ID CLCC1_MOUSE Reviewed; 539 AA. AC Q99LI2; A2AEK9; DT 21-AUG-2007, integrated into UniProtKB/Swiss-Prot. DT 01-JUN-2001, sequence version 1. DT 02-OCT-2024, entry version 134. DE RecName: Full=Chloride channel CLIC-like protein 1; DE AltName: Full=ER anion channel 1 {ECO:0000303|PubMed:37142673}; DE Short=ERAC1 {ECO:0000303|PubMed:37142673}; DE Flags: Precursor; GN Name=Clcc1 {ECO:0000303|PubMed:25698737, ECO:0000312|MGI:MGI:2385186}; 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 [LARGE SCALE MRNA]. RC STRAIN=NOD; TISSUE=Thymus; 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 [2] 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 [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC STRAIN=FVB/N; TISSUE=Mammary tumor; 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 [4] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=17242355; DOI=10.1073/pnas.0609836104; RA Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.; RT "Large-scale phosphorylation analysis of mouse liver."; RL Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007). RN [5] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19144319; DOI=10.1016/j.immuni.2008.11.006; RA Trost M., English L., Lemieux S., Courcelles M., Desjardins M., RA Thibault P.; RT "The phagosomal proteome in interferon-gamma-activated macrophages."; RL Immunity 30:143-154(2009). RN [6] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-429 AND SER-498, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Kidney, Liver, Lung, 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 [7] RP FUNCTION, AND DISEASE. RX PubMed=25698737; DOI=10.1523/jneurosci.3678-14.2015; RA Jia Y., Jucius T.J., Cook S.A., Ackerman S.L.; RT "Loss of Clcc1 results in ER stress, misfolded protein accumulation, and RT neurodegeneration."; RL J. Neurosci. 35:3001-3009(2015). RN [8] RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=30157172; DOI=10.1371/journal.pgen.1007504; RA Li L., Jiao X., D'Atri I., Ono F., Nelson R., Chan C.C., Nakaya N., Ma Z., RA Ma Y., Cai X., Zhang L., Lin S., Hameed A., Chioza B.A., Hardy H., Arno G., RA Hull S., Khan M.I., Fasham J., Harlalka G.V., Michaelides M., Moore A.T., RA Coban Akdemir Z.H., Jhangiani S., Lupski J.R., Cremers F.P.M., Qamar R., RA Salman A., Chilton J., Self J., Ayyagari R., Kabir F., Naeem M.A., Ali M., RA Akram J., Sieving P.A., Riazuddin S., Baple E.L., Riazuddin S.A., RA Crosby A.H., Hejtmancik J.F.; RT "Mutation in the intracellular chloride channel CLCC1 associated with RT autosomal recessive retinitis pigmentosa."; RL PLoS Genet. 14:E1007504-E1007504(2018). RN [9] RP FUNCTION, TRANSPORTER ACTIVITY, ACTIVITY REGULATION, SUBUNIT, SUBCELLULAR RP LOCATION, TOPOLOGY, TISSUE SPECIFICITY, AND MUTAGENESIS OF LYS-298. RX PubMed=37142673; DOI=10.1038/s41422-023-00798-z; RA Guo L., Mao Q., He J., Liu X., Piao X., Luo L., Hao X., Yu H., Song Q., RA Xiao B., Fan D., Gao Z., Jia Y.; RT "Disruption of ER ion homeostasis maintained by an ER anion channel CLCC1 RT contributes to ALS-like pathologies."; RL Cell Res. 33:497-515(2023). CC -!- FUNCTION: Anion-selective channel with Ca(2+)-dependent and voltage- CC independent gating. Permeable to small monovalent anions with CC selectivity for bromide > chloride > nitrate > fluoride CC (PubMed:37142673). Operates in the endoplasmic reticulum (ER) membrane CC where it mediates chloride efflux to compensate for the loss of CC positive charges from the ER lumen upon Ca(2+) release. Contributes to CC the maintenance of ER Ca(2+) pools and activation of unfolded protein CC response to prevent accumulation of misfolded proteins in the ER lumen. CC Particularly involved in ER homeostasis mechanisms underlying motor CC neurons and retinal photoreceptors survival (PubMed:25698737, CC PubMed:30157172, PubMed:37142673). {ECO:0000269|PubMed:25698737, CC ECO:0000269|PubMed:30157172, ECO:0000269|PubMed:37142673}. CC -!- CATALYTIC ACTIVITY: CC Reaction=chloride(in) = chloride(out); Xref=Rhea:RHEA:29823, CC ChEBI:CHEBI:17996; Evidence={ECO:0000269|PubMed:37142673}; CC -!- CATALYTIC ACTIVITY: CC Reaction=bromide(in) = bromide(out); Xref=Rhea:RHEA:75383, CC ChEBI:CHEBI:15858; Evidence={ECO:0000269|PubMed:37142673}; CC -!- CATALYTIC ACTIVITY: CC Reaction=nitrate(in) = nitrate(out); Xref=Rhea:RHEA:34923, CC ChEBI:CHEBI:17632; Evidence={ECO:0000269|PubMed:37142673}; CC -!- CATALYTIC ACTIVITY: CC Reaction=fluoride(in) = fluoride(out); Xref=Rhea:RHEA:76159, CC ChEBI:CHEBI:17051; Evidence={ECO:0000269|PubMed:37142673}; CC -!- ACTIVITY REGULATION: Activated by membrane phosphatidylinositol 4,5- CC bisphosphate (PI(4,5)P2, PIP2). Inhibited by lumenal Ca(2+). CC {ECO:0000269|PubMed:37142673}. CC -!- SUBUNIT: Homomultimers (PubMed:37142673). Interacts with mitochondrial CC protein PIGBOS1 (via C-terminus); the interaction occurs at the CC mitochondria-associated endoplasmic reticulum (ER) membrane, a zone of CC contact between the ER and mitochondrial membranes, but does not appear CC to play a role in ER-mitochondria tethering and is not affected by ER CC stress (By similarity). Interacts with CALR (By similarity). CC {ECO:0000250|UniProtKB:Q96S66, ECO:0000269|PubMed:37142673}. CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane CC {ECO:0000269|PubMed:37142673}; Multi-pass membrane protein CC {ECO:0000255}. Note=Within the endoplasmic reticulum (ER), localizes to CC the mitochondria-associated ER membrane, a zone of contact between the CC ER and mitochondrial membranes (By similarity). Enriched in the rough CC ER (PubMed:37142673). {ECO:0000250|UniProtKB:Q96S66, CC ECO:0000269|PubMed:37142673}. CC -!- TISSUE SPECIFICITY: Expressed in cerebellum (at protein level). CC {ECO:0000269|PubMed:37142673}. CC -!- DISEASE: Note=NM2453 (NM/NM) mice carrying a spontaneous hypomorphic CC CLCC1 allele develop progressive cerebellar granule neuron degeneration CC with muscle atrophy and peripheral neuropathy reminiscent of CC amyotrophic lateral sclerosis. {ECO:0000269|PubMed:25698737}. CC -!- DISRUPTION PHENOTYPE: Embryonic lethal. {ECO:0000269|PubMed:30157172}. CC -!- SIMILARITY: Belongs to the chloride channel MCLC family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=CAM17753.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AK169803; BAE41377.1; -; mRNA. DR EMBL; AK171296; BAE42376.1; -; mRNA. DR EMBL; AL671917; CAM17753.1; ALT_SEQ; Genomic_DNA. DR EMBL; AL671917; CAM17754.1; -; Genomic_DNA. DR EMBL; BC003247; AAH03247.1; -; mRNA. DR CCDS; CCDS17766.1; -. DR RefSeq; NP_001171242.1; NM_001177771.1. DR RefSeq; NP_663518.1; NM_145543.2. DR RefSeq; XP_006501479.1; XM_006501416.3. DR RefSeq; XP_017175050.1; XM_017319561.1. DR AlphaFoldDB; Q99LI2; -. DR BioGRID; 230895; 3. DR IntAct; Q99LI2; 3. DR MINT; Q99LI2; -. DR STRING; 10090.ENSMUSP00000102224; -. DR iPTMnet; Q99LI2; -. DR PhosphoSitePlus; Q99LI2; -. DR SwissPalm; Q99LI2; -. DR jPOST; Q99LI2; -. DR PaxDb; 10090-ENSMUSP00000102224; -. DR PeptideAtlas; Q99LI2; -. DR ProteomicsDB; 283375; -. DR Pumba; Q99LI2; -. DR Antibodypedia; 2391; 182 antibodies from 29 providers. DR DNASU; 229725; -. DR Ensembl; ENSMUST00000029483.15; ENSMUSP00000029483.9; ENSMUSG00000027884.17. DR Ensembl; ENSMUST00000106609.8; ENSMUSP00000102220.2; ENSMUSG00000027884.17. DR GeneID; 229725; -. DR KEGG; mmu:229725; -. DR UCSC; uc008qzk.2; mouse. DR AGR; MGI:2385186; -. DR CTD; 23155; -. DR MGI; MGI:2385186; Clcc1. DR VEuPathDB; HostDB:ENSMUSG00000027884; -. DR eggNOG; ENOG502QSP7; Eukaryota. DR GeneTree; ENSGT00390000016611; -. DR HOGENOM; CLU_034552_1_1_1; -. DR InParanoid; Q99LI2; -. DR OMA; TELWTYI; -. DR OrthoDB; 3823720at2759; -. DR BioGRID-ORCS; 229725; 8 hits in 76 CRISPR screens. DR ChiTaRS; Clcc1; mouse. DR PRO; PR:Q99LI2; -. DR Proteomes; UP000000589; Chromosome 3. DR RNAct; Q99LI2; protein. DR Bgee; ENSMUSG00000027884; Expressed in spermatocyte and 240 other cell types or tissues. DR ExpressionAtlas; Q99LI2; baseline and differential. DR GO; GO:0034707; C:chloride channel complex; IEA:UniProtKB-KW. DR GO; GO:0005737; C:cytoplasm; ISO:MGI. DR GO; GO:0005783; C:endoplasmic reticulum; ISO:MGI. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB. DR GO; GO:0005794; C:Golgi apparatus; ISO:MGI. DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell. DR GO; GO:0044233; C:mitochondria-associated endoplasmic reticulum membrane contact site; ISS:UniProtKB. DR GO; GO:0031965; C:nuclear membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005634; C:nucleus; ISO:MGI. DR GO; GO:0005254; F:chloride channel activity; IDA:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IDA:UniProtKB. DR GO; GO:0006821; P:chloride transport; ISO:MGI. DR GO; GO:0032469; P:endoplasmic reticulum calcium ion homeostasis; IMP:UniProtKB. DR InterPro; IPR009231; Chloride_chnl_CLIC-like. DR PANTHER; PTHR34093; CHLORIDE CHANNEL CLIC-LIKE PROTEIN 1; 1. DR PANTHER; PTHR34093:SF1; CHLORIDE CHANNEL CLIC-LIKE PROTEIN 1; 1. DR Pfam; PF05934; MCLC; 1. PE 1: Evidence at protein level; KW Chloride; Chloride channel; Endoplasmic reticulum; Ion channel; KW Ion transport; Membrane; Phosphoprotein; Reference proteome; Signal; KW Transmembrane; Transmembrane helix; Transport. FT SIGNAL 1..18 FT /evidence="ECO:0000255" FT CHAIN 19..539 FT /note="Chloride channel CLIC-like protein 1" FT /id="PRO_0000297683" FT TOPO_DOM 19..184 FT /note="Lumenal" FT /evidence="ECO:0000305|PubMed:37142673" FT TRANSMEM 185..205 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 206..215 FT /note="Cytoplasmic" FT /evidence="ECO:0000305|PubMed:37142673" FT TRANSMEM 216..236 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 237..329 FT /note="Lumenal" FT /evidence="ECO:0000305|PubMed:37142673" FT TRANSMEM 330..350 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 351..539 FT /note="Cytoplasmic" FT /evidence="ECO:0000305|PubMed:37142673" FT REGION 41..61 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 361..410 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 444..539 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 45..61 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 365..390 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 458..507 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT SITE 25 FT /note="Ca(2+)-mediated inhibition of channel activity" FT /evidence="ECO:0000250|UniProtKB:Q96S66" FT SITE 181 FT /note="Ca(2+)-mediated inhibition of channel activity" FT /evidence="ECO:0000250|UniProtKB:Q96S66" FT MOD_RES 429 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT MOD_RES 433 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q96S66" FT MOD_RES 459 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q96S66" FT MOD_RES 476 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:Q96S66" FT MOD_RES 498 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT MOD_RES 513 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q96S66" FT MOD_RES 521 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q96S66" FT MUTAGEN 298 FT /note="K->A: Decreases protein expression and abolishes FT PIP2-dependent channel activity. Acts as a dominant- FT negative and suppresses ATP-induced Ca(2+) release from the FT ER. In a knockin mouse model causes enhanced ER stress FT response, accumulation of unfolded proteins in cerebellum FT and motor neuron degeneration in compound heterozygosity FT with a hypomorphic allele; leads to embryonic lethality FT with a KO allele." FT /evidence="ECO:0000269|PubMed:37142673" FT MUTAGEN 298 FT /note="K->E: Abolishes PIP2-dependent channel activity." FT /evidence="ECO:0000269|PubMed:37142673" SQ SEQUENCE 539 AA; 60621 MW; 252A3E095B56C1C4 CRC64; MLCRLLLCEC LLLITGYAHD DDWIDPTDML NYDAASGTMR KSQVRSGTSE KKEVSPDSSE AEELSDCLHR LDSLTHKVDS CEKKKMKDYE SQSNPVFRRY LNKILIEAGK LGLPDENKVE MRYDAEILLS RQTLLEIQKF LSGEEWKPGA LDDALSDILI NFKCHDSEAW KWQFEDYFGV DPYNVFMVLL CLLCLVVLVA TELWTYVRWY TQMKRIFIIS FLLSLAWNWI YLYKMAFAQH QANIAGMEPF DNLCAKKMDW TGSLWEWFTS SWTYKDDPCQ KYYELLIVNP IWLVPPTKAL AITFTNFVTE PLKHIGKGAG EFIKALMKEI PVLLQIPVLA ILALAVLSFC YGAGRSVPML RHFGGPDREP PRALEPDDRR RQKGLDYRLH GGAGDADFSY RGPAGSIEQG PYDKMHASKR DALRQRFHSG NKSPEVLRAF DLPDTEAQEH PEVVPSHKSP IMNTNLETGE LPGESTPTEY SQSAKDVSGQ VPSAGKSSPT VDKAQLKTDS ECSPPGGCPP SKEAAVAAHG TEPVSSPCG //