ID KCNA6_HUMAN Reviewed; 529 AA. AC P17658; DT 01-AUG-1990, integrated into UniProtKB/Swiss-Prot. DT 01-AUG-1990, sequence version 1. DT 24-JAN-2024, entry version 198. DE RecName: Full=Potassium voltage-gated channel subfamily A member 6; DE AltName: Full=Voltage-gated potassium channel HBK2 {ECO:0000303|PubMed:2347305}; DE AltName: Full=Voltage-gated potassium channel subunit Kv1.6; GN Name=KCNA6; 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], FUNCTION, AND SUBCELLULAR LOCATION. RC TISSUE=Brain; RX PubMed=2347305; DOI=10.1002/j.1460-2075.1990.tb08299.x; RA Grupe A., Schroeter K.H., Ruppersberg J.P., Stocker M., Drewes T., RA Beckh S., Pongs O.; RT "Cloning and expression of a human voltage-gated potassium channel. A novel RT member of the RCK potassium channel family."; RL EMBO J. 9:1749-1756(1990). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. 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 [3] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=14575698; DOI=10.1016/j.bbrc.2003.09.167; RA Guihard G., Bellocq C., Grelet E., Escande D.; RT "Human Kv1.6 current displays a C-type-like inactivation when re-expressed RT in cos-7 cells."; RL Biochem. Biophys. Res. Commun. 311:83-89(2003). RN [4] RP VARIANTS GLU-261; PHE-447; ILE-449 AND LEU-456, AND CHARACTERIZATION OF RP VARIANTS PHE-447; ILE-449 AND LEU-456. RX PubMed=36318112; DOI=10.1111/epi.17455; RG SYNAPS Study Group; RA Salpietro V., Galassi-Deforie V., Efthymiou S., O'Connor E., Marce-Grau A., RA Maroofian R., Striano P., Zara F., Morrow M., Reich A., Blevins A., RA Sala-Coromina J., Accogli A., Fortuna S., Alesandrini M., Au P.Y.B., RA Singhal N.S., Cogne B., Isidor B., Hanna M.G., Macaya A., Kullmann D.M., RA Houlden H., Maennikkoe R.; RT "De novo KCNA6 variants with attenuated KV 1.6 channel deactivation in RT patients with epilepsy."; RL Epilepsia 0:0-0(2022). CC -!- FUNCTION: Voltage-gated potassium channel that mediates transmembrane CC potassium transport in excitable membranes. Forms tetrameric potassium- CC selective channels through which potassium ions pass in accordance with CC their electrochemical gradient (PubMed:2347305, PubMed:14575698). The CC channel alternates between opened and closed conformations in response CC to the voltage difference across the membrane (PubMed:2347305, CC PubMed:14575698). Can form functional homotetrameric channels and CC heterotetrameric channels that contain variable proportions of KCNA1, CC KCNA2, KCNA4, KCNA6, and possibly other family members as well; channel CC properties depend on the type of alpha subunits that are part of the CC channel (By similarity). Channel properties are modulated by CC cytoplasmic beta subunits that regulate the subcellular location of the CC alpha subunits and promote rapid inactivation (By similarity). CC Homotetrameric channels display rapid activation and slow inactivation CC (PubMed:2347305). {ECO:0000250|UniProtKB:P17659, CC ECO:0000269|PubMed:14575698, ECO:0000269|PubMed:2347305}. CC -!- SUBUNIT: Homotetramer and heterotetramer of potassium channel proteins CC (By similarity). Interacts with KCNAB1 and KCNAB2 (By similarity). CC {ECO:0000250|UniProtKB:P17659, ECO:0000305}. CC -!- INTERACTION: CC P17658; Q9UPQ8: DOLK; NbExp=4; IntAct=EBI-6426142, EBI-8645574; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:14575698, CC ECO:0000269|PubMed:2347305}; Multi-pass membrane protein {ECO:0000305}. CC -!- DOMAIN: The N-terminus may be important in determining the rate of CC inactivation of the channel while the tail may play a role in CC modulation of channel activity and/or targeting of the channel to CC specific subcellular compartments. CC -!- DOMAIN: The transmembrane segment S4 functions as a voltage-sensor and CC is characterized by a series of positively charged amino acids at every CC third position. Channel opening and closing is effected by a CC conformation change that affects the position and orientation of the CC voltage-sensor paddle formed by S3 and S4 within the membrane. A CC transmembrane electric field that is positive inside would push the CC positively charged S4 segment outwards, thereby opening the pore, while CC a field that is negative inside would pull the S4 segment inwards and CC close the pore. Changes in the position and orientation of S4 are then CC transmitted to the activation gate formed by the inner helix bundle via CC the S4-S5 linker region. {ECO:0000250|UniProtKB:P63142}. CC -!- SIMILARITY: Belongs to the potassium channel family. A (Shaker) CC (TC 1.A.1.2) subfamily. Kv1.6/KCNA6 sub-subfamily. {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; X17622; CAA35623.1; -; mRNA. DR EMBL; BC069355; AAH69355.1; -; mRNA. DR CCDS; CCDS8534.1; -. DR PIR; S12787; S12787. DR RefSeq; NP_002226.1; NM_002235.3. DR RefSeq; XP_005253743.1; XM_005253686.3. DR RefSeq; XP_011519257.1; XM_011520955.2. DR RefSeq; XP_016874759.1; XM_017019270.1. DR RefSeq; XP_016874760.1; XM_017019271.1. DR RefSeq; XP_016874761.1; XM_017019272.1. DR AlphaFoldDB; P17658; -. DR SMR; P17658; -. DR BioGRID; 109944; 18. DR IntAct; P17658; 5. DR STRING; 9606.ENSP00000280684; -. DR BindingDB; P17658; -. DR ChEMBL; CHEMBL5279; -. DR DrugBank; DB06637; Dalfampridine. DR DrugBank; DB00228; Enflurane. DR DrugBank; DB01110; Miconazole. DR DrugBank; DB01069; Promethazine. DR DrugCentral; P17658; -. DR GuidetoPHARMACOLOGY; 543; -. DR TCDB; 1.A.1.2.29; the voltage-gated ion channel (vic) superfamily. DR iPTMnet; P17658; -. DR PhosphoSitePlus; P17658; -. DR BioMuta; HGNC:6225; -. DR DMDM; 116434; -. DR MassIVE; P17658; -. DR PaxDb; 9606-ENSP00000280684; -. DR PeptideAtlas; P17658; -. DR ProteomicsDB; 53501; -. DR ABCD; P17658; 1 sequenced antibody. DR Antibodypedia; 3161; 138 antibodies from 22 providers. DR DNASU; 3742; -. DR Ensembl; ENST00000280684.4; ENSP00000280684.3; ENSG00000151079.8. DR GeneID; 3742; -. DR KEGG; hsa:3742; -. DR MANE-Select; ENST00000280684.4; ENSP00000280684.3; NM_002235.5; NP_002226.1. DR UCSC; uc001qng.4; human. DR AGR; HGNC:6225; -. DR CTD; 3742; -. DR DisGeNET; 3742; -. DR GeneCards; KCNA6; -. DR HGNC; HGNC:6225; KCNA6. DR HPA; ENSG00000151079; Tissue enriched (brain). DR MIM; 176257; gene. DR neXtProt; NX_P17658; -. DR OpenTargets; ENSG00000151079; -. DR PharmGKB; PA30022; -. DR VEuPathDB; HostDB:ENSG00000151079; -. DR eggNOG; KOG1545; Eukaryota. DR GeneTree; ENSGT00940000162469; -. DR HOGENOM; CLU_011722_4_0_1; -. DR InParanoid; P17658; -. DR OMA; STPHRVY; -. DR OrthoDB; 1478695at2759; -. DR PhylomeDB; P17658; -. DR TreeFam; TF313103; -. DR PathwayCommons; P17658; -. DR Reactome; R-HSA-1296072; Voltage gated Potassium channels. DR SignaLink; P17658; -. DR BioGRID-ORCS; 3742; 20 hits in 1145 CRISPR screens. DR ChiTaRS; KCNA6; human. DR GeneWiki; KCNA6; -. DR GenomeRNAi; 3742; -. DR Pharos; P17658; Tclin. DR PRO; PR:P17658; -. DR Proteomes; UP000005640; Chromosome 12. DR RNAct; P17658; Protein. DR Bgee; ENSG00000151079; Expressed in cortical plate and 76 other cell types or tissues. DR GO; GO:0043679; C:axon terminus; IEA:Ensembl. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA. DR GO; GO:0005886; C:plasma membrane; IDA:HPA. DR GO; GO:0034705; C:potassium channel complex; ISS:UniProtKB. DR GO; GO:0008076; C:voltage-gated potassium channel complex; ISS:UniProtKB. DR GO; GO:0005251; F:delayed rectifier potassium channel activity; IDA:UniProtKB. DR GO; GO:0005249; F:voltage-gated potassium channel activity; TAS:ProtInc. DR GO; GO:0071805; P:potassium ion transmembrane transport; IDA:UniProtKB. DR GO; GO:0006813; P:potassium ion transport; TAS:ProtInc. DR GO; GO:0051260; P:protein homooligomerization; IEA:InterPro. DR CDD; cd18407; BTB_POZ_KCNA6; 1. DR Gene3D; 1.10.287.70; -; 1. DR Gene3D; 1.20.120.350; Voltage-gated potassium channels. Chain C; 1. DR InterPro; IPR000210; BTB/POZ_dom. DR InterPro; IPR005821; Ion_trans_dom. DR InterPro; IPR003968; K_chnl_volt-dep_Kv. DR InterPro; IPR003972; K_chnl_volt-dep_Kv1. DR InterPro; IPR004053; KCNA6. DR InterPro; IPR046988; KCNA6_BTB_POZ. DR InterPro; IPR011333; SKP1/BTB/POZ_sf. DR InterPro; IPR003131; T1-type_BTB. DR InterPro; IPR027359; Volt_channel_dom_sf. DR PANTHER; PTHR11537:SF104; POTASSIUM VOLTAGE-GATED CHANNEL SUBFAMILY A MEMBER 6; 1. DR PANTHER; PTHR11537; VOLTAGE-GATED POTASSIUM CHANNEL; 1. DR Pfam; PF02214; BTB_2; 1. DR Pfam; PF00520; Ion_trans; 1. DR PRINTS; PR00169; KCHANNEL. DR PRINTS; PR01513; KV16CHANNEL. DR PRINTS; PR01491; KVCHANNEL. DR PRINTS; PR01496; SHAKERCHANEL. DR SMART; SM00225; BTB; 1. DR SUPFAM; SSF54695; POZ domain; 1. DR SUPFAM; SSF81324; Voltage-gated potassium channels; 1. DR Genevisible; P17658; HS. PE 1: Evidence at protein level; KW Cell membrane; Ion channel; Ion transport; Lipoprotein; Membrane; KW Palmitate; Phosphoprotein; Potassium; Potassium channel; KW Potassium transport; Reference proteome; Transmembrane; KW Transmembrane helix; Transport; Voltage-gated channel. FT CHAIN 1..529 FT /note="Potassium voltage-gated channel subfamily A member FT 6" FT /id="PRO_0000053990" FT TOPO_DOM 1..171 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:P63142" FT TRANSMEM 172..193 FT /note="Helical; Name=Segment S1" FT /evidence="ECO:0000250|UniProtKB:P63142" FT TOPO_DOM 194..262 FT /note="Extracellular" FT /evidence="ECO:0000250|UniProtKB:P63142" FT TRANSMEM 263..284 FT /note="Helical; Name=Segment S2" FT /evidence="ECO:0000250|UniProtKB:P63142" FT TOPO_DOM 285..295 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:P63142" FT TRANSMEM 296..316 FT /note="Helical; Name=Segment S3" FT /evidence="ECO:0000250|UniProtKB:P63142" FT TOPO_DOM 317..337 FT /note="Extracellular" FT /evidence="ECO:0000250|UniProtKB:P63142" FT TRANSMEM 338..358 FT /note="Helical; Voltage-sensor; Name=Segment S4" FT /evidence="ECO:0000250|UniProtKB:P63142" FT TOPO_DOM 359..373 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:P63142" FT TRANSMEM 374..395 FT /note="Helical; Name=Segment S5" FT /evidence="ECO:0000250|UniProtKB:P63142" FT TOPO_DOM 396..409 FT /note="Extracellular" FT /evidence="ECO:0000250|UniProtKB:P63142" FT INTRAMEM 410..421 FT /note="Helical; Name=Pore helix" FT /evidence="ECO:0000250|UniProtKB:P63142" FT INTRAMEM 422..429 FT /evidence="ECO:0000250|UniProtKB:P63142" FT TOPO_DOM 430..436 FT /note="Extracellular" FT /evidence="ECO:0000250|UniProtKB:P63142" FT TRANSMEM 437..465 FT /note="Helical; Name=Segment S6" FT /evidence="ECO:0000250|UniProtKB:P63142" FT TOPO_DOM 466..529 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:P63142" FT REGION 1..33 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 210..233 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 360..373 FT /note="S4-S5 linker" FT /evidence="ECO:0000250|UniProtKB:P63142" FT REGION 488..513 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 422..427 FT /note="Selectivity filter" FT /evidence="ECO:0000250|UniProtKB:P63142" FT MOTIF 527..529 FT /note="PDZ-binding" FT /evidence="ECO:0000255" FT MOD_RES 3 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q61923" FT MOD_RES 511 FT /note="Phosphoserine; by PKA" FT /evidence="ECO:0000305" FT LIPID 285 FT /note="S-palmitoyl cysteine" FT /evidence="ECO:0000255" FT VARIANT 261 FT /note="D -> E (found in a patient with neurodevelopmental FT anomalies; uncertain significance)" FT /evidence="ECO:0000269|PubMed:36318112" FT /id="VAR_087560" FT VARIANT 447 FT /note="V -> F (found in a patient with epilepsy but without FT evidence of neurodevelopmental impairment; uncertain FT significance; affects channel properties resulting in FT slower channel deactivation)" FT /evidence="ECO:0000269|PubMed:36318112" FT /id="VAR_087561" FT VARIANT 449 FT /note="T -> I (found in a patient with epilepsy and FT neurodevelopmental anomalies; uncertain significance; FT affects channel properties resulting in slower channel FT deactivation)" FT /evidence="ECO:0000269|PubMed:36318112" FT /id="VAR_087562" FT VARIANT 456 FT /note="V -> L (found in a patient with epilepsy and FT neurodevelopmental anomalies; uncertain significance; FT affects channel properties resulting in slower channel FT deactivation)" FT /evidence="ECO:0000269|PubMed:36318112" FT /id="VAR_087563" SQ SEQUENCE 529 AA; 58729 MW; CFF0710A1F9CD69F CRC64; MRSEKSLTLA APGEVRGPEG EQQDAGDFPE AGGGGGCCSS ERLVINISGL RFETQLRTLS LFPDTLLGDP GRRVRFFDPL RNEYFFDRNR PSFDAILYYY QSGGRLRRPV NVPLDIFLEE IRFYQLGDEA LAAFREDEGC LPEGGEDEKP LPSQPFQRQV WLLFEYPESS GPARGIAIVS VLVILISIVI FCLETLPQFR VDGRGGNNGG VSRVSPVSRG SQEEEEDEDD SYTFHHGITP GEMGTGGSSS LSTLGGSFFT DPFFLVETLC IVWFTFELLV RFSACPSKPA FFRNIMNIID LVAIFPYFIT LGTELVQQQE QQPASGGGGQ NGQQAMSLAI LRVIRLVRVF RIFKLSRHSK GLQILGKTLQ ASMRELGLLI FFLFIGVILF SSAVYFAEAD DDDSLFPSIP DAFWWAVVTM TTVGYGDMYP MTVGGKIVGS LCAIAGVLTI ALPVPVIVSN FNYFYHRETE QEEQGQYTHV TCGQPAPDLR ATDNGLGKPD FPEANRERRP SYLPTPHRAY AEKRMLTEV //