HCN1_HUMAN
ID HCN1_HUMAN Reviewed; 890 AA.
AC O60741;
DT 28-FEB-2003, integrated into UniProtKB/Swiss-Prot.
DT 05-MAY-2009, sequence version 3.
DT 03-AUG-2022, entry version 174.
DE RecName: Full=Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1;
DE AltName: Full=Brain cyclic nucleotide-gated channel 1;
DE Short=BCNG-1;
GN Name=HCN1; Synonyms=BCNG1;
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 [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M.,
RA Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A.,
RA Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R.,
RA Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L.,
RA Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N.,
RA Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J.,
RA Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A.,
RA Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 122-862, AND TISSUE SPECIFICITY.
RC TISSUE=Brain;
RX PubMed=9630217; DOI=10.1016/s0092-8674(00)81434-8;
RA Santoro B., Liu D.T., Yao H., Bartsch D., Kandel E.R., Siegelbaum S.A.,
RA Tibbs G.R.;
RT "Identification of a gene encoding a hyperpolarization-activated
RT 'pacemaker' channel of brain.";
RL Cell 93:717-729(1998).
RN [3]
RP FUNCTION, SUBCELLULAR LOCATION, AND ACTIVITY REGULATION.
RX PubMed=15351778; DOI=10.1038/sj.bjp.0705945;
RA Gill C.H., Randall A., Bates S.A., Hill K., Owen D., Larkman P.M.,
RA Cairns W., Yusaf S.P., Murdock P.R., Strijbos P.J., Powell A.J.,
RA Benham C.D., Davies C.H.;
RT "Characterization of the human HCN1 channel and its inhibition by
RT capsazepine.";
RL Br. J. Pharmacol. 143:411-421(2004).
RN [4] {ECO:0007744|PDB:5U6O, ECO:0007744|PDB:5U6P}
RP STRUCTURE BY ELECTRON MICROSCOPY (3.50 ANGSTROMS) OF APOPROTEIN AND IN
RP COMPLEX WITH CAMP, FUNCTION, SUBCELLULAR LOCATION, TOPOLOGY, SUBUNIT, AND
RP ACTIVITY REGULATION.
RX PubMed=28086084; DOI=10.1016/j.cell.2016.12.023;
RA Lee C.H., MacKinnon R.;
RT "Structures of the human HCN1 hyperpolarization-activated channel.";
RL Cell 168:111-120(2017).
RN [5]
RP INVOLVEMENT IN DEE24, VARIANTS DEE24 VAL-47; PHE-100; PRO-272; TYR-279;
RP THR-297 AND HIS-401, AND CHARACTERIZATION OF VARIANTS DEE24 PHE-100;
RP PRO-272; TYR-279; THR-297 AND HIS-401.
RX PubMed=24747641; DOI=10.1038/ng.2952;
RG EuroEPINOMICS RES Consortium;
RA Nava C., Dalle C., Rastetter A., Striano P., de Kovel C.G., Nabbout R.,
RA Cances C., Ville D., Brilstra E.H., Gobbi G., Raffo E., Bouteiller D.,
RA Marie Y., Trouillard O., Robbiano A., Keren B., Agher D., Roze E.,
RA Lesage S., Nicolas A., Brice A., Baulac M., Vogt C., El Hajj N.,
RA Schneider E., Suls A., Weckhuysen S., Gormley P., Lehesjoki A.E.,
RA De Jonghe P., Helbig I., Baulac S., Zara F., Koeleman B.P., Haaf T.,
RA LeGuern E., Depienne C.;
RT "De novo mutations in HCN1 cause early infantile epileptic
RT encephalopathy.";
RL Nat. Genet. 46:640-645(2014).
RN [6]
RP VARIANTS DEE24 ILE-153 AND ASP-391.
RX PubMed=27864847; DOI=10.1002/humu.23149;
RG Clinical Study Group;
RA Parrini E., Marini C., Mei D., Galuppi A., Cellini E., Pucatti D.,
RA Chiti L., Rutigliano D., Bianchini C., Virdo S., De Vita D., Bigoni S.,
RA Barba C., Mari F., Montomoli M., Pisano T., Rosati A., Guerrini R.;
RT "Diagnostic targeted resequencing in 349 patients with drug-resistant
RT pediatric epilepsies identifies causative mutations in 30 different
RT genes.";
RL Hum. Mutat. 38:216-225(2017).
RN [7]
RP VARIANTS GEFSP10 ALA-85; ARG-171; PRO-172; ARG-243; ILE-260; SER-329;
RP CYS-391; SER-391; MET-414; GLN-590; TYR-680 AND GLY-715, VARIANTS DEE24
RP TYR-143; ILE-153; GLU-261; LEU-305; ASP-391; LEU-397 AND PRO-399,
RP CHARACTERIZATION OF VARIANTS DEE24 ILE-153; LEU-305; ASP-391; LEU-397 AND
RP PRO-399, CHARACTERIZATION OF VARIANTS GEFSP10 ARG-243; SER-329; CYS-391;
RP SER-391; MET-414 AND GLN-590, VARIANTS CYS-264; THR-275 AND ARG-379,
RP INVOLVEMENT IN DEE24, INVOLVEMENT IN GEFSP10, SUBCELLULAR LOCATION, AND
RP FUNCTION.
RX PubMed=30351409; DOI=10.1093/brain/awy263;
RA Marini C., Porro A., Rastetter A., Dalle C., Rivolta I., Bauer D.,
RA Oegema R., Nava C., Parrini E., Mei D., Mercer C., Dhamija R., Chambers C.,
RA Coubes C., Thevenon J., Kuentz P., Julia S., Pasquier L., Dubourg C.,
RA Carre W., Rosati A., Melani F., Pisano T., Giardino M., Innes A.M.,
RA Alembik Y., Scheidecker S., Santos M., Figueiroa S., Garrido C., Fusco C.,
RA Frattini D., Spagnoli C., Binda A., Granata T., Ragona F., Freri E.,
RA Franceschetti S., Canafoglia L., Castellotti B., Gellera C., Milanesi R.,
RA Mancardi M.M., Clark D.R., Kok F., Helbig K.L., Ichikawa S., Sadler L.,
RA Neupauerova J., Lassuthova P., Sterbova K., Laridon A., Brilstra E.,
RA Koeleman B., Lemke J.R., Zara F., Striano P., Soblet J., Smits G.,
RA Deconinck N., Barbuti A., DiFrancesco D., LeGuern E., Guerrini R.,
RA Santoro B., Hamacher K., Thiel G., Moroni A., DiFrancesco J.C.,
RA Depienne C.;
RT "HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign
RT generalized epilepsy and beyond.";
RL Brain 141:3160-3178(2018).
RN [8]
RP VARIANT GEFSP10 VAL-157, CHARACTERIZATION OF VARIANT GEFSP10 VAL-157,
RP INVOLVEMENT IN GEFSP10, AND FUNCTION.
RX PubMed=29936235; DOI=10.1016/j.nbd.2018.06.012;
RA Bonzanni M., DiFrancesco J.C., Milanesi R., Campostrini G., Castellotti B.,
RA Bucchi A., Baruscotti M., Ferrarese C., Franceschetti S., Canafoglia L.,
RA Ragona F., Freri E., Labate A., Gambardella A., Costa C., Rivolta I.,
RA Gellera C., Granata T., Barbuti A., DiFrancesco D.;
RT "A novel de novo HCN1 loss-of-function mutation in genetic generalized
RT epilepsy causing increased neuronal excitability.";
RL Neurobiol. Dis. 118:55-63(2018).
RN [9]
RP VARIANTS 72-GLY--GLY-74 DEL AND ALA-851, AND CHARACTERIZATION OF VARIANT
RP ALA-851.
RX PubMed=34621433; DOI=10.1002/joa3.12598;
RA Yu H., Gall B., Newman M., Hathaway Q., Brundage K., Ammer A., Mathers P.,
RA Siderovski D., Hull R.W.;
RT "Contribution of HCN1 variant to sinus bradycardia: A case report.";
RL J. Arrhythm. 37:1337-1347(2021).
CC -!- FUNCTION: Hyperpolarization-activated ion channel exhibiting weak
CC selectivity for potassium over sodium ions (PubMed:28086084).
CC Contributes to the native pacemaker currents in heart (If) and in
CC neurons (Ih). May mediate responses to sour stimuli.
CC {ECO:0000269|PubMed:15351778, ECO:0000269|PubMed:28086084,
CC ECO:0000269|PubMed:29936235, ECO:0000269|PubMed:30351409}.
CC -!- ACTIVITY REGULATION: Activated by cAMP, and at 10-100 times higher
CC concentrations, also by cGMP. cAMP binding promotes tetramerization and
CC formation of an active channel. Compared to other family members, cAMP
CC has less stimulatory effect on HCN1 because part of the molecules
CC already contain bound cAMP and form homotetramers when cAMP levels are
CC low. Inhibited by Cs(1+), zatebradine, capsazepine and ZD7288.
CC {ECO:0000269|PubMed:15351778, ECO:0000269|PubMed:28086084}.
CC -!- SUBUNIT: Homotetramer (PubMed:28086084). Heterotetramer with HCN2. The
CC potassium channel is composed of a homo- or heterotetrameric complex of
CC pore-forming subunits. Interacts with KCNE2. Interacts with the SH3
CC domain of CSK (By similarity). {ECO:0000250|UniProtKB:O88704,
CC ECO:0000269|PubMed:28086084}.
CC -!- INTERACTION:
CC O60741; Q4ACU6-1: Shank3; Xeno; NbExp=4; IntAct=EBI-11173743, EBI-16201983;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:15351778,
CC ECO:0000269|PubMed:28086084, ECO:0000269|PubMed:30351409}; Multi-pass
CC membrane protein {ECO:0000269|PubMed:15351778,
CC ECO:0000269|PubMed:28086084, ECO:0000269|PubMed:30351409}.
CC -!- TISSUE SPECIFICITY: Detected in brain, in particular in amygdala and
CC hippocampus, while expression in caudate nucleus, corpus callosum,
CC substantia nigra, subthalamic nucleus and thalamus is very low or not
CC detectable. Detected at very low levels in muscle and pancreas.
CC {ECO:0000269|PubMed:9630217}.
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:0000305|PubMed:28086084}.
CC -!- DISEASE: Developmental and epileptic encephalopathy 24 (DEE24)
CC [MIM:615871]: A disease characterized by early-onset seizures,
CC intellectual disability of varying degrees, and behavioral disturbances
CC or autistic features in most individuals. {ECO:0000269|PubMed:24747641,
CC ECO:0000269|PubMed:27864847, ECO:0000269|PubMed:30351409}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Generalized epilepsy with febrile seizures plus 10 (GEFSP10)
CC [MIM:618482]: An autosomal dominant neurologic disorder with incomplete
CC penetrance, characterized by variable types of seizures including
CC absence, tonic-clonic, febrile, focal, and eyelid myoclonia. Some
CC patients have normal neurologic development. Others have mild-to-
CC moderate intellectual disability or autism spectrum disorder.
CC {ECO:0000269|PubMed:29936235, ECO:0000269|PubMed:30351409}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the potassium channel HCN family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAC39759.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305};
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DR EMBL; AC099514; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC114975; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC117529; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC138520; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AF064876; AAC39759.1; ALT_SEQ; mRNA.
DR CCDS; CCDS3952.1; -.
DR RefSeq; NP_066550.2; NM_021072.3.
DR PDB; 5U6O; EM; 3.50 A; A/B/C/D=1-890.
DR PDB; 5U6P; EM; 3.51 A; A/B/C/D=1-890.
DR PDB; 6UQF; EM; 3.04 A; A/B/C/D=1-890.
DR PDB; 6UQG; EM; 3.54 A; A/B/C/D=1-890.
DR PDBsum; 5U6O; -.
DR PDBsum; 5U6P; -.
DR PDBsum; 6UQF; -.
DR PDBsum; 6UQG; -.
DR AlphaFoldDB; O60741; -.
DR SMR; O60741; -.
DR BioGRID; 131543; 63.
DR ComplexPortal; CPX-261; HCN1 channel complex.
DR DIP; DIP-62038N; -.
DR IntAct; O60741; 1.
DR STRING; 9606.ENSP00000307342; -.
DR BindingDB; O60741; -.
DR ChEMBL; CHEMBL1795171; -.
DR DrugCentral; O60741; -.
DR GuidetoPHARMACOLOGY; 400; -.
DR TCDB; 1.A.1.5.32; the voltage-gated ion channel (vic) superfamily.
DR GlyGen; O60741; 4 sites, 1 O-linked glycan (3 sites).
DR iPTMnet; O60741; -.
DR PhosphoSitePlus; O60741; -.
DR BioMuta; HCN1; -.
DR jPOST; O60741; -.
DR MassIVE; O60741; -.
DR MaxQB; O60741; -.
DR PaxDb; O60741; -.
DR PeptideAtlas; O60741; -.
DR PRIDE; O60741; -.
DR ProteomicsDB; 49583; -.
DR Antibodypedia; 23274; 376 antibodies from 33 providers.
DR DNASU; 348980; -.
DR Ensembl; ENST00000303230.6; ENSP00000307342.4; ENSG00000164588.8.
DR GeneID; 348980; -.
DR KEGG; hsa:348980; -.
DR MANE-Select; ENST00000303230.6; ENSP00000307342.4; NM_021072.4; NP_066550.2.
DR UCSC; uc003jok.4; human.
DR CTD; 348980; -.
DR DisGeNET; 348980; -.
DR GeneCards; HCN1; -.
DR HGNC; HGNC:4845; HCN1.
DR HPA; ENSG00000164588; Group enriched (brain, retina).
DR MalaCards; HCN1; -.
DR MIM; 602780; gene.
DR MIM; 615871; phenotype.
DR MIM; 618482; phenotype.
DR neXtProt; NX_O60741; -.
DR OpenTargets; ENSG00000164588; -.
DR Orphanet; 36387; Generalized epilepsy with febrile seizures-plus.
DR Orphanet; 442835; Non-specific early-onset epileptic encephalopathy.
DR PharmGKB; PA77; -.
DR VEuPathDB; HostDB:ENSG00000164588; -.
DR eggNOG; KOG0498; Eukaryota.
DR GeneTree; ENSGT00940000158207; -.
DR HOGENOM; CLU_005746_15_1_1; -.
DR InParanoid; O60741; -.
DR OMA; KMVNVSW; -.
DR OrthoDB; 281394at2759; -.
DR PhylomeDB; O60741; -.
DR TreeFam; TF318250; -.
DR PathwayCommons; O60741; -.
DR Reactome; R-HSA-1296061; HCN channels.
DR SignaLink; O60741; -.
DR BioGRID-ORCS; 348980; 15 hits in 1061 CRISPR screens.
DR ChiTaRS; HCN1; human.
DR GeneWiki; HCN1; -.
DR GenomeRNAi; 348980; -.
DR Pharos; O60741; Tclin.
DR PRO; PR:O60741; -.
DR Proteomes; UP000005640; Chromosome 5.
DR RNAct; O60741; protein.
DR Bgee; ENSG00000164588; Expressed in endothelial cell and 114 other tissues.
DR ExpressionAtlas; O60741; baseline and differential.
DR Genevisible; O60741; HS.
DR GO; GO:0030424; C:axon; IBA:GO_Central.
DR GO; GO:0030425; C:dendrite; IBA:GO_Central.
DR GO; GO:0098855; C:HCN channel complex; IDA:UniProtKB.
DR GO; GO:0005887; C:integral component of plasma membrane; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0030552; F:cAMP binding; IDA:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; IEA:Ensembl.
DR GO; GO:0005222; F:intracellular cAMP-activated cation channel activity; ISS:UniProtKB.
DR GO; GO:0005267; F:potassium channel activity; NAS:UniProtKB.
DR GO; GO:0022843; F:voltage-gated cation channel activity; IDA:UniProtKB.
DR GO; GO:0005249; F:voltage-gated potassium channel activity; IMP:UniProtKB.
DR GO; GO:0005248; F:voltage-gated sodium channel activity; IMP:UniProtKB.
DR GO; GO:0045176; P:apical protein localization; IEA:Ensembl.
DR GO; GO:0071320; P:cellular response to cAMP; IDA:UniProtKB.
DR GO; GO:0051967; P:negative regulation of synaptic transmission, glutamatergic; IEA:Ensembl.
DR GO; GO:0071805; P:potassium ion transmembrane transport; IMP:UniProtKB.
DR GO; GO:0051289; P:protein homotetramerization; IDA:UniProtKB.
DR GO; GO:2001257; P:regulation of cation channel activity; IC:ComplexPortal.
DR GO; GO:0086091; P:regulation of heart rate by cardiac conduction; IC:ComplexPortal.
DR GO; GO:0003254; P:regulation of membrane depolarization; IDA:ComplexPortal.
DR GO; GO:0042391; P:regulation of membrane potential; IMP:UniProtKB.
DR GO; GO:0098907; P:regulation of SA node cell action potential; IC:ComplexPortal.
DR GO; GO:0046549; P:retinal cone cell development; IEA:Ensembl.
DR GO; GO:0035725; P:sodium ion transmembrane transport; IMP:UniProtKB.
DR CDD; cd00038; CAP_ED; 1.
DR DisProt; DP01317; -.
DR Gene3D; 2.60.120.10; -; 1.
DR InterPro; IPR018490; cNMP-bd-like.
DR InterPro; IPR018488; cNMP-bd_CS.
DR InterPro; IPR000595; cNMP-bd_dom.
DR InterPro; IPR005821; Ion_trans_dom.
DR InterPro; IPR013621; Ion_trans_N.
DR InterPro; IPR030169; K/Na_HCN1.
DR InterPro; IPR003938; K_chnl_volt-dep_EAG/ELK/ERG.
DR InterPro; IPR014710; RmlC-like_jellyroll.
DR PANTHER; PTHR45689:SF3; PTHR45689:SF3; 1.
DR Pfam; PF00027; cNMP_binding; 1.
DR Pfam; PF00520; Ion_trans; 1.
DR Pfam; PF08412; Ion_trans_N; 1.
DR PRINTS; PR01463; EAGCHANLFMLY.
DR SMART; SM00100; cNMP; 1.
DR SUPFAM; SSF51206; SSF51206; 1.
DR PROSITE; PS00888; CNMP_BINDING_1; 1.
DR PROSITE; PS50042; CNMP_BINDING_3; 1.
PE 1: Evidence at protein level;
KW 3D-structure; cAMP; cAMP-binding; Cell membrane; Disease variant; Epilepsy;
KW Glycoprotein; Ion channel; Ion transport; Ligand-gated ion channel;
KW Membrane; Nucleotide-binding; Potassium; Potassium channel;
KW Potassium transport; Reference proteome; Sodium; Sodium channel;
KW Sodium transport; Transmembrane; Transmembrane helix; Transport;
KW Voltage-gated channel.
FT CHAIN 1..890
FT /note="Potassium/sodium hyperpolarization-activated cyclic
FT nucleotide-gated channel 1"
FT /id="PRO_0000054107"
FT TOPO_DOM 1..142
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:28086084"
FT TRANSMEM 143..164
FT /note="Helical; Name=Segment S1"
FT /evidence="ECO:0000269|PubMed:28086084"
FT TOPO_DOM 165..173
FT /note="Extracellular"
FT /evidence="ECO:0000269|PubMed:28086084"
FT TRANSMEM 174..194
FT /note="Helical; Name=Segment S2"
FT /evidence="ECO:0000269|PubMed:28086084"
FT TOPO_DOM 195..215
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:28086084"
FT TRANSMEM 216..236
FT /note="Helical; Name=Segment S3"
FT /evidence="ECO:0000269|PubMed:28086084"
FT TOPO_DOM 237..260
FT /note="Extracellular"
FT /evidence="ECO:0000269|PubMed:28086084"
FT TRANSMEM 261..281
FT /note="Helical; Voltage-sensor; Name=Segment S4"
FT /evidence="ECO:0000269|PubMed:28086084"
FT TOPO_DOM 282..295
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:28086084"
FT TRANSMEM 296..318
FT /note="Helical; Name=Segment S5"
FT /evidence="ECO:0000269|PubMed:28086084"
FT TOPO_DOM 319..344
FT /note="Extracellular"
FT /evidence="ECO:0000269|PubMed:28086084"
FT INTRAMEM 345..366
FT /note="Pore-forming; Name=Segment H5"
FT /evidence="ECO:0000269|PubMed:28086084"
FT TOPO_DOM 367..371
FT /note="Extracellular"
FT /evidence="ECO:0000269|PubMed:28086084"
FT TRANSMEM 372..392
FT /note="Helical; Name=Segment S6"
FT /evidence="ECO:0000269|PubMed:28086084"
FT TOPO_DOM 393..890
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:28086084"
FT REGION 1..93
FT /note="Disordered"
FT /evidence="ECO:0000305|PubMed:28086084"
FT REGION 644..692
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 725..796
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 845..890
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 358..362
FT /note="Selectivity filter"
FT /evidence="ECO:0000305|PubMed:28086084"
FT COMPBIAS 1..19
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 725..745
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 759..796
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 853..867
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 539..542
FT /ligand="3',5'-cyclic AMP"
FT /ligand_id="ChEBI:CHEBI:58165"
FT /evidence="ECO:0000305|PubMed:28086084,
FT ECO:0007744|PDB:5U6P"
FT BINDING 549..550
FT /ligand="3',5'-cyclic AMP"
FT /ligand_id="ChEBI:CHEBI:58165"
FT /evidence="ECO:0000305|PubMed:28086084,
FT ECO:0007744|PDB:5U6P"
FT BINDING 590..593
FT /ligand="3',5'-cyclic AMP"
FT /ligand_id="ChEBI:CHEBI:58165"
FT /evidence="ECO:0000250|UniProtKB:O88704"
FT CARBOHYD 338
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VARIANT 42
FT /note="P -> S (in dbSNP:rs56164833)"
FT /id="VAR_061105"
FT VARIANT 47
FT /note="G -> V (in DEE24; likely benign variant;
FT dbSNP:rs544994462)"
FT /evidence="ECO:0000269|PubMed:24747641"
FT /id="VAR_071825"
FT VARIANT 72..74
FT /note="Missing"
FT /evidence="ECO:0000269|PubMed:34621433"
FT /id="VAR_085692"
FT VARIANT 85
FT /note="E -> A (in GEFSP10; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:30351409"
FT /id="VAR_082653"
FT VARIANT 100
FT /note="S -> F (in DEE24; dominant-negative mutation
FT resulting in gain of channel function; dbSNP:rs587777492)"
FT /evidence="ECO:0000269|PubMed:24747641"
FT /id="VAR_071826"
FT VARIANT 143
FT /note="F -> Y (in DEE24; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:30351409"
FT /id="VAR_082654"
FT VARIANT 153
FT /note="M -> I (in DEE24; affects channel gating properties;
FT the half-activation voltage is shifted to the depolarizing
FT direction; significantly faster activation and slower
FT deactivation kinetics than wild-type channel;
FT dbSNP:rs1057519548)"
FT /evidence="ECO:0000269|PubMed:27864847,
FT ECO:0000269|PubMed:30351409"
FT /id="VAR_078216"
FT VARIANT 157
FT /note="L -> V (in GEFSP10; unknown pathological
FT significance; reduced current density; affects channel
FT gating properties as the half-activation voltage is shifted
FT to the depolarizing direction; neurons expressing mutant
FT channels show increased excitability; dbSNP:rs1561230606)"
FT /evidence="ECO:0000269|PubMed:29936235"
FT /id="VAR_082655"
FT VARIANT 171
FT /note="T -> R (in GEFSP10; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:30351409"
FT /id="VAR_082656"
FT VARIANT 172
FT /note="T -> P (in GEFSP10; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:30351409"
FT /id="VAR_082657"
FT VARIANT 243
FT /note="M -> R (in GEFSP10; significantly decreased current
FT densities; dbSNP:rs1561230486)"
FT /evidence="ECO:0000269|PubMed:30351409"
FT /id="VAR_082658"
FT VARIANT 260
FT /note="T -> I (in GEFSP10; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:30351409"
FT /id="VAR_082659"
FT VARIANT 261
FT /note="K -> E (in DEE24; unknown pathological significance;
FT dbSNP:rs1554037378)"
FT /evidence="ECO:0000269|PubMed:30351409"
FT /id="VAR_082660"
FT VARIANT 264
FT /note="S -> C (found in a patient with infantile-onset
FT epilepsy; unknown pathological significance;
FT dbSNP:rs763339068)"
FT /evidence="ECO:0000269|PubMed:30351409"
FT /id="VAR_082661"
FT VARIANT 272
FT /note="S -> P (in DEE24; dominant-negative mutation
FT resulting in loss of channel currents; dbSNP:rs587777493)"
FT /evidence="ECO:0000269|PubMed:24747641"
FT /id="VAR_071827"
FT VARIANT 275
FT /note="I -> T (found in a patient with childhood focal
FT epilepsy; unknown pathological significance)"
FT /evidence="ECO:0000269|PubMed:30351409"
FT /id="VAR_082662"
FT VARIANT 279
FT /note="H -> Y (in DEE24; results in a gain of channel
FT function; dbSNP:rs587777495)"
FT /evidence="ECO:0000269|PubMed:24747641"
FT /id="VAR_071828"
FT VARIANT 297
FT /note="R -> T (in DEE24; dominant-negative mutation
FT resulting in loss of channel currents; dbSNP:rs587777494)"
FT /evidence="ECO:0000269|PubMed:24747641"
FT /id="VAR_071829"
FT VARIANT 305
FT /note="M -> L (in DEE24; absence of hyperpolarization-
FT activated currents; highly reduced amount of protein at the
FT cell membrane; dbSNP:rs1057521989)"
FT /evidence="ECO:0000269|PubMed:30351409"
FT /id="VAR_082663"
FT VARIANT 329
FT /note="C -> S (in GEFSP10; decreased current density;
FT voltage-dependence of activation as well as the activation
FT and deactivation kinetics are not altered;
FT dbSNP:rs1318391259)"
FT /evidence="ECO:0000269|PubMed:30351409"
FT /id="VAR_082664"
FT VARIANT 379
FT /note="M -> R (found in a patient with intellectual
FT disability and language delay; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:30351409"
FT /id="VAR_082665"
FT VARIANT 391
FT /note="G -> C (in GEFSP10; affects channel gating
FT properties as the half-activation voltage is shifted to the
FT hyperpolarizing direction)"
FT /evidence="ECO:0000269|PubMed:30351409"
FT /id="VAR_082666"
FT VARIANT 391
FT /note="G -> D (in DEE24; results in absence of
FT hyperpolarization-activated currents; reduced amount of
FT protein at the cell membrane; dbSNP:rs1057519547)"
FT /evidence="ECO:0000269|PubMed:27864847,
FT ECO:0000269|PubMed:30351409"
FT /id="VAR_078217"
FT VARIANT 391
FT /note="G -> S (in GEFSP10; affects channel gating
FT properties as the half-activation voltage is shifted to the
FT depolarizing direction; reduced amount of protein at the
FT cell membrane; dbSNP:rs1561139569)"
FT /evidence="ECO:0000269|PubMed:30351409"
FT /id="VAR_082667"
FT VARIANT 397
FT /note="I -> L (in DEE24; the half-activation voltage is
FT shifted to the depolarizing direction; reduced amount of
FT protein at the cell membrane)"
FT /evidence="ECO:0000269|PubMed:30351409"
FT /id="VAR_082668"
FT VARIANT 399
FT /note="S -> P (in DEE24; results in absence of
FT hyperpolarization-activated currents; reduced amount of
FT protein at the cell membrane)"
FT /evidence="ECO:0000269|PubMed:30351409"
FT /id="VAR_082669"
FT VARIANT 401
FT /note="D -> H (in DEE24; results in a gain of channel
FT function; dbSNP:rs587777491)"
FT /evidence="ECO:0000269|PubMed:24747641"
FT /id="VAR_071830"
FT VARIANT 414
FT /note="V -> M (in GEFSP10; results in a depolarizing shift
FT of the half-activation voltage and faster activation
FT kinetics; dbSNP:rs1561120793)"
FT /evidence="ECO:0000269|PubMed:30351409"
FT /id="VAR_082670"
FT VARIANT 590
FT /note="R -> Q (in GEFSP10; decreased current densities;
FT half-activation voltage is slightly shifted to the
FT hyperpolarizing direction; dbSNP:rs1561081319)"
FT /evidence="ECO:0000269|PubMed:30351409"
FT /id="VAR_082671"
FT VARIANT 680
FT /note="S -> Y (in GEFSP10; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:30351409"
FT /id="VAR_082672"
FT VARIANT 715
FT /note="R -> G (in GEFSP10; unknown pathological
FT significance; dbSNP:rs1486444621)"
FT /evidence="ECO:0000269|PubMed:30351409"
FT /id="VAR_082673"
FT VARIANT 851
FT /note="P -> A (found in a patient with sinus bradychardia;
FT unknown pathological significance; affects channel
FT properties as it results in a negative shift in the
FT threshold voltage of activation and slower activation
FT kinetics compared to the wild-type)"
FT /evidence="ECO:0000269|PubMed:34621433"
FT /id="VAR_085693"
FT CONFLICT 786
FT /note="L -> F (in Ref. 2; AAC39759)"
FT /evidence="ECO:0000305"
FT CONFLICT 789
FT /note="S -> W (in Ref. 2; AAC39759)"
FT /evidence="ECO:0000305"
FT CONFLICT 841
FT /note="L -> F (in Ref. 2; AAC39759)"
FT /evidence="ECO:0000305"
FT CONFLICT 857
FT /note="P -> L (in Ref. 2; AAC39759)"
FT /evidence="ECO:0000305"
FT CONFLICT 861
FT /note="P -> L (in Ref. 2; AAC39759)"
FT /evidence="ECO:0000305"
FT HELIX 95..102
FT /evidence="ECO:0007829|PDB:6UQF"
FT HELIX 108..114
FT /evidence="ECO:0007829|PDB:6UQF"
FT HELIX 117..128
FT /evidence="ECO:0007829|PDB:6UQF"
FT STRAND 130..133
FT /evidence="ECO:0007829|PDB:5U6O"
FT HELIX 140..166
FT /evidence="ECO:0007829|PDB:6UQF"
FT HELIX 173..192
FT /evidence="ECO:0007829|PDB:6UQF"
FT STRAND 198..200
FT /evidence="ECO:0007829|PDB:6UQF"
FT TURN 201..203
FT /evidence="ECO:0007829|PDB:6UQF"
FT STRAND 204..206
FT /evidence="ECO:0007829|PDB:6UQF"
FT TURN 209..211
FT /evidence="ECO:0007829|PDB:6UQF"
FT HELIX 212..220
FT /evidence="ECO:0007829|PDB:6UQF"
FT HELIX 222..229
FT /evidence="ECO:0007829|PDB:6UQF"
FT HELIX 233..239
FT /evidence="ECO:0007829|PDB:6UQF"
FT HELIX 253..257
FT /evidence="ECO:0007829|PDB:6UQF"
FT HELIX 258..264
FT /evidence="ECO:0007829|PDB:6UQF"
FT HELIX 265..270
FT /evidence="ECO:0007829|PDB:6UQF"
FT HELIX 273..288
FT /evidence="ECO:0007829|PDB:6UQF"
FT HELIX 291..321
FT /evidence="ECO:0007829|PDB:6UQF"
FT TURN 322..324
FT /evidence="ECO:0007829|PDB:6UQF"
FT HELIX 330..334
FT /evidence="ECO:0007829|PDB:6UQF"
FT STRAND 337..339
FT /evidence="ECO:0007829|PDB:6UQF"
FT HELIX 341..356
FT /evidence="ECO:0007829|PDB:6UQF"
FT STRAND 362..364
FT /evidence="ECO:0007829|PDB:6UQF"
FT HELIX 369..400
FT /evidence="ECO:0007829|PDB:6UQF"
FT HELIX 402..420
FT /evidence="ECO:0007829|PDB:6UQF"
FT HELIX 425..439
FT /evidence="ECO:0007829|PDB:6UQF"
FT HELIX 446..452
FT /evidence="ECO:0007829|PDB:6UQF"
FT HELIX 455..465
FT /evidence="ECO:0007829|PDB:6UQF"
FT HELIX 467..472
FT /evidence="ECO:0007829|PDB:6UQF"
FT HELIX 474..478
FT /evidence="ECO:0007829|PDB:6UQF"
FT HELIX 481..490
FT /evidence="ECO:0007829|PDB:6UQF"
FT STRAND 492..496
FT /evidence="ECO:0007829|PDB:6UQF"
FT STRAND 501..503
FT /evidence="ECO:0007829|PDB:6UQF"
FT STRAND 505..507
FT /evidence="ECO:0007829|PDB:5U6O"
FT STRAND 511..518
FT /evidence="ECO:0007829|PDB:6UQF"
FT STRAND 520..523
FT /evidence="ECO:0007829|PDB:6UQF"
FT STRAND 525..527
FT /evidence="ECO:0007829|PDB:6UQF"
FT STRAND 530..532
FT /evidence="ECO:0007829|PDB:6UQF"
FT HELIX 541..545
FT /evidence="ECO:0007829|PDB:6UQF"
FT STRAND 551..557
FT /evidence="ECO:0007829|PDB:6UQF"
FT STRAND 559..565
FT /evidence="ECO:0007829|PDB:6UQF"
FT HELIX 566..575
FT /evidence="ECO:0007829|PDB:6UQF"
FT HELIX 577..594
FT /evidence="ECO:0007829|PDB:6UQF"
FT HELIX 599..610
FT /evidence="ECO:0007829|PDB:6UQF"
FT HELIX 616..634
FT /evidence="ECO:0007829|PDB:6UQF"
SQ SEQUENCE 890 AA; 98796 MW; A62F5E79C01257A2 CRC64;
MEGGGKPNSS SNSRDDGNSV FPAKASATGA GPAAAEKRLG TPPGGGGAGA KEHGNSVCFK
VDGGGGGGGG GGGGEEPAGG FEDAEGPRRQ YGFMQRQFTS MLQPGVNKFS LRMFGSQKAV
EKEQERVKTA GFWIIHPYSD FRFYWDLIML IMMVGNLVII PVGITFFTEQ TTTPWIIFNV
ASDTVFLLDL IMNFRTGTVN EDSSEIILDP KVIKMNYLKS WFVVDFISSI PVDYIFLIVE
KGMDSEVYKT ARALRIVRFT KILSLLRLLR LSRLIRYIHQ WEEIFHMTYD LASAVVRIFN
LIGMMLLLCH WDGCLQFLVP LLQDFPPDCW VSLNEMVNDS WGKQYSYALF KAMSHMLCIG
YGAQAPVSMS DLWITMLSMI VGATCYAMFV GHATALIQSL DSSRRQYQEK YKQVEQYMSF
HKLPADMRQK IHDYYEHRYQ GKIFDEENIL NELNDPLREE IVNFNCRKLV ATMPLFANAD
PNFVTAMLSK LRFEVFQPGD YIIREGAVGK KMYFIQHGVA GVITKSSKEM KLTDGSYFGE
ICLLTKGRRT ASVRADTYCR LYSLSVDNFN EVLEEYPMMR RAFETVAIDR LDRIGKKNSI
LLQKFQKDLN TGVFNNQENE ILKQIVKHDR EMVQAIAPIN YPQMTTLNST SSTTTPTSRM
RTQSPPVYTA TSLSHSNLHS PSPSTQTPQP SAILSPCSYT TAVCSPPVQS PLAARTFHYA
SPTASQLSLM QQQPQQQVQQ SQPPQTQPQQ PSPQPQTPGS STPKNEVHKS TQALHNTNLT
REVRPLSASQ PSLPHEVSTL ISRPHPTVGE SLASIPQPVT AVPGTGLQAG GRSTVPQRVT
LFRQMSSGAI PPNRGVPPAP PPPAAALPRE SSSVLNTDPD AEKPRFASNL
