3"
FT /evidence="ECO:0000250"
FT COMPBIAS 662..694
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 867..881
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 170
FT /ligand="chloride"
FT /ligand_id="ChEBI:CHEBI:17996"
FT /evidence="ECO:0000250"
FT BINDING 467
FT /ligand="chloride"
FT /ligand_id="ChEBI:CHEBI:17996"
FT /evidence="ECO:0000250"
FT BINDING 561
FT /ligand="chloride"
FT /ligand_id="ChEBI:CHEBI:17996"
FT /evidence="ECO:0000250"
FT MOD_RES 28
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 768
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P35525"
FT CONFLICT 667
FT /note="P -> S (in Ref. 1; AAD50604)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 908 AA; 99447 MW; 6CF58033B60CA578 CRC64;
MAAATAAAAA AAAAGEGMEP RALQYEQTLM YGRYTQELGA FAKEEAARIR LGGPEPWKGS
PSARATPELL EYGQSRCARC RICSVRCHKF LVSRVGEDWI FLVLLGLLMA LVSWAMDYAI
AVCLQAQQWM SRGLNTNILL QYLAWVTYPV VLITFSAGFT QILAPQAVGS GIPEMKTILR
GVVLKEYLTL KTFVAKVIGL TCALGSGMPL GKEGPFVHIA SMCAALLSKF LSLFGGIYEH
ESRNTEMLAA ACAVGVGCCF AAPIGGVLFS IEVTSTFFAV RNYWRGFFAA TFSAFIFRVL
AVWNRDEETI TALFKTRFRL DFPFDLQELP AFAVIGIASG FGGALFVYLN RKIVQVMRKQ
KTINRFLMRK RLLFPALVTL LISTLTFPPG FGQFMAGQLS QKETLVTLFD NRTWVRQGLV
EDLELPSTSQ AWSPPRANVF LTLVIFILMK FWMSALATTI PVPCGAFMPV FVIGAAFGRL
VGESMAAWFP DGIHTDSSTY RIVPGGYAVV GAAALAGAVT HTVSTAVIVF ELTGQIAHIL
PVMIAVILAN AVAQSLQPSL YDSIIRIKKL PYLPELGWGR HQQYRVRVED IMVRDVPHVA
LSCTFRDLRL ALHRTKGRML ALVESPESMI LLGSIERSQV VALLGAQLSP ARRRQHMQKL
RKAQLSPPSD QESPPSSETS IRFQVNTEDS GFSGAHGQTH KPLKPALKRG PSNSTSLQEG
TTGNMESAGI ALRSLFCGSP PLEATSELEK SESCDKRKLK RVRISLASDS DPEAEMSPEE
ILEWEEQQLD EPVNFSDCKI DPAPFQLVER TSLHKTHTIF SLLGVDHAYV TSIGRLIGIV
TLKELRKAIE GSVTAQGVKV RPPLASFRDS ATSSSDTETT EVHALWGPRS RHGLPREGTP
SDSDDKCQ
