KCNH1_HUMAN
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 03-AUG-2022, entry version 204.
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},
GN EAG1 {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) (TC
CC 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="http://atlasgeneticsoncology.org/Genes/KCNH1ID41048ch1q32.html";
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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; 11.
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.I.1.1.3; the nuclear pore complex (npc) family.
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; O95259; -.
DR PeptideAtlas; O95259; -.
DR PRIDE; O95259; -.
DR ProteomicsDB; 50755; -. [O95259-1]
DR ProteomicsDB; 50756; -. [O95259-2]
DR Antibodypedia; 20707; 224 antibodies from 28 providers.
DR DNASU; 3756; -.
DR Ensembl; ENST00000271751.10; ENSP00000271751.4; ENSG00000143473.13. [O95259-1]
DR Ensembl; ENST00000638960.1; ENSP00000492302.1; ENSG00000143473.13. [O95259-2]
DR Ensembl; ENST00000639952.1; ENSP00000492697.1; ENSG00000143473.13. [O95259-2]
DR Ensembl; ENST00000640528.1; ENSP00000491725.1; ENSG00000143473.13. [O95259-2]
DR Ensembl; ENST00000640710.1; ENSP00000492513.1; ENSG00000143473.13. [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 CTD; 3756; -.
DR DisGeNET; 3756; -.
DR GeneCards; KCNH1; -.
DR HGNC; HGNC:6250; KCNH1.
DR HPA; ENSG00000143473; Group enriched (brain, choroid plexus).
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; 464006at2759; -.
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 1071 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 103 other tissues.
DR ExpressionAtlas; O95259; baseline and differential.
DR Genevisible; O95259; HS.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-KW.
DR GO; GO:0030673; C:axolemma; IEA:Ensembl.
DR GO; GO:0009986; C:cell surface; IEA:Ensembl.
DR GO; GO:0030425; C:dendrite; IEA:UniProtKB-SubCell.
DR GO; GO:0031901; C:early endosome membrane; IDA:UniProtKB.
DR GO; GO:0005887; C:integral component of plasma membrane; IDA:UniProtKB.
DR GO; GO:0099056; C:integral component of presynaptic membrane; IEA:Ensembl.
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:0048471; C:perinuclear region of cytoplasm; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0098839; C:postsynaptic density membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0008076; C:voltage-gated potassium channel complex; IDA:UniProtKB.
DR GO; GO:0071889; F:14-3-3 protein binding; IEA:Ensembl.
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:0042802; F:identical protein binding; IEA:Ensembl.
DR GO; GO:1902936; F:phosphatidylinositol bisphosphate binding; IDA:UniProtKB.
DR GO; GO:0019901; F:protein kinase binding; IEA:Ensembl.
DR GO; GO:0044877; F:protein-containing complex binding; IEA:Ensembl.
DR GO; GO:0044325; F:transmembrane transporter binding; IEA:Ensembl.
DR GO; GO:0005249; F:voltage-gated potassium channel activity; IBA:GO_Central.
DR GO; GO:0071277; P:cellular response to calcium ion; IMP:UniProtKB.
DR GO; GO:0007520; P:myoblast fusion; TAS:ProtInc.
DR GO; GO:0048015; P:phosphatidylinositol-mediated signaling; IMP:UniProtKB.
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:0034765; P:regulation of ion transmembrane transport; IEA:UniProtKB-KW.
DR GO; GO:0042391; P:regulation of membrane potential; IBA:GO_Central.
DR GO; GO:0001964; P:startle response; IEA:Ensembl.
DR CDD; cd00038; CAP_ED; 1.
DR CDD; cd00130; PAS; 1.
DR Gene3D; 2.60.120.10; -; 1.
DR InterPro; IPR018490; cNMP-bd-like.
DR InterPro; IPR000595; cNMP-bd_dom.
DR InterPro; IPR030170; EAG1.
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 PANTHER; PTHR10217:SF530; PTHR10217:SF530; 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; SSF51206; 1.
DR SUPFAM; SSF55785; SSF55785; 1.
DR TIGRFAMs; TIGR00229; sensory_box; 1.
DR PROSITE; PS50042; CNMP_BINDING_3; 1.
DR PROSITE; PS50113; PAC; 1.
DR PROSITE; PS50112; PAS; 1.
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
