ID KCNH1_HUMAN Reviewed; 989 AA. AC O95259; B1AQ26; O76035; Q14CL3; DT 28-NOV-2002, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-1999, sequence version 1. DT 27-MAR-2024, entry version 213. DE RecName: Full=Potassium voltage-gated channel subfamily H member 1; DE AltName: Full=Ether-a-go-go potassium channel 1 {ECO:0000303|PubMed:27325704}; DE Short=EAG channel 1 {ECO:0000303|PubMed:23881642, ECO:0000303|PubMed:27325704}; DE Short=h-eag; DE Short=hEAG1 {ECO:0000303|PubMed:23881642, ECO:0000303|PubMed:27325704}; DE AltName: Full=Voltage-gated potassium channel subunit Kv10.1; GN Name=KCNH1; GN Synonyms=EAG {ECO:0000303|PubMed:10523298}, EAG1 GN {ECO:0000303|PubMed:23881642, ECO:0000303|PubMed:27325704}; 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), FUNCTION, AND SUBCELLULAR LOCATION. RC TISSUE=Myoblast; RX PubMed=9738473; DOI=10.1016/s0014-5793(98)00973-9; RA Occhiodoro T., Bernheim L., Liu J.-H., Bijlenga P., Sinnreich M., RA Bader C.R., Fischer-Lougheed J.; RT "Cloning of a human ether-a-go-go potassium channel expressed in myoblasts RT at the onset of fusion."; RL FEBS Lett. 434:177-182(1998). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2). RC TISSUE=Brain; RX PubMed=10523298; DOI=10.1093/emboj/18.20.5540; RA Pardo L.A., del Camino D., Sanchez A., Alves F., Brueggemann A., Beckh S., RA Stuehmer W.; RT "Oncogenic potential of EAG K(+) channels."; RL EMBO J. 18:5540-5547(1999). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16710414; DOI=10.1038/nature04727; RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K., RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.; RT "The DNA sequence and biological annotation of human chromosome 1."; RL Nature 441:315-321(2006). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). 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 [6] RP FUNCTION, SUBCELLULAR LOCATION, CALMODULIN-BINDING DOMAIN, AND ACTIVITY RP REGULATION. RX PubMed=10880439; DOI=10.1093/emboj/19.13.3263; RA Schoenherr R., Lober K., Heinemann S.H.; RT "Inhibition of human ether a go-go potassium channels by RT Ca(2+)/calmodulin."; RL EMBO J. 19:3263-3271(2000). RN [7] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH KCNH5. RX PubMed=11943152; DOI=10.1016/s0014-5793(02)02365-7; RA Schoenherr R., Gessner G., Loeber K., Heinemann S.H.; RT "Functional distinction of human EAG1 and EAG2 potassium channels."; RL FEBS Lett. 514:204-208(2002). RN [8] RP SUBCELLULAR LOCATION. RX PubMed=21559285; DOI=10.1371/journal.pone.0019257; RA Chen Y., Sanchez A., Rubio M.E., Kohl T., Pardo L.A., Stuhmer W.; RT "Functional K(v)10.1 channels localize to the inner nuclear membrane."; RL PLoS ONE 6:E19257-E19257(2011). RN [9] RP SUBCELLULAR LOCATION. RX PubMed=22841712; DOI=10.1016/j.febslet.2012.07.055; RA Ninkovic M., Mitkovski M., Kohl T., Stuhmer W., Pardo L.A.; RT "Physical and functional interaction of KV10.1 with Rabaptin-5 impacts ion RT channel trafficking."; RL FEBS Lett. 586:3077-3084(2012). RN [10] RP INTERACTION WITH CTTN. RX PubMed=23144454; DOI=10.1074/jbc.m112.372540; RA Herrmann S., Ninkovic M., Kohl T., Lorinczi E., Pardo L.A.; RT "Cortactin controls surface expression of the voltage-gated potassium RT channel K(V)10.1."; RL J. Biol. Chem. 287:44151-44163(2012). RN [11] RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF 699-TYR--LEU-701. RX PubMed=22732247; DOI=10.1016/j.jmb.2012.06.025; RA Marques-Carvalho M.J., Sahoo N., Muskett F.W., Vieira-Pires R.S., RA Gabant G., Cadene M., Schonherr R., Morais-Cabral J.H.; RT "Structural, biochemical, and functional characterization of the cyclic RT nucleotide binding homology domain from the mouse EAG1 potassium channel."; RL J. Mol. Biol. 423:34-46(2012). RN [12] RP FUNCTION. RX PubMed=23881642; DOI=10.1002/jcp.24435; RA Zhang Y.Y., Yue J., Che H., Sun H.Y., Tse H.F., Li G.R.; RT "BKCa and hEag1 channels regulate cell proliferation and differentiation in RT human bone marrow-derived mesenchymal stem cells."; RL J. Cell. Physiol. 229:202-212(2014). RN [13] RP PHOSPHORYLATION. RX PubMed=24587194; DOI=10.1371/journal.pone.0090024; RA Schlichter L.C., Jiang J., Wang J., Newell E.W., Tsui F.W., Lam D.; RT "Regulation of hERG and hEAG channels by Src and by SHP-1 tyrosine RT phosphatase via an ITIM region in the cyclic nucleotide binding domain."; RL PLoS ONE 9:E90024-E90024(2014). RN [14] RP FUNCTION, AND SUBCELLULAR LOCATION. RX PubMed=25556795; DOI=10.1113/jphysiol.2014.281600; RA Mortensen L.S., Schmidt H., Farsi Z., Barrantes-Freer A., Rubio M.E., RA Ufartes R., Eilers J., Sakaba T., Stuehmer W., Pardo L.A.; RT "KV 10.1 opposes activity-dependent increase in Ca2+ influx into the RT presynaptic terminal of the parallel fibre-Purkinje cell synapse."; RL J. Physiol. (Lond.) 593:181-196(2015). RN [15] RP INVOLVEMENT IN TMBTS, VARIANTS TMBTS ASN-217; PHE-489; VAL-494 AND ARG-503, RP AND CHARACTERIZATION OF VARIANTS TMBTS ASN-217; PHE-489; VAL-494 AND RP ARG-503. RX PubMed=25420144; DOI=10.1038/ng.3153; RA Simons C., Rash L.D., Crawford J., Ma L., Cristofori-Armstrong B., RA Miller D., Ru K., Baillie G.J., Alanay Y., Jacquinet A., Debray F.G., RA Verloes A., Shen J., Yesil G., Guler S., Yuksel A., Cleary J.G., RA Grimmond S.M., McGaughran J., King G.F., Gabbett M.T., Taft R.J.; RT "Mutations in the voltage-gated potassium channel gene KCNH1 cause Temple- RT Baraitser syndrome and epilepsy."; RL Nat. Genet. 47:73-77(2015). RN [16] RP INVOLVEMENT IN ZLS1, VARIANTS ZLS1 TYR-352; ARG-375; VAL-379; LEU-383; RP VAL-494 AND ARG-496, AND CHARACTERIZATION OF VARIANTS ZLS1 TYR-352; RP ARG-375; VAL-379; LEU-383; VAL-494 AND ARG-496. RX PubMed=25915598; DOI=10.1038/ng.3282; RA Kortuem F., Caputo V., Bauer C.K., Stella L., Ciolfi A., Alawi M., RA Bocchinfuso G., Flex E., Paolacci S., Dentici M.L., Grammatico P., RA Korenke G.C., Leuzzi V., Mowat D., Nair L.D., Nguyen T.T., Thierry P., RA White S.M., Dallapiccola B., Pizzuti A., Campeau P.M., Tartaglia M., RA Kutsche K.; RT "Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome."; RL Nat. Genet. 47:661-667(2015). RN [17] RP FUNCTION, SUBCELLULAR LOCATION, ACTIVITY REGULATION, AND DOMAIN. RX PubMed=27325704; DOI=10.1074/jbc.m116.733576; RA Loerinczi E., Helliwell M., Finch A., Stansfeld P.J., Davies N.W., RA Mahaut-Smith M., Muskett F.W., Mitcheson J.S.; RT "Calmodulin regulates human ether a go-go 1 (hEAG1) potassium channels RT through interactions of the Eag domain with the cyclic nucleotide binding RT homology domain."; RL J. Biol. Chem. 291:17907-17918(2016). RN [18] RP FUNCTION, SUBCELLULAR LOCATION, AND ACTIVITY REGULATION. RX PubMed=27005320; DOI=10.1038/srep23417; RA Han B., He K., Cai C., Tang Y., Yang L., Heinemann S.H., Hoshi T., Hou S.; RT "Human EAG channels are directly modulated by PIP2 as revealed by RT electrophysiological and optical interference investigations."; RL Sci. Rep. 6:23417-23417(2016). RN [19] RP FUNCTION, SUBCELLULAR LOCATION, ACTIVITY REGULATION, INTERACTION WITH CALM, RP AND MUTAGENESIS OF VAL-737 AND LEU-740. RX PubMed=27618660; DOI=10.1016/j.str.2016.07.020; RA Marques-Carvalho M.J., Oppermann J., Munoz E., Fernandes A.S., Gabant G., RA Cadene M., Heinemann S.H., Schoenherr R., Morais-Cabral J.H.; RT "Molecular insights into the mechanism of calmodulin inhibition of the EAG1 RT potassium channel."; RL Structure 24:1742-1754(2016). RN [20] RP ACTIVITY REGULATION, AND SUBUNIT. RX PubMed=30149017; DOI=10.1016/j.bcp.2018.08.038; RA Ma L., Chin Y.K.Y., Dekan Z., Herzig V., Chow C.Y., Heighway J., Lam S.W., RA Guillemin G.J., Alewood P.F., King G.F.; RT "Novel venom-derived inhibitors of the human EAG channel, a putative RT antiepileptic drug target."; RL Biochem. Pharmacol. 158:60-72(2018). RN [21] RP X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) OF 1-146. RX PubMed=27487920; DOI=10.1107/s2053230x16009419; RA Tang X., Shao J., Qin X.; RT "Crystal structure of the PAS domain of the hEAG potassium channel."; RL Acta Crystallogr. F Struct. Biol. Commun. 72:578-585(2016). CC -!- FUNCTION: Pore-forming (alpha) subunit of a voltage-gated delayed CC rectifier potassium channel (PubMed:9738473, PubMed:11943152, CC PubMed:10880439, PubMed:22732247, PubMed:25556795, PubMed:27325704, CC PubMed:27005320, PubMed:27618660). Channel properties are modulated by CC subunit assembly (PubMed:11943152). Mediates IK(NI) current in CC myoblasts (PubMed:9738473). Involved in the regulation of cell CC proliferation and differentiation, in particular adipogenic and CC osteogenic differentiation in bone marrow-derived mesenchymal stem CC cells (MSCs) (PubMed:23881642). {ECO:0000269|PubMed:10880439, CC ECO:0000269|PubMed:11943152, ECO:0000269|PubMed:22732247, CC ECO:0000269|PubMed:23881642, ECO:0000269|PubMed:25556795, CC ECO:0000269|PubMed:27005320, ECO:0000269|PubMed:27325704, CC ECO:0000269|PubMed:27618660, ECO:0000269|PubMed:9738473}. CC -!- ACTIVITY REGULATION: Channel activity is inhibited by interaction with CC Ca(2+)-bound calmodulin (PubMed:10880439, PubMed:27325704, CC PubMed:27005320, PubMed:27618660). Interaction of a single pore-forming CC alpha subunit with a calmodulin chain is sufficient to promote channel CC closure (PubMed:10880439). Channel activity is not regulated by cyclic CC nucleotides (By similarity). Channel activity is inhibited by binding CC intracellular phosphatidylinositol-3,5-bisphosphate and CC phosphatidylinositol-4,5-bisphosphate (PIP2), but is not inhibited by CC phosphatidylinositol 4-phosphate (PubMed:27005320). Inhibited by the CC spider kappa-theraphotoxin-Aa1a and mu/kappa-theraphotoxin-Ap1a CC (PubMed:30149017). {ECO:0000250|UniProtKB:Q60603, CC ECO:0000269|PubMed:10880439, ECO:0000269|PubMed:27005320, CC ECO:0000269|PubMed:27325704, ECO:0000269|PubMed:27618660}. CC -!- SUBUNIT: The potassium channel is composed of a homo- or CC heterotetrameric complex of pore-forming alpha subunits that can CC associate with modulating beta subunits. Heteromultimer with KCNH5/EAG2 CC (PubMed:11943152). Interacts with ALG10B (By similarity). Interacts CC with RABEP1 (By similarity). Interacts (via C-terminus) with CTTN CC (PubMed:23144454). Interacts (via C-terminal cytoplasmic region) with CC Ca(2+)-bound calmodulin (PubMed:10880439, PubMed:27325704, CC PubMed:27618660). Interacts with the spider kappa-theraphotoxin-Aa1a CC and mu/kappa-theraphotoxin-Ap1a (PubMed:30149017). CC {ECO:0000250|UniProtKB:Q63472, ECO:0000269|PubMed:10880439, CC ECO:0000269|PubMed:11943152, ECO:0000269|PubMed:23144454, CC ECO:0000269|PubMed:27325704, ECO:0000269|PubMed:27618660}. CC -!- INTERACTION: CC O95259; P62158: CALM3; NbExp=4; IntAct=EBI-2909270, EBI-397435; CC O95259; Q7L8L6: FASTKD5; NbExp=3; IntAct=EBI-2909270, EBI-747570; CC O95259; Q96HA8: NTAQ1; NbExp=3; IntAct=EBI-2909270, EBI-741158; CC O95259; O00560: SDCBP; NbExp=3; IntAct=EBI-2909270, EBI-727004; CC O95259; P02638: S100B; Xeno; NbExp=3; IntAct=EBI-2909270, EBI-458452; CC O95259-2; P62158: CALM3; NbExp=8; IntAct=EBI-9836801, EBI-397435; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:10880439, CC ECO:0000269|PubMed:11943152, ECO:0000269|PubMed:21559285, CC ECO:0000269|PubMed:22732247, ECO:0000269|PubMed:22841712, CC ECO:0000269|PubMed:25556795, ECO:0000269|PubMed:27005320, CC ECO:0000269|PubMed:27325704, ECO:0000269|PubMed:27618660, CC ECO:0000269|PubMed:9738473}; Multi-pass membrane protein CC {ECO:0000269|PubMed:21559285}. Nucleus inner membrane CC {ECO:0000269|PubMed:21559285}; Multi-pass membrane protein CC {ECO:0000269|PubMed:21559285}. Cell projection, dendrite CC {ECO:0000250|UniProtKB:Q63472}. Cell projection, axon CC {ECO:0000250|UniProtKB:Q63472}. Presynaptic cell membrane CC {ECO:0000250|UniProtKB:Q63472}. Perikaryon CC {ECO:0000250|UniProtKB:Q63472}. Postsynaptic density membrane CC {ECO:0000250|UniProtKB:Q63472}. Early endosome membrane CC {ECO:0000269|PubMed:22841712}. Note=Perinuclear KCNH1 is located to CC NPC-free islands. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=2; Synonyms=hEAGB; CC IsoId=O95259-1; Sequence=Displayed; CC Name=1; Synonyms=hEAG; CC IsoId=O95259-2; Sequence=VSP_000964; CC -!- TISSUE SPECIFICITY: Highly expressed in brain and in myoblasts at the CC onset of fusion, but not in other tissues. Detected in HeLa (cervical CC carcinoma), SH-SY5Y (neuroblastoma) and MCF-7 (epithelial tumor) cells, CC but not in normal epithelial cells. CC -!- DOMAIN: The segment S4 is probably the voltage-sensor and is CC characterized by a series of positively charged amino acids at every CC third position. {ECO:0000250|UniProtKB:Q63472}. CC -!- DOMAIN: The C-terminal region interacts with the cyclic nucleotide- CC binding domain and contributes to regulate channel gating. CC {ECO:0000250|UniProtKB:Q60603}. CC -!- DOMAIN: The PAS and PAC domain interact with the cyclic nucleotide- CC binding domain and contribute to the regulation of channel gating CC (PubMed:27325704). Calmodulin binding clamps together the PAS and PAC CC domain with the cyclic nucleotide-binding domain from a neighboring CC subunit and causes a conformation change that leads to channel closure. CC {ECO:0000250|UniProtKB:Q63472, ECO:0000269|PubMed:27325704}. CC -!- DOMAIN: The cyclic nucleotide-binding domain lacks residues that are CC essential for nucleotide-binding and cannot bind cyclic nucleotides. CC Instead, residues from the C-terminal domain (the so-called intrinsic CC ligand) bind in the cavity that would be expected to bind cyclic CC nucleotides. Interaction with the C-terminal region hinders interaction CC with CALM and reduces the affinity for CALM. CC {ECO:0000250|UniProtKB:Q60603}. CC -!- PTM: Channel activity is regulated via tyrosine CC phosphorylation/dephosphorylation by SRC and PTPN6 (PubMed:24587194). CC {ECO:0000269|PubMed:24587194}. CC -!- DISEASE: Temple-Baraitser syndrome (TMBTS) [MIM:611816]: A CC developmental disorder characterized by intellectual disability, CC epilepsy, hypoplasia or aplasia of the thumb and great toe nails, and CC broadening and/or elongation of the thumbs and halluces, which have a CC tubular aspect. Some patients show facial dysmorphism. CC {ECO:0000269|PubMed:25420144}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Zimmermann-Laband syndrome 1 (ZLS1) [MIM:135500]: A form of CC Zimmermann-Laband syndrome, a rare developmental disorder characterized CC by facial dysmorphism with bulbous nose and thick floppy ears, gingival CC enlargement, hypoplasia or aplasia of terminal phalanges and nails, CC hypertrichosis, joint hyperextensibility, and hepatosplenomegaly. Some CC patients manifest intellectual disability with or without epilepsy. CC ZLS1 inheritance is autosomal dominant. {ECO:0000269|PubMed:25915598}. CC Note=The disease is caused by variants affecting the gene represented CC in this entry. CC -!- SIMILARITY: Belongs to the potassium channel family. H (Eag) CC (TC 1.A.1.20) subfamily. Kv10.1/KCNH1 sub-subfamily. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="https://atlasgeneticsoncology.org/gene/41048/KCNH1"; 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; AJ001366; CAA04700.1; -; mRNA. DR EMBL; AF078741; AAC68668.1; -; mRNA. DR EMBL; AF078742; AAC68669.1; -; mRNA. DR EMBL; AC092017; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC096636; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC099755; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL590132; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471100; EAW93424.1; -; Genomic_DNA. DR EMBL; CH471100; EAW93425.1; -; Genomic_DNA. DR EMBL; BC113709; AAI13710.1; -; mRNA. DR EMBL; BC143599; AAI43600.1; -; mRNA. DR CCDS; CCDS1496.1; -. [O95259-1] DR CCDS; CCDS31015.1; -. [O95259-2] DR RefSeq; NP_002229.1; NM_002238.3. [O95259-2] DR RefSeq; NP_758872.1; NM_172362.2. [O95259-1] DR PDB; 5J7E; X-ray; 1.90 A; A/B/C/D/E/F=1-146. DR PDBsum; 5J7E; -. DR AlphaFoldDB; O95259; -. DR SMR; O95259; -. DR BioGRID; 109958; 15. DR IntAct; O95259; 11. DR MINT; O95259; -. DR STRING; 9606.ENSP00000271751; -. DR BindingDB; O95259; -. DR ChEMBL; CHEMBL3841; -. DR DrugBank; DB00637; Astemizole. DR DrugBank; DB00228; Enflurane. DR DrugBank; DB00458; Imipramine. DR DrugBank; DB01110; Miconazole. DR DrugBank; DB01069; Promethazine. DR DrugCentral; O95259; -. DR GuidetoPHARMACOLOGY; 570; -. DR TCDB; 1.A.1.20.10; the voltage-gated ion channel (vic) superfamily. DR TCDB; 1.I.1.1.3; the nuclear pore complex (npc) family. DR GlyCosmos; O95259; 3 sites, 1 glycan. DR GlyGen; O95259; 3 sites, 1 O-linked glycan (1 site). DR iPTMnet; O95259; -. DR PhosphoSitePlus; O95259; -. DR BioMuta; KCNH1; -. DR MassIVE; O95259; -. DR MaxQB; O95259; -. DR PaxDb; 9606-ENSP00000271751; -. DR PeptideAtlas; O95259; -. DR ProteomicsDB; 50755; -. [O95259-1] DR ProteomicsDB; 50756; -. [O95259-2] DR ABCD; O95259; 9 sequenced antibodies. DR Antibodypedia; 20707; 275 antibodies from 28 providers. DR DNASU; 3756; -. DR Ensembl; ENST00000271751.10; ENSP00000271751.4; ENSG00000143473.14. [O95259-1] DR Ensembl; ENST00000638960.1; ENSP00000492302.1; ENSG00000143473.14. [O95259-2] DR Ensembl; ENST00000639952.1; ENSP00000492697.1; ENSG00000143473.14. [O95259-2] DR Ensembl; ENST00000640528.1; ENSP00000491725.1; ENSG00000143473.14. [O95259-2] DR Ensembl; ENST00000640710.1; ENSP00000492513.1; ENSG00000143473.14. [O95259-2] DR GeneID; 3756; -. DR KEGG; hsa:3756; -. DR MANE-Select; ENST00000271751.10; ENSP00000271751.4; NM_172362.3; NP_758872.1. DR UCSC; uc001hib.3; human. [O95259-1] DR AGR; HGNC:6250; -. DR CTD; 3756; -. DR DisGeNET; 3756; -. DR GeneCards; KCNH1; -. DR HGNC; HGNC:6250; KCNH1. DR HPA; ENSG00000143473; Tissue enriched (brain). DR MalaCards; KCNH1; -. DR MIM; 135500; phenotype. DR MIM; 603305; gene. DR MIM; 611816; phenotype. DR neXtProt; NX_O95259; -. DR OpenTargets; ENSG00000143473; -. DR Orphanet; 420561; Temple-Baraitser syndrome. DR Orphanet; 3473; Zimmermann-Laband syndrome. DR PharmGKB; PA30037; -. DR VEuPathDB; HostDB:ENSG00000143473; -. DR eggNOG; KOG0501; Eukaryota. DR GeneTree; ENSGT00940000155793; -. DR HOGENOM; CLU_005746_3_1_1; -. DR InParanoid; O95259; -. DR OMA; HEMISNV; -. DR OrthoDB; 66005at2759; -. DR PhylomeDB; O95259; -. DR TreeFam; TF313130; -. DR PathwayCommons; O95259; -. DR Reactome; R-HSA-1296072; Voltage gated Potassium channels. DR SignaLink; O95259; -. DR BioGRID-ORCS; 3756; 6 hits in 1151 CRISPR screens. DR ChiTaRS; KCNH1; human. DR GeneWiki; KCNH1; -. DR GenomeRNAi; 3756; -. DR Pharos; O95259; Tclin. DR PRO; PR:O95259; -. DR Proteomes; UP000005640; Chromosome 1. DR RNAct; O95259; Protein. DR Bgee; ENSG00000143473; Expressed in Brodmann (1909) area 9 and 104 other cell types or tissues. DR ExpressionAtlas; O95259; baseline and differential. DR GO; GO:0030424; C:axon; IEA:UniProtKB-SubCell. DR GO; GO:0030425; C:dendrite; IEA:UniProtKB-SubCell. DR GO; GO:0031901; C:early endosome membrane; IDA:UniProtKB. DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA. DR GO; GO:0005637; C:nuclear inner membrane; IEA:UniProtKB-SubCell. DR GO; GO:0043204; C:perikaryon; IEA:UniProtKB-SubCell. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0098839; C:postsynaptic density membrane; IEA:UniProtKB-SubCell. DR GO; GO:0042734; C:presynaptic membrane; IEA:UniProtKB-SubCell. DR GO; GO:0008076; C:voltage-gated potassium channel complex; IDA:UniProtKB. DR GO; GO:0005516; F:calmodulin binding; IEA:UniProtKB-KW. DR GO; GO:0005251; F:delayed rectifier potassium channel activity; IDA:UniProtKB. DR GO; GO:1902936; F:phosphatidylinositol bisphosphate binding; IDA:UniProtKB. DR GO; GO:0071277; P:cellular response to calcium ion; IMP:UniProtKB. DR GO; GO:0007520; P:myoblast fusion; 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:0042127; P:regulation of cell population proliferation; IMP:UniProtKB. DR GO; GO:0042391; P:regulation of membrane potential; IBA:GO_Central. DR CDD; cd00038; CAP_ED; 1. DR CDD; cd00130; PAS; 1. DR Gene3D; 1.10.1200.260; -; 1. DR Gene3D; 1.10.287.70; -; 1. DR Gene3D; 2.60.120.10; Jelly Rolls; 1. DR Gene3D; 3.30.450.20; PAS domain; 1. DR InterPro; IPR000595; cNMP-bd_dom. DR InterPro; IPR018490; cNMP-bd_dom_sf. DR InterPro; IPR005821; Ion_trans_dom. DR InterPro; IPR003949; K_chnl_volt-dep_EAG. DR InterPro; IPR003938; K_chnl_volt-dep_EAG/ELK/ERG. DR InterPro; IPR001610; PAC. DR InterPro; IPR000014; PAS. DR InterPro; IPR000700; PAS-assoc_C. DR InterPro; IPR035965; PAS-like_dom_sf. DR InterPro; IPR014710; RmlC-like_jellyroll. DR NCBIfam; TIGR00229; sensory_box; 1. DR PANTHER; PTHR10217:SF530; POTASSIUM VOLTAGE-GATED CHANNEL SUBFAMILY H MEMBER 1; 1. DR PANTHER; PTHR10217; VOLTAGE AND LIGAND GATED POTASSIUM CHANNEL; 1. DR Pfam; PF00027; cNMP_binding; 1. DR Pfam; PF00520; Ion_trans; 1. DR Pfam; PF13426; PAS_9; 1. DR PRINTS; PR01463; EAGCHANLFMLY. DR PRINTS; PR01464; EAGCHANNEL. DR SMART; SM00100; cNMP; 1. DR SMART; SM00086; PAC; 1. DR SUPFAM; SSF51206; cAMP-binding domain-like; 1. DR SUPFAM; SSF55785; PYP-like sensor domain (PAS domain); 1. DR SUPFAM; SSF81324; Voltage-gated potassium channels; 1. DR PROSITE; PS50042; CNMP_BINDING_3; 1. DR PROSITE; PS50113; PAC; 1. DR PROSITE; PS50112; PAS; 1. DR Genevisible; O95259; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Calmodulin-binding; Cell membrane; KW Cell projection; Disease variant; Endosome; Epilepsy; Glycoprotein; KW Intellectual disability; Ion channel; Ion transport; Lipid-binding; KW Membrane; Nucleus; Phosphoprotein; Postsynaptic cell membrane; Potassium; KW Potassium channel; Potassium transport; Reference proteome; Synapse; KW Transmembrane; Transmembrane helix; Transport; Voltage-gated channel. FT CHAIN 1..989 FT /note="Potassium voltage-gated channel subfamily H member FT 1" FT /id="PRO_0000053994" FT TOPO_DOM 1..220 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:Q63472" FT TRANSMEM 221..241 FT /note="Helical; Name=Segment S1" FT /evidence="ECO:0000250|UniProtKB:Q63472" FT TOPO_DOM 242..248 FT /note="Extracellular" FT /evidence="ECO:0000250|UniProtKB:Q63472" FT TRANSMEM 249..269 FT /note="Helical; Name=Segment S2" FT /evidence="ECO:0000250|UniProtKB:Q63472" FT TOPO_DOM 270..290 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:Q63472" FT TRANSMEM 291..309 FT /note="Helical; Name=Segment S3" FT /evidence="ECO:0000250|UniProtKB:Q63472" FT TOPO_DOM 310..345 FT /note="Extracellular" FT /evidence="ECO:0000250|UniProtKB:Q63472" FT TRANSMEM 346..368 FT /note="Helical; Voltage-sensor; Name=Segment S4" FT /evidence="ECO:0000250|UniProtKB:Q63472" FT TOPO_DOM 369..377 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:Q63472" FT TRANSMEM 378..399 FT /note="Helical; Name=Segment S5" FT /evidence="ECO:0000250|UniProtKB:Q63472" FT TOPO_DOM 400..448 FT /note="Extracellular" FT /evidence="ECO:0000250|UniProtKB:Q63472" FT INTRAMEM 449..470 FT /note="Pore-forming; Name=Segment H5" FT /evidence="ECO:0000250|UniProtKB:Q63472" FT TOPO_DOM 471..477 FT /note="Extracellular" FT /evidence="ECO:0000250|UniProtKB:Q63472" FT TRANSMEM 478..498 FT /note="Helical; Name=Segment S6" FT /evidence="ECO:0000250|UniProtKB:Q63472" FT TOPO_DOM 499..989 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:Q63472" FT DOMAIN 14..94 FT /note="PAS" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00140" FT DOMAIN 93..145 FT /note="PAC" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00141" FT REGION 151..162 FT /note="Required for phosphatidylinositol bisphosphate FT binding" FT /evidence="ECO:0000269|PubMed:27005320" FT REGION 673..770 FT /note="Calmodulin-binding" FT /evidence="ECO:0000269|PubMed:10880439" FT REGION 699..701 FT /note="Interaction with cyclic nucleotide-binding pocket" FT /evidence="ECO:0000250|UniProtKB:Q60603" FT REGION 855..886 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 924..964 FT /note="CAD (involved in subunit assembly)" FT /evidence="ECO:0000250|UniProtKB:Q63472" FT REGION 962..989 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 463..468 FT /note="Selectivity filter" FT /evidence="ECO:0000250|UniProtKB:Q63472" FT COMPBIAS 855..874 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 974 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q60603" FT MOD_RES 978 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q60603" FT MOD_RES 981 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q60603" FT CARBOHYD 415 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 433 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT VAR_SEQ 318..344 FT /note="Missing (in isoform 1)" FT /evidence="ECO:0000303|PubMed:10523298, FT ECO:0000303|PubMed:15489334" FT /id="VSP_000964" FT VARIANT 217 FT /note="K -> N (in TMBTS; gain-of-function mutation FT resulting in a decreased threshold of channel activation FT and slower deactivation compared to wild-type; FT dbSNP:rs727502822)" FT /evidence="ECO:0000269|PubMed:25420144" FT /id="VAR_072612" FT VARIANT 352 FT /note="S -> Y (in ZLS1; gain-of-function effect; FT accelerated channel activation and slower deactivation; FT associated in cis with L-383; dbSNP:rs730882172)" FT /evidence="ECO:0000269|PubMed:25915598" FT /id="VAR_073957" FT VARIANT 375 FT /note="G -> R (in ZLS1; gain-of-function effect; FT accelerated channel activation and slower deactivation; FT dbSNP:rs730882174)" FT /evidence="ECO:0000269|PubMed:25915598" FT /id="VAR_073958" FT VARIANT 379 FT /note="L -> V (in ZLS1; dbSNP:rs730882176)" FT /evidence="ECO:0000269|PubMed:25915598" FT /id="VAR_073959" FT VARIANT 383 FT /note="V -> L (in ZLS1; gain-of-function effect; FT accelerated channel activation and slower deactivation; FT associated in cis with Y-352; dbSNP:rs730882173)" FT /evidence="ECO:0000269|PubMed:25915598" FT /id="VAR_073960" FT VARIANT 489 FT /note="L -> F (in TMBTS; gain-of-function mutation FT resulting in a decreased threshold of channel activation FT and slower deactivation compared to wild-type; FT dbSNP:rs1553345948)" FT /evidence="ECO:0000269|PubMed:25420144" FT /id="VAR_072613" FT VARIANT 494 FT /note="I -> V (in TMBTS and ZLS1; gain-of-function effect; FT resulting in a decreased threshold of channel activation FT and slower deactivation; dbSNP:rs727502819)" FT /evidence="ECO:0000269|PubMed:25420144, FT ECO:0000269|PubMed:25915598" FT /id="VAR_072614" FT VARIANT 496 FT /note="G -> R (in ZLS1; gain-of-function effect; increased FT conductance at negative potentials; dbSNP:rs730882175)" FT /evidence="ECO:0000269|PubMed:25915598" FT /id="VAR_073961" FT VARIANT 503 FT /note="Q -> R (in TMBTS; gain-of-function mutation FT resulting in a decreased threshold of channel activation FT and slower deactivation compared to wild-type; FT dbSNP:rs727502821)" FT /evidence="ECO:0000269|PubMed:25420144" FT /id="VAR_072615" FT MUTAGEN 699..701 FT /note="YNL->ANA: Shifts the voltage-dependence of channel FT gating and decreases the rate of channel opening." FT /evidence="ECO:0000269|PubMed:22732247" FT MUTAGEN 737 FT /note="V->S: Abolishes inhibition of channel activity by FT elevated cytoplasmic Ca(2+)." FT /evidence="ECO:0000269|PubMed:27618660" FT MUTAGEN 740 FT /note="L->S: Abolishes inhibition of channel activity by FT elevated cytoplasmic Ca(2+)." FT /evidence="ECO:0000269|PubMed:27618660" FT STRAND 29..34 FT /evidence="ECO:0007829|PDB:5J7E" FT STRAND 41..45 FT /evidence="ECO:0007829|PDB:5J7E" FT HELIX 47..53 FT /evidence="ECO:0007829|PDB:5J7E" FT HELIX 57..59 FT /evidence="ECO:0007829|PDB:5J7E" FT TURN 60..62 FT /evidence="ECO:0007829|PDB:5J7E" FT HELIX 68..70 FT /evidence="ECO:0007829|PDB:5J7E" FT HELIX 77..88 FT /evidence="ECO:0007829|PDB:5J7E" FT STRAND 93..100 FT /evidence="ECO:0007829|PDB:5J7E" FT STRAND 106..117 FT /evidence="ECO:0007829|PDB:5J7E" FT STRAND 123..132 FT /evidence="ECO:0007829|PDB:5J7E" SQ SEQUENCE 989 AA; 111423 MW; CAA8CB251300C7E5 CRC64; MTMAGGRRGL VAPQNTFLEN IVRRSNDTNF VLGNAQIVDW PIVYSNDGFC KLSGYHRAEV MQKSSTCSFM YGELTDKDTI EKVRQTFENY EMNSFEILMY KKNRTPVWFF VKIAPIRNEQ DKVVLFLCTF SDITAFKQPI EDDSCKGWGK FARLTRALTS SRGVLQQLAP SVQKGENVHK HSRLAEVLQL GSDILPQYKQ EAPKTPPHII LHYCVFKTTW DWIILILTFY TAILVPYNVS FKTRQNNVAW LVVDSIVDVI FLVDIVLNFH TTFVGPAGEV ISDPKLIRMN YLKTWFVIDL LSCLPYDVIN AFENVDEVSA FMGDPGKIGF ADQIPPPLEG RESQGISSLF SSLKVVRLLR LGRVARKLDH YIEYGAAVLV LLVCVFGLAA HWMACIWYSI GDYEIFDEDT KTIRNNSWLY QLAMDIGTPY QFNGSGSGKW EGGPSKNSVY ISSLYFTMTS LTSVGFGNIA PSTDIEKIFA VAIMMIGSLL YATIFGNVTT IFQQMYANTN RYHEMLNSVR DFLKLYQVPK GLSERVMDYI VSTWSMSRGI DTEKVLQICP KDMRADICVH LNRKVFKEHP AFRLASDGCL RALAMEFQTV HCAPGDLIYH AGESVDSLCF VVSGSLEVIQ DDEVVAILGK GDVFGDVFWK EATLAQSCAN VRALTYCDLH VIKRDALQKV LEFYTAFSHS FSRNLILTYN LRKRIVFRKI SDVKREEEER MKRKNEAPLI LPPDHPVRRL FQRFRQQKEA RLAAERGGRD LDDLDVEKGN VLTEHASANH SLVKASVVTV RESPATPVSF QAASTSGVPD HAKLQAPGSE CLGPKGGGGD CAKRKSWARF KDACGKSEDW NKVSKAESME TLPERTKASG EATLKKTDSC DSGITKSDLR LDNVGEARSP QDRSPILAEV KHSFYPIPEQ TLQATVLEVR HELKEDIKAL NAKMTNIEKQ LSEILRILTS RRSSQSPQEL FEISRPQSPE SERDIFGAS //