ID S12A5_HUMAN Reviewed; 1139 AA. AC Q9H2X9; A2RTX2; Q5VZ41; Q9H4Z0; Q9ULP4; DT 13-DEC-2002, integrated into UniProtKB/Swiss-Prot. DT 04-DEC-2007, sequence version 3. DT 27-MAR-2024, entry version 183. DE RecName: Full=Solute carrier family 12 member 5; DE AltName: Full=Electroneutral potassium-chloride cotransporter 2; DE AltName: Full=K-Cl cotransporter 2; DE Short=hKCC2; DE AltName: Full=Neuronal K-Cl cotransporter; GN Name=SLC12A5 {ECO:0000312|HGNC:HGNC:13818}; GN Synonyms=KCC2 {ECO:0000303|PubMed:12106695}, KIAA1176; 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 2), TRANSPORTER ACTIVITY, FUNCTION, RP BIOPHYSICOCHEMICAL PROPERTIES, TISSUE SPECIFICITY, AND SUBCELLULAR RP LOCATION. RC TISSUE=Brain; RX PubMed=12106695; DOI=10.1016/s0169-328x(02)00190-0; RA Song L., Mercado A., Vazquez N., Xie Q., Desai R., George A.L. Jr., RA Gamba G., Mount D.B.; RT "Molecular, functional, and genomic characterization of human KCC2, the RT neuronal K-Cl cotransporter."; RL Brain Res. Mol. Brain Res. 103:91-105(2002). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=11780052; DOI=10.1038/414865a; RA Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R., RA Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L., RA Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P., RA Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J., Buck D., Burrill W.D., RA Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G., RA Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E., RA Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D., RA Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P., RA Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E., RA Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J., RA Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D., RA Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S., RA Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D., RA Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A., RA Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T., RA Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I., RA Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M., RA Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D., RA Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M., RA Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A., RA Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L., RA Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L., RA Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J.; RT "The DNA sequence and comparative analysis of human chromosome 20."; RL Nature 414:865-871(2001). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). 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 NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-175 (ISOFORM 1). RX PubMed=16344560; DOI=10.1101/gr.4039406; RA Kimura K., Wakamatsu A., Suzuki Y., Ota T., Nishikawa T., Yamashita R., RA Yamamoto J., Sekine M., Tsuritani K., Wakaguri H., Ishii S., Sugiyama T., RA Saito K., Isono Y., Irie R., Kushida N., Yoneyama T., Otsuka R., Kanda K., RA Yokoi T., Kondo H., Wagatsuma M., Murakawa K., Ishida S., Ishibashi T., RA Takahashi-Fujii A., Tanase T., Nagai K., Kikuchi H., Nakai K., Isogai T., RA Sugano S.; RT "Diversification of transcriptional modulation: large-scale identification RT and characterization of putative alternative promoters of human genes."; RL Genome Res. 16:55-65(2006). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 9-1109 (ISOFORM 2), AND VARIANT RP LEU-1100. RC TISSUE=Brain; RX PubMed=10574461; DOI=10.1093/dnares/6.5.329; RA Hirosawa M., Nagase T., Ishikawa K., Kikuno R., Nomura N., Ohara O.; RT "Characterization of cDNA clones selected by the GeneMark analysis from RT size-fractionated cDNA libraries from human brain."; RL DNA Res. 6:329-336(1999). RN [6] RP ACTIVITY REGULATION, PHOSPHORYLATION AT THR-929 AND THR-1030, AND RP MUTAGENESIS OF THR-929 AND THR-1030. RX PubMed=19665974; DOI=10.1016/j.cell.2009.05.031; RA Rinehart J., Maksimova Y.D., Tanis J.E., Stone K.L., Hodson C.A., Zhang J., RA Risinger M., Pan W., Wu D., Colangelo C.M., Forbush B., Joiner C.H., RA Gulcicek E.E., Gallagher P.G., Lifton R.P.; RT "Sites of regulated phosphorylation that control K-Cl cotransporter RT activity."; RL Cell 138:525-536(2009). RN [7] RP ACTIVITY REGULATION. RX PubMed=21613606; DOI=10.1152/ajpcell.00070.2011; RA Cruz-Rangel S., Melo Z., Vazquez N., Meade P., Bobadilla N.A., RA Pasantes-Morales H., Gamba G., Mercado A.; RT "Similar Effects of all WNK3 Variants upon SLC12 Cotransporters."; RL Am. J. Physiol. 301:C601-C608(2011). RN [8] RP STRUCTURE BY ELECTRON MICROSCOPY (3.20 ANGSTROMS) OF 26-1139. RX PubMed=33199848; DOI=10.1038/s41422-020-00437-x; RA Chi X., Li X., Chen Y., Zhang Y., Su Q., Zhou Q.; RT "Cryo-EM structures of the full-length human KCC2 and KCC3 cation-chloride RT cotransporters."; RL Cell Res. 31:482-484(2021). RN [9] RP ERRATUM OF PUBMED:33199848. RX PubMed=34267353; DOI=10.1038/s41422-021-00536-3; RA Chi X., Li X., Chen Y., Zhang Y., Su Q., Zhou Q.; RT "Author Correction: Cryo-EM structures of the full-length human KCC2 and RT KCC3 cation-chloride cotransporters."; RL Cell Res. 31:941-941(2021). RN [10] RP FUNCTION, INVOLVEMENT IN EIG14, VARIANT EIG14 HIS-975, AND CHARACTERIZATION RP OF VARIANT EIG14 HIS-975. RX PubMed=24668262; DOI=10.1002/embr.201438749; RA Puskarjov M., Seja P., Heron S.E., Williams T.C., Ahmad F., Iona X., RA Oliver K.L., Grinton B.E., Vutskits L., Scheffer I.E., Petrou S., RA Blaesse P., Dibbens L.M., Berkovic S.F., Kaila K.; RT "A variant of KCC2 from patients with febrile seizures impairs neuronal RT Cl- extrusion and dendritic spine formation."; RL EMBO Rep. 15:723-729(2014). RN [11] RP INVOLVEMENT IN DEE34, VARIANTS DEE34 HIS-311; PRO-426 AND ASP-551, AND RP CHARACTERIZATION OF VARIANTS DEE34 HIS-311; PRO-426 AND ASP-551. RX PubMed=26333769; DOI=10.1038/ncomms9038; RA Stoedberg T., McTague A., Ruiz A.J., Hirata H., Zhen J., Long P., RA Farabella I., Meyer E., Kawahara A., Vassallo G., Stivaros S.M., RA Bjursell M.K., Stranneheim H., Tigerschioeld S., Persson B., Bangash I., RA Das K., Hughes D., Lesko N., Lundeberg J., Scott R.C., Poduri A., RA Scheffer I.E., Smith H., Gissen P., Schorge S., Reith M.E., Topf M., RA Kullmann D.M., Harvey R.J., Wedell A., Kurian M.A.; RT "Mutations in SLC12A5 in epilepsy of infancy with migrating focal RT seizures."; RL Nat. Commun. 6:8038-8038(2015). RN [12] RP VARIANT [LARGE SCALE ANALYSIS] ASP-847. RX PubMed=16959974; DOI=10.1126/science.1133427; RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V., RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., RA Velculescu V.E.; RT "The consensus coding sequences of human breast and colorectal cancers."; RL Science 314:268-274(2006). RN [13] RP INVOLVEMENT IN EIG14, VARIANTS EIG14 HIS-975 AND CYS-1072, AND RP CHARACTERIZATION OF VARIANTS EIG14 HIS-975 AND CYS-1072. RX PubMed=24928908; DOI=10.15252/embr.201438840; RA Kahle K.T., Merner N.D., Friedel P., Silayeva L., Liang B., Khanna A., RA Shang Y., Lachance-Touchette P., Bourassa C., Levert A., Dion P.A., RA Walcott B., Spiegelman D., Dionne-Laporte A., Hodgkinson A., Awadalla P., RA Nikbakht H., Majewski J., Cossette P., Deeb T.Z., Moss S.J., Medina I., RA Rouleau G.A.; RT "Genetically encoded impairment of neuronal KCC2 cotransporter function in RT human idiopathic generalized epilepsy."; RL EMBO Rep. 15:766-774(2014). RN [14] RP VARIANT TRP-1071, AND VARIANTS EIG14 HIS-975 AND CYS-1072. RX PubMed=26528127; DOI=10.3389/fncel.2015.00386; RA Merner N.D., Chandler M.R., Bourassa C., Liang B., Khanna A.R., Dion P., RA Rouleau G.A., Kahle K.T.; RT "Regulatory domain or CpG site variation in SLC12A5, encoding the chloride RT transporter KCC2, in human autism and schizophrenia."; RL Front. Cell. Neurosci. 9:386-386(2015). CC -!- FUNCTION: Mediates electroneutral potassium-chloride cotransport in CC mature neurons and is required for neuronal Cl(-) homeostasis CC (PubMed:12106695). As major extruder of intracellular chloride, it CC establishes the low neuronal Cl(-) levels required for chloride influx CC after binding of GABA-A and glycine to their receptors, with subsequent CC hyperpolarization and neuronal inhibition (By similarity). Involved in CC the regulation of dendritic spine formation and maturation CC (PubMed:24668262). {ECO:0000250|UniProtKB:Q63633, CC ECO:0000269|PubMed:12106695, ECO:0000269|PubMed:24668262}. CC -!- CATALYTIC ACTIVITY: CC Reaction=chloride(in) + K(+)(in) = chloride(out) + K(+)(out); CC Xref=Rhea:RHEA:72427, ChEBI:CHEBI:17996, ChEBI:CHEBI:29103; CC Evidence={ECO:0000269|PubMed:12106695}; CC -!- ACTIVITY REGULATION: Inhibited following phosphorylation by OXSR1/OSR1 CC and STK39/SPAK: phosphorylation takes place downstream of WNK kinases CC (WNK1, WNK2, WNK3 or WNK4) in response to hyperosmotic stress and CC subsequent cell shrinkage. {ECO:0000269|PubMed:19665974, CC ECO:0000269|PubMed:21613606}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=9.3 mM for Rb(+) {ECO:0000269|PubMed:12106695}; CC KM=6.8 mM for chloride {ECO:0000269|PubMed:12106695}; CC -!- SUBUNIT: Homodimer (By similarity). Heteromultimer with other K-Cl CC cotransporters (By similarity). Interacts with AP2A1 (By similarity). CC {ECO:0000250|UniProtKB:Q63633, ECO:0000250|UniProtKB:Q91V14}. CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:Q91V14}; CC Multi-pass membrane protein {ECO:0000250|UniProtKB:Q91V14}. Cell CC projection, dendrite {ECO:0000250|UniProtKB:Q91V14}. Note=Detected on CC dendrites, but not on axons of spinal cord neurons and at GPHN-positive CC inhibitory synapses. {ECO:0000250|UniProtKB:Q91V14}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; Synonyms=KCC2a; CC IsoId=Q9H2X9-1; Sequence=Displayed; CC Name=2; Synonyms=KCC2b; CC IsoId=Q9H2X9-2; Sequence=VSP_029909; CC -!- TISSUE SPECIFICITY: Brain specific. Detected in neuronal cells. CC {ECO:0000269|PubMed:12106695}. CC -!- PTM: Phosphorylated at Thr-929 and Thr-1030 by OXSR1/OSR1 and CC STK39/SPAK downstream of WNK kinases (WNK1, WNK2, WNK3 or WNK4), CC inhibiting the potassium-chloride cotransport activity. CC {ECO:0000269|PubMed:19665974}. CC -!- DISEASE: Developmental and epileptic encephalopathy 34 (DEE34) CC [MIM:616645]: A form of epileptic encephalopathy, a heterogeneous group CC of severe early-onset epilepsies characterized by refractory seizures, CC neurodevelopmental impairment, and poor prognosis. Development is CC normal prior to seizure onset, after which cognitive and motor delays CC become apparent. DEE34 is characterized by onset of refractory CC migrating focal seizures in infancy. Affected children show CC developmental regression and are severely impaired globally. CC {ECO:0000269|PubMed:26333769}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Epilepsy, idiopathic generalized 14 (EIG14) [MIM:616685]: An CC autosomal dominant form of idiopathic generalized epilepsy, a disorder CC characterized by recurring generalized seizures in the absence of CC detectable brain lesions and/or metabolic abnormalities. Generalized CC seizures arise diffusely and simultaneously from both hemispheres of CC the brain. Seizure types include juvenile myoclonic seizures, absence CC seizures, and generalized tonic-clonic seizures. CC {ECO:0000269|PubMed:24668262, ECO:0000269|PubMed:24928908, CC ECO:0000269|PubMed:26528127}. Note=Disease susceptibility is associated CC with variants affecting the gene represented in this entry. CC -!- MISCELLANEOUS: Inhibited by furosemide and bumetanide. CC -!- SIMILARITY: Belongs to the SLC12A transporter family. {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; AF208159; AAG43493.1; -; mRNA. DR EMBL; AL162458; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC132668; AAI32669.1; -; mRNA. DR EMBL; BC132670; AAI32671.1; -; mRNA. DR EMBL; AB033002; BAA86490.1; -; mRNA. DR EMBL; DA102113; -; NOT_ANNOTATED_CDS; mRNA. DR EMBL; DA328785; -; NOT_ANNOTATED_CDS; mRNA. DR CCDS; CCDS13391.1; -. [Q9H2X9-2] DR CCDS; CCDS46610.1; -. [Q9H2X9-1] DR RefSeq; NP_001128243.1; NM_001134771.1. [Q9H2X9-1] DR RefSeq; NP_065759.1; NM_020708.4. [Q9H2X9-2] DR PDB; 6M23; EM; 3.20 A; A/B=26-1139. DR PDB; 7D8Z; EM; 3.40 A; A/B=1-1139. DR PDBsum; 6M23; -. DR PDBsum; 7D8Z; -. DR AlphaFoldDB; Q9H2X9; -. DR EMDB; EMD-30061; -. DR EMDB; EMD-30615; -. DR EMDB; EMD-30617; -. DR SMR; Q9H2X9; -. DR BioGRID; 121538; 6. DR IntAct; Q9H2X9; 6. DR MINT; Q9H2X9; -. DR STRING; 9606.ENSP00000387694; -. DR BindingDB; Q9H2X9; -. DR ChEMBL; CHEMBL1615384; -. DR DrugBank; DB00887; Bumetanide. DR DrugBank; DB00761; Potassium chloride. DR GuidetoPHARMACOLOGY; 972; -. DR TCDB; 2.A.30.1.18; the cation-chloride cotransporter (ccc) family. DR GlyCosmos; Q9H2X9; 2 sites, No reported glycans. DR GlyGen; Q9H2X9; 2 sites. DR iPTMnet; Q9H2X9; -. DR PhosphoSitePlus; Q9H2X9; -. DR SwissPalm; Q9H2X9; -. DR BioMuta; SLC12A5; -. DR DMDM; 161784306; -. DR EPD; Q9H2X9; -. DR jPOST; Q9H2X9; -. DR MassIVE; Q9H2X9; -. DR MaxQB; Q9H2X9; -. DR PaxDb; 9606-ENSP00000387694; -. DR PeptideAtlas; Q9H2X9; -. DR ProteomicsDB; 80632; -. [Q9H2X9-1] DR ProteomicsDB; 80633; -. [Q9H2X9-2] DR ABCD; Q9H2X9; 1 sequenced antibody. DR Antibodypedia; 1580; 390 antibodies from 29 providers. DR DNASU; 57468; -. DR Ensembl; ENST00000243964.7; ENSP00000243964.4; ENSG00000124140.15. [Q9H2X9-2] DR Ensembl; ENST00000454036.6; ENSP00000387694.1; ENSG00000124140.15. [Q9H2X9-1] DR GeneID; 57468; -. DR KEGG; hsa:57468; -. DR MANE-Select; ENST00000243964.7; ENSP00000243964.4; NM_020708.5; NP_065759.1. [Q9H2X9-2] DR UCSC; uc002xrb.3; human. [Q9H2X9-1] DR AGR; HGNC:13818; -. DR CTD; 57468; -. DR DisGeNET; 57468; -. DR GeneCards; SLC12A5; -. DR GeneReviews; SLC12A5; -. DR HGNC; HGNC:13818; SLC12A5. DR HPA; ENSG00000124140; Tissue enhanced (brain, retina). DR MalaCards; SLC12A5; -. DR MIM; 606726; gene. DR MIM; 616645; phenotype. DR MIM; 616685; phenotype. DR neXtProt; NX_Q9H2X9; -. DR OpenTargets; ENSG00000124140; -. DR Orphanet; 293181; Malignant migrating focal seizures of infancy. DR PharmGKB; PA37814; -. DR VEuPathDB; HostDB:ENSG00000124140; -. DR eggNOG; KOG2082; Eukaryota. DR GeneTree; ENSGT00940000160827; -. DR HOGENOM; CLU_001883_1_2_1; -. DR InParanoid; Q9H2X9; -. DR OMA; AMFPANT; -. DR OrthoDB; 5490251at2759; -. DR PhylomeDB; Q9H2X9; -. DR TreeFam; TF313657; -. DR PathwayCommons; Q9H2X9; -. DR Reactome; R-HSA-426117; Cation-coupled Chloride cotransporters. DR SignaLink; Q9H2X9; -. DR SIGNOR; Q9H2X9; -. DR BioGRID-ORCS; 57468; 22 hits in 1161 CRISPR screens. DR GeneWiki; Chloride_potassium_symporter_5; -. DR GenomeRNAi; 57468; -. DR Pharos; Q9H2X9; Tchem. DR PRO; PR:Q9H2X9; -. DR Proteomes; UP000005640; Chromosome 20. DR RNAct; Q9H2X9; Protein. DR Bgee; ENSG00000124140; Expressed in right hemisphere of cerebellum and 132 other cell types or tissues. DR ExpressionAtlas; Q9H2X9; baseline and differential. DR GO; GO:0071944; C:cell periphery; IDA:ARUK-UCL. DR GO; GO:0032590; C:dendrite membrane; IEA:Ensembl. DR GO; GO:0016020; C:membrane; IDA:UniProtKB. DR GO; GO:0043005; C:neuron projection; IDA:ARUK-UCL. DR GO; GO:0043025; C:neuronal cell body; IDA:ARUK-UCL. DR GO; GO:0043204; C:perikaryon; IEA:Ensembl. DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central. DR GO; GO:0045202; C:synapse; IEA:GOC. DR GO; GO:0008519; F:ammonium transmembrane transporter activity; IEA:Ensembl. DR GO; GO:0015108; F:chloride transmembrane transporter activity; IDA:UniProtKB. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0015379; F:potassium:chloride symporter activity; IDA:UniProtKB. DR GO; GO:0019901; F:protein kinase binding; IPI:ParkinsonsUK-UCL. DR GO; GO:0006884; P:cell volume homeostasis; IBA:GO_Central. DR GO; GO:0007268; P:chemical synaptic transmission; IBA:GO_Central. DR GO; GO:0055064; P:chloride ion homeostasis; IBA:GO_Central. DR GO; GO:1902476; P:chloride transmembrane transport; IBA:GO_Central. DR GO; GO:0060996; P:dendritic spine development; IDA:UniProtKB. DR GO; GO:0006971; P:hypotonic response; IDA:UniProtKB. DR GO; GO:0030644; P:intracellular chloride ion homeostasis; IDA:UniProtKB. DR GO; GO:0051452; P:intracellular pH reduction; IEA:Ensembl. DR GO; GO:0007612; P:learning; IEA:Ensembl. DR GO; GO:0006811; P:monoatomic ion transport; IDA:UniProtKB. DR GO; GO:0035264; P:multicellular organism growth; IEA:Ensembl. DR GO; GO:0055075; P:potassium ion homeostasis; IBA:GO_Central. DR GO; GO:1990573; P:potassium ion import across plasma membrane; IBA:GO_Central. DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl. DR GO; GO:0040040; P:thermosensory behavior; IEA:Ensembl. DR Gene3D; 1.20.1740.10; Amino acid/polyamine transporter I; 1. DR InterPro; IPR004841; AA-permease/SLC12A_dom. DR InterPro; IPR000076; KCL_cotranspt. DR InterPro; IPR018491; SLC12_C. DR InterPro; IPR004842; SLC12A_fam. DR NCBIfam; TIGR00930; 2a30; 1. DR PANTHER; PTHR11827:SF54; SOLUTE CARRIER FAMILY 12 MEMBER 5; 1. DR PANTHER; PTHR11827; SOLUTE CARRIER FAMILY 12, CATION COTRANSPORTERS; 1. DR Pfam; PF00324; AA_permease; 2. DR Pfam; PF03522; SLC12; 3. DR PRINTS; PR01081; KCLTRNSPORT. DR Genevisible; Q9H2X9; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cell membrane; Cell projection; KW Chloride; Disease variant; Disulfide bond; Epilepsy; Glycoprotein; KW Ion transport; Membrane; Metal-binding; Phosphoprotein; Potassium; KW Potassium transport; Reference proteome; Symport; Transmembrane; KW Transmembrane helix; Transport. FT CHAIN 1..1139 FT /note="Solute carrier family 12 member 5" FT /id="PRO_0000178034" FT TOPO_DOM 1..122 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:Q91V14" FT TRANSMEM 123..143 FT /note="Discontinuously helical" FT /evidence="ECO:0000250|UniProtKB:Q91V14" FT TOPO_DOM 144..151 FT /note="Extracellular" FT /evidence="ECO:0000250|UniProtKB:Q91V14" FT TRANSMEM 152..176 FT /note="Helical" FT /evidence="ECO:0000250|UniProtKB:Q91V14" FT TOPO_DOM 177..197 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:Q91V14" FT TRANSMEM 198..227 FT /note="Helical" FT /evidence="ECO:0000250|UniProtKB:Q91V14" FT TOPO_DOM 228..251 FT /note="Extracellular" FT /evidence="ECO:0000250|UniProtKB:Q91V14" FT TRANSMEM 252..273 FT /note="Helical" FT /evidence="ECO:0000250|UniProtKB:Q91V14" FT TRANSMEM 274..299 FT /note="Helical" FT /evidence="ECO:0000250|UniProtKB:Q91V14" FT TOPO_DOM 300..422 FT /note="Extracellular" FT /evidence="ECO:0000250|UniProtKB:Q91V14" FT TRANSMEM 423..443 FT /note="Helical" FT /evidence="ECO:0000250|UniProtKB:Q91V14" FT TOPO_DOM 444..452 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:Q91V14" FT TRANSMEM 453..476 FT /note="Helical" FT /evidence="ECO:0000250|UniProtKB:Q91V14" FT TOPO_DOM 477..508 FT /note="Extracellular" FT /evidence="ECO:0000250|UniProtKB:Q91V14" FT TRANSMEM 509..537 FT /note="Helical" FT /evidence="ECO:0000250|UniProtKB:Q91V14" FT TOPO_DOM 538..557 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:Q91V14" FT TRANSMEM 558..574 FT /note="Helical" FT /evidence="ECO:0000250|UniProtKB:Q91V14" FT TOPO_DOM 575..576 FT /note="Extracellular" FT /evidence="ECO:0000250|UniProtKB:Q91V14" FT TRANSMEM 577..601 FT /note="Helical" FT /evidence="ECO:0000250|UniProtKB:Q91V14" FT TOPO_DOM 602..618 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:Q91V14" FT TRANSMEM 619..636 FT /note="Helical" FT /evidence="ECO:0000250|UniProtKB:Q91V14" FT TOPO_DOM 637 FT /note="Extracellular" FT /evidence="ECO:0000250|UniProtKB:Q91V14" FT TRANSMEM 638..655 FT /note="Helical" FT /evidence="ECO:0000250|UniProtKB:Q91V14" FT TOPO_DOM 656..1139 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:Q91V14" FT REGION 1..63 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 92..116 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 942..1052 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 19..44 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 98..112 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 942..966 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 980..996 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1021..1040 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 133 FT /ligand="K(+)" FT /ligand_id="ChEBI:CHEBI:29103" FT /evidence="ECO:0000250|UniProtKB:Q9UP95" FT BINDING 134 FT /ligand="K(+)" FT /ligand_id="ChEBI:CHEBI:29103" FT /evidence="ECO:0000250|UniProtKB:Q9UP95" FT BINDING 218 FT /ligand="K(+)" FT /ligand_id="ChEBI:CHEBI:29103" FT /evidence="ECO:0000250|UniProtKB:Q9UP95" FT BINDING 432 FT /ligand="K(+)" FT /ligand_id="ChEBI:CHEBI:29103" FT /evidence="ECO:0000250|UniProtKB:Q9UP95" FT BINDING 435 FT /ligand="K(+)" FT /ligand_id="ChEBI:CHEBI:29103" FT /evidence="ECO:0000250|UniProtKB:Q9UP95" FT BINDING 436 FT /ligand="chloride" FT /ligand_id="ChEBI:CHEBI:17996" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q9UP95" FT BINDING 437 FT /ligand="chloride" FT /ligand_id="ChEBI:CHEBI:17996" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q9UP95" FT BINDING 438 FT /ligand="chloride" FT /ligand_id="ChEBI:CHEBI:17996" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q9UP95" FT BINDING 592 FT /ligand="chloride" FT /ligand_id="ChEBI:CHEBI:17996" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q9UP95" FT BINDING 592 FT /ligand="chloride" FT /ligand_id="ChEBI:CHEBI:17996" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:Q9UP95" FT MOD_RES 57 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:Q63633" FT MOD_RES 929 FT /note="Phosphothreonine; by OXSR1 and STK39" FT /evidence="ECO:0000269|PubMed:19665974" FT MOD_RES 1030 FT /note="Phosphothreonine; by OXSR1 and STK39" FT /evidence="ECO:0000269|PubMed:19665974" FT MOD_RES 1045 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q91V14" FT MOD_RES 1048 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q91V14" FT MOD_RES 1049 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q91V14" FT CARBOHYD 314 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 333 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 351 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 362 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 310..325 FT /evidence="ECO:0000250|UniProtKB:Q9UP95" FT DISULFID 345..354 FT /evidence="ECO:0000250|UniProtKB:Q9UP95" FT VAR_SEQ 1..40 FT /note="MSRRFTVTSLPPAGPARSPDPESRRHSVADPRHLPGEDVK -> MLNNLTDC FT EDGDGGANP (in isoform 2)" FT /evidence="ECO:0000303|PubMed:10574461, FT ECO:0000303|PubMed:12106695, ECO:0000303|PubMed:15489334" FT /id="VSP_029909" FT VARIANT 311 FT /note="L -> H (in DEE34; results in reduced chloride FT transport; decreased localization at the cell surface; FT dbSNP:rs863225306)" FT /evidence="ECO:0000269|PubMed:26333769" FT /id="VAR_075078" FT VARIANT 407 FT /note="P -> A (in dbSNP:rs16985442)" FT /id="VAR_027414" FT VARIANT 426 FT /note="L -> P (in DEE34; results in loss of chloride FT transport; decreased localization at the cell surface; FT dbSNP:rs863225304)" FT /evidence="ECO:0000269|PubMed:26333769" FT /id="VAR_075079" FT VARIANT 551 FT /note="G -> D (in DEE34; results in loss of chloride FT transport; decreased localization at the cell surface; FT dbSNP:rs863225305)" FT /evidence="ECO:0000269|PubMed:26333769" FT /id="VAR_075080" FT VARIANT 847 FT /note="G -> D (in a colorectal cancer sample; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:16959974" FT /id="VAR_036557" FT VARIANT 975 FT /note="R -> H (in EIG14; rare variant associated with FT disease susceptibility; results in reduced chloride FT transport; decreased localization at the cell surface; FT unable to induce cortical dendritic spines formation; FT dbSNP:rs142740233)" FT /evidence="ECO:0000269|PubMed:24668262, FT ECO:0000269|PubMed:24928908, ECO:0000269|PubMed:26528127" FT /id="VAR_075081" FT VARIANT 1071 FT /note="R -> W (in dbSNP:rs369042030)" FT /evidence="ECO:0000269|PubMed:26528127" FT /id="VAR_075082" FT VARIANT 1072 FT /note="R -> C (in EIG14; rare variant associated with FT disease susceptibility; results in reduced chloride FT transport; dbSNP:rs548424453)" FT /evidence="ECO:0000269|PubMed:24928908, FT ECO:0000269|PubMed:26528127" FT /id="VAR_075083" FT VARIANT 1100 FT /note="P -> L (in dbSNP:rs17297532)" FT /evidence="ECO:0000269|PubMed:10574461" FT /id="VAR_024994" FT MUTAGEN 929 FT /note="T->A: Decreased phosphorylation by WNK kinases, FT leading to increased potassium-chloride cotransport FT activity; when associated with A-1030." FT /evidence="ECO:0000269|PubMed:19665974" FT MUTAGEN 1030 FT /note="T->A: Decreased phosphorylation by WNK kinases, FT leading to increased potassium-chloride cotransport FT activity; when associated with A-929." FT /evidence="ECO:0000269|PubMed:19665974" FT HELIX 82..88 FT /evidence="ECO:0007829|PDB:7D8Z" FT HELIX 99..102 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 103..105 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 122..125 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 127..133 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 137..141 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 143..149 FT /evidence="ECO:0007829|PDB:6M23" FT TURN 152..154 FT /evidence="ECO:0007829|PDB:6M23" FT TURN 156..162 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 163..177 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 188..191 FT /evidence="ECO:0007829|PDB:6M23" FT TURN 192..194 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 198..201 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 203..228 FT /evidence="ECO:0007829|PDB:6M23" FT STRAND 241..243 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 245..270 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 272..277 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 279..299 FT /evidence="ECO:0007829|PDB:6M23" FT TURN 300..302 FT /evidence="ECO:0007829|PDB:6M23" FT STRAND 308..314 FT /evidence="ECO:0007829|PDB:6M23" FT STRAND 326..328 FT /evidence="ECO:0007829|PDB:6M23" FT STRAND 332..334 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 341..344 FT /evidence="ECO:0007829|PDB:6M23" FT STRAND 348..352 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 356..359 FT /evidence="ECO:0007829|PDB:6M23" FT STRAND 364..369 FT /evidence="ECO:0007829|PDB:6M23" FT TURN 371..373 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 378..380 FT /evidence="ECO:0007829|PDB:6M23" FT STRAND 395..397 FT /evidence="ECO:0007829|PDB:6M23" FT STRAND 412..414 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 423..430 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 431..433 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 437..441 FT /evidence="ECO:0007829|PDB:6M23" FT STRAND 442..446 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 450..463 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 466..476 FT /evidence="ECO:0007829|PDB:6M23" FT TURN 477..479 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 482..485 FT /evidence="ECO:0007829|PDB:6M23" FT TURN 489..495 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 500..502 FT /evidence="ECO:0007829|PDB:6M23" FT STRAND 503..505 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 508..520 FT /evidence="ECO:0007829|PDB:6M23" FT TURN 521..524 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 525..538 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 543..549 FT /evidence="ECO:0007829|PDB:6M23" FT STRAND 555..558 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 559..567 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 569..571 FT /evidence="ECO:0007829|PDB:6M23" FT TURN 572..574 FT /evidence="ECO:0007829|PDB:6M23" FT TURN 577..579 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 581..605 FT /evidence="ECO:0007829|PDB:6M23" FT STRAND 614..616 FT /evidence="ECO:0007829|PDB:6M23" FT TURN 618..620 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 621..634 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 638..644 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 646..663 FT /evidence="ECO:0007829|PDB:6M23" FT STRAND 664..666 FT /evidence="ECO:0007829|PDB:7D8Z" FT HELIX 667..681 FT /evidence="ECO:0007829|PDB:6M23" FT STRAND 685..687 FT /evidence="ECO:0007829|PDB:6M23" FT STRAND 688..691 FT /evidence="ECO:0007829|PDB:7D8Z" FT STRAND 698..700 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 713..722 FT /evidence="ECO:0007829|PDB:6M23" FT STRAND 729..736 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 738..741 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 743..756 FT /evidence="ECO:0007829|PDB:6M23" FT TURN 757..760 FT /evidence="ECO:0007829|PDB:6M23" FT STRAND 763..772 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 773..782 FT /evidence="ECO:0007829|PDB:6M23" FT STRAND 793..796 FT /evidence="ECO:0007829|PDB:6M23" FT STRAND 803..806 FT /evidence="ECO:0007829|PDB:6M23" FT TURN 808..810 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 812..823 FT /evidence="ECO:0007829|PDB:6M23" FT STRAND 827..832 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 834..836 FT /evidence="ECO:0007829|PDB:6M23" FT STRAND 850..852 FT /evidence="ECO:0007829|PDB:6M23" FT STRAND 854..856 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 859..868 FT /evidence="ECO:0007829|PDB:6M23" FT STRAND 871..876 FT /evidence="ECO:0007829|PDB:6M23" FT STRAND 880..885 FT /evidence="ECO:0007829|PDB:6M23" FT STRAND 887..889 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 894..903 FT /evidence="ECO:0007829|PDB:6M23" FT TURN 904..906 FT /evidence="ECO:0007829|PDB:6M23" FT STRAND 910..915 FT /evidence="ECO:0007829|PDB:6M23" FT TURN 923..927 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 931..940 FT /evidence="ECO:0007829|PDB:6M23" FT TURN 946..948 FT /evidence="ECO:0007829|PDB:6M23" FT STRAND 949..951 FT /evidence="ECO:0007829|PDB:6M23" FT TURN 953..957 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 1078..1087 FT /evidence="ECO:0007829|PDB:6M23" FT STRAND 1088..1091 FT /evidence="ECO:0007829|PDB:6M23" FT STRAND 1093..1096 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 1104..1106 FT /evidence="ECO:0007829|PDB:6M23" FT TURN 1107..1110 FT /evidence="ECO:0007829|PDB:6M23" FT HELIX 1111..1117 FT /evidence="ECO:0007829|PDB:6M23" FT TURN 1118..1120 FT /evidence="ECO:0007829|PDB:6M23" FT STRAND 1122..1128 FT /evidence="ECO:0007829|PDB:6M23" FT CONFLICT Q9H2X9-2:2 FT /note="L -> P (in Ref. 1; AAG43493)" FT /evidence="ECO:0000305" SQ SEQUENCE 1139 AA; 126184 MW; 100C097AF1FD4B3E CRC64; MSRRFTVTSL PPAGPARSPD PESRRHSVAD PRHLPGEDVK GDGNPKESSP FINSTDTEKG KEYDGKNMAL FEEEMDTSPM VSSLLSGLAN YTNLPQGSRE HEEAENNEGG KKKPVQAPRM GTFMGVYLPC LQNIFGVILF LRLTWVVGIA GIMESFCMVF ICCSCTMLTA ISMSAIATNG VVPAGGSYYM ISRSLGPEFG GAVGLCFYLG TTFAGAMYIL GTIEILLAYL FPAMAIFKAE DASGEAAAML NNMRVYGTCV LTCMATVVFV GVKYVNKFAL VFLGCVILSI LAIYAGVIKS AFDPPNFPIC LLGNRTLSRH GFDVCAKLAW EGNETVTTRL WGLFCSSRFL NATCDEYFTR NNVTEIQGIP GAASGLIKEN LWSSYLTKGV IVERSGMTSV GLADGTPIDM DHPYVFSDMT SYFTLLVGIY FPSVTGIMAG SNRSGDLRDA QKSIPTGTIL AIATTSAVYI SSVVLFGACI EGVVLRDKFG EAVNGNLVVG TLAWPSPWVI VIGSFFSTCG AGLQSLTGAP RLLQAISRDG IVPFLQVFGH GKANGEPTWA LLLTACICEI GILIASLDEV APILSMFFLM CYMFVNLACA VQTLLRTPNW RPRFRYYHWT LSFLGMSLCL ALMFICSWYY ALVAMLIAGL IYKYIEYRGA EKEWGDGIRG LSLSAARYAL LRLEEGPPHT KNWRPQLLVL VRVDQDQNVV HPQLLSLTSQ LKAGKGLTIV GSVLEGTFLE NHPQAQRAEE SIRRLMEAEK VKGFCQVVIS SNLRDGVSHL IQSGGLGGLQ HNTVLVGWPR NWRQKEDHQT WRNFIELVRE TTAGHLALLV TKNVSMFPGN PERFSEGSID VWWIVHDGGM LMLLPFLLRH HKVWRKCKMR IFTVAQMDDN SIQMKKDLTT FLYHLRITAE VEVVEMHESD ISAYTYEKTL VMEQRSQILK QMHLTKNERE REIQSITDES RGSIRRKNPA NTRLRLNVPE ETAGDSEEKP EEEVQLIHDQ SAPSCPSSSP SPGEEPEGEG ETDPEKVHLT WTKDKSVAEK NKGPSPVSSE GIKDFFSMKP EWENLNQSNV RRMHTAVRLN EVIVKKSRDA KLVLLNMPGP PRNRNGDENY MEFLEVLTEH LDRVMLVRGG GREVITIYS //