HCN4_HUMAN
ID HCN4_HUMAN Reviewed; 1203 AA.
AC Q9Y3Q4; Q9UMQ7;
DT 28-FEB-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1999, sequence version 1.
DT 03-AUG-2022, entry version 185.
DE RecName: Full=Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4;
GN Name=HCN4;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION, AND TISSUE
RP SPECIFICITY.
RC TISSUE=Heart;
RX PubMed=10228147; DOI=10.1093/emboj/18.9.2323;
RA Ludwig A., Zong X., Stieber J., Hullin R., Hofmann F., Biel M.;
RT "Two pacemaker channels from human heart with profoundly different
RT activation kinetics.";
RL EMBO J. 18:2323-2329(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION, AND TISSUE
RP SPECIFICITY.
RC TISSUE=Thalamus;
RX PubMed=10430953; DOI=10.1073/pnas.96.16.9391;
RA Seifert R., Scholten A., Gauss R., Mincheva A., Lichter P., Kaupp U.B.;
RT "Molecular characterization of a slowly gating human hyperpolarization-
RT activated channel predominantly expressed in thalamus, heart, and testis.";
RL Proc. Natl. Acad. Sci. U.S.A. 96:9391-9396(1999).
RN [3]
RP FUNCTION, AND POSSIBLE INVOLVEMENT IN BRGDA8.
RX PubMed=19165230; DOI=10.1038/jhg.2008.16;
RA Ueda K., Hirano Y., Higashiuesato Y., Aizawa Y., Hayashi T., Inagaki N.,
RA Tana T., Ohya Y., Takishita S., Muratani H., Hiraoka M., Kimura A.;
RT "Role of HCN4 channel in preventing ventricular arrhythmia.";
RL J. Hum. Genet. 54:115-121(2009).
RN [4]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 521-739 IN COMPLEX WITH CAMP,
RP NUCLEOTIDE-BINDING, FUNCTION, ACTIVITY REGULATION, AND SUBUNIT.
RX PubMed=20829353; DOI=10.1074/jbc.m110.152033;
RA Xu X., Vysotskaya Z.V., Liu Q., Zhou L.;
RT "Structural basis for the cAMP-dependent gating in the human HCN4
RT channel.";
RL J. Biol. Chem. 285:37082-37091(2010).
RN [5]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 521-723 IN COMPLEX WITH CAMP,
RP NUCLEOTIDE-BINDING, ACTIVITY REGULATION, AND SUBUNIT.
RX PubMed=22006928; DOI=10.1074/jbc.m111.297606;
RA Lolicato M., Nardini M., Gazzarrini S., Moller S., Bertinetti D.,
RA Herberg F.W., Bolognesi M., Martin H., Fasolini M., Bertrand J.A.,
RA Arrigoni C., Thiel G., Moroni A.;
RT "Tetramerization dynamics of C-terminal domain underlies isoform-specific
RT cAMP gating in hyperpolarization-activated cyclic nucleotide-gated
RT channels.";
RL J. Biol. Chem. 286:44811-44820(2011).
RN [6]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 521-724, AND CHARACTERIZATION OF
RP VARIANT SSS2 ARG-672.
RX PubMed=23103389; DOI=10.1016/j.str.2012.09.017;
RA Xu X., Marni F., Wu S., Su Z., Musayev F., Shrestha S., Xie C., Gao W.,
RA Liu Q., Zhou L.;
RT "Local and global interpretations of a disease-causing mutation near the
RT ligand entry path in hyperpolarization-activated cAMP-gated channel.";
RL Structure 20:2116-2123(2012).
RN [7]
RP VARIANT SSS2 ASN-553.
RX PubMed=15123648; DOI=10.1074/jbc.m311953200;
RA Ueda K., Nakamura K., Hayashi T., Inagaki N., Takahashi M., Arimura T.,
RA Morita H., Higashiuesato Y., Hirano Y., Yasunami M., Takishita S.,
RA Yamashina A., Ohe T., Sunamori M., Hiraoka M., Kimura A.;
RT "Functional characterization of a trafficking-defective HCN4 mutation,
RT D553N, associated with cardiac arrhythmia.";
RL J. Biol. Chem. 279:27194-27198(2004).
RN [8]
RP VARIANT SSS2 ARG-672, FUNCTION, ACTIVITY REGULATION, SUBCELLULAR LOCATION,
RP AND CHARACTERIZATION OF VARIANT SSS2 ARG-672.
RX PubMed=16407510; DOI=10.1056/nejmoa052475;
RA Milanesi R., Baruscotti M., Gnecchi-Ruscone T., DiFrancesco D.;
RT "Familial sinus bradycardia associated with a mutation in the cardiac
RT pacemaker channel.";
RL N. Engl. J. Med. 354:151-157(2006).
RN [9]
RP VARIANT SSS2 VAL-485, AND CHARACTERIZATION OF VARIANT SSS2 VAL-485.
RX PubMed=20662977; DOI=10.1111/j.1540-8167.2010.01844.x;
RA Laish-Farkash A., Glikson M., Brass D., Marek-Yagel D., Pras E., Dascal N.,
RA Antzelevitch C., Nof E., Reznik H., Eldar M., Luria D.;
RT "A novel mutation in the HCN4 gene causes symptomatic sinus bradycardia in
RT Moroccan Jews.";
RL J. Cardiovasc. Electrophysiol. 21:1365-1372(2010).
RN [10]
RP VARIANT EIG18 CYS-550, CHARACTERIZATION OF VARIANT EIG18 CYS-550, AND
RP INVOLVEMENT IN EIG18.
RX PubMed=30127718; DOI=10.3389/fnmol.2018.00269;
RA Campostrini G., DiFrancesco J.C., Castellotti B., Milanesi R.,
RA Gnecchi-Ruscone T., Bonzanni M., Bucchi A., Baruscotti M., Ferrarese C.,
RA Franceschetti S., Canafoglia L., Ragona F., Freri E., Labate A.,
RA Gambardella A., Costa C., Gellera C., Granata T., Barbuti A.,
RA DiFrancesco D.;
RT "A loss-of-function HCN4 mutation associated with familial benign myoclonic
RT epilepsy in infancy causes increased neuronal excitability.";
RL Front. Mol. Neurosci. 11:269-269(2018).
CC -!- FUNCTION: Hyperpolarization-activated ion channel with very slow
CC activation and inactivation exhibiting weak selectivity for potassium
CC over sodium ions. Contributes to the native pacemaker currents in heart
CC (If) that regulate the rhythm of heart beat. May contribute to the
CC native pacemaker currents in neurons (Ih). May mediate responses to
CC sour stimuli. {ECO:0000269|PubMed:10228147,
CC ECO:0000269|PubMed:10430953, ECO:0000269|PubMed:16407510,
CC ECO:0000269|PubMed:19165230, ECO:0000269|PubMed:20829353}.
CC -!- ACTIVITY REGULATION: Activated by cAMP. cAMP binding causes a
CC conformation change that leads to the assembly of an active tetramer
CC and channel opening. {ECO:0000269|PubMed:16407510,
CC ECO:0000269|PubMed:20829353, ECO:0000269|PubMed:22006928}.
CC -!- SUBUNIT: Homotetramer. The potassium channel is composed of a homo- or
CC heterotetrameric complex of pore-forming subunits.
CC {ECO:0000269|PubMed:20829353, ECO:0000269|PubMed:22006928}.
CC -!- INTERACTION:
CC Q9Y3Q4; Q9Y3Q4: HCN4; NbExp=3; IntAct=EBI-1753521, EBI-1753521;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:10228147,
CC ECO:0000269|PubMed:10430953, ECO:0000269|PubMed:16407510}; Multi-pass
CC membrane protein {ECO:0000269|PubMed:10228147,
CC ECO:0000269|PubMed:10430953, ECO:0000269|PubMed:16407510}.
CC -!- TISSUE SPECIFICITY: Highly expressed in thalamus, testis and in heart,
CC both in ventricle and atrium. Detected at much lower levels in
CC amygdala, substantia nigra, cerebellum and hippocampus.
CC {ECO:0000269|PubMed:10228147, ECO:0000269|PubMed:10430953}.
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.
CC -!- DISEASE: Sick sinus syndrome 2 (SSS2) [MIM:163800]: The term 'sick
CC sinus syndrome' encompasses a variety of conditions caused by sinus
CC node dysfunction. The most common clinical manifestations are syncope,
CC presyncope, dizziness, and fatigue. Electrocardiogram typically shows
CC sinus bradycardia, sinus arrest, and/or sinoatrial block. Episodes of
CC atrial tachycardias coexisting with sinus bradycardia ('tachycardia-
CC bradycardia syndrome') are also common in this disorder. SSS occurs
CC most often in the elderly associated with underlying heart disease or
CC previous cardiac surgery, but can also occur in the fetus, infant, or
CC child without heart disease or other contributing factors. SSS2 onset
CC is in utero or at birth. {ECO:0000269|PubMed:15123648,
CC ECO:0000269|PubMed:16407510, ECO:0000269|PubMed:20662977,
CC ECO:0000269|PubMed:23103389}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Brugada syndrome 8 (BRGDA8) [MIM:613123]: A tachyarrhythmia
CC characterized by right bundle branch block and ST segment elevation on
CC an electrocardiogram (ECG). It can cause the ventricles to beat so fast
CC that the blood is prevented from circulating efficiently in the body.
CC When this situation occurs, the individual will faint and may die in a
CC few minutes if the heart is not reset. {ECO:0000269|PubMed:19165230}.
CC Note=The gene represented in this entry may be involved in disease
CC pathogenesis.
CC -!- DISEASE: Epilepsy, idiopathic generalized 18 (EIG18) [MIM:619521]: An
CC autosomal dominant form of idiopathic generalized epilepsy, a disorder
CC characterized by recurring generalized seizures in the absence of
CC detectable brain lesions and/or metabolic abnormalities. Generalized
CC seizures arise diffusely and simultaneously from both hemispheres of
CC the brain. Seizure types include juvenile myoclonic seizures, absence
CC seizures, and generalized tonic-clonic seizures. EIG18 is characterized
CC by onset of myoclonic seizures in infancy. Although the seizures remit,
CC some patients may have later speech or cognitive impairment.
CC {ECO:0000269|PubMed:30127718}. Note=Disease susceptibility is
CC associated with variants affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: Inhibited by extracellular cesium ions.
CC -!- SIMILARITY: Belongs to the potassium channel HCN family. {ECO:0000305}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; AJ132429; CAB42604.1; -; mRNA.
DR EMBL; AJ238850; CAB52754.1; -; mRNA.
DR CCDS; CCDS10248.1; -.
DR RefSeq; NP_005468.1; NM_005477.2.
DR PDB; 2MNG; NMR; -; A=579-707.
DR PDB; 3OTF; X-ray; 2.40 A; A=521-739.
DR PDB; 3U11; X-ray; 2.50 A; A/B=521-723.
DR PDB; 4HBN; X-ray; 2.60 A; A=521-724.
DR PDB; 4KL1; X-ray; 2.70 A; A/B/C/D=521-713.
DR PDB; 4NVP; X-ray; 2.50 A; A=521-723.
DR PDB; 6GYN; EM; 3.40 A; A/B/C/D=201-719.
DR PDB; 6GYO; EM; 3.40 A; A/B/C/D=201-719.
DR PDBsum; 2MNG; -.
DR PDBsum; 3OTF; -.
DR PDBsum; 3U11; -.
DR PDBsum; 4HBN; -.
DR PDBsum; 4KL1; -.
DR PDBsum; 4NVP; -.
DR PDBsum; 6GYN; -.
DR PDBsum; 6GYO; -.
DR AlphaFoldDB; Q9Y3Q4; -.
DR SMR; Q9Y3Q4; -.
DR BioGRID; 115338; 5.
DR ComplexPortal; CPX-131; HCN4 channel complex.
DR DIP; DIP-52325N; -.
DR IntAct; Q9Y3Q4; 3.
DR STRING; 9606.ENSP00000261917; -.
DR BindingDB; Q9Y3Q4; -.
DR ChEMBL; CHEMBL1250417; -.
DR DrugCentral; Q9Y3Q4; -.
DR GuidetoPHARMACOLOGY; 403; -.
DR TCDB; 1.A.1.5.10; the voltage-gated ion channel (vic) superfamily.
DR TCDB; 1.A.1.5.11; the voltage-gated ion channel (vic) superfamily.
DR GlyGen; Q9Y3Q4; 1 site.
DR iPTMnet; Q9Y3Q4; -.
DR PhosphoSitePlus; Q9Y3Q4; -.
DR BioMuta; HCN4; -.
DR DMDM; 38605641; -.
DR EPD; Q9Y3Q4; -.
DR jPOST; Q9Y3Q4; -.
DR MassIVE; Q9Y3Q4; -.
DR MaxQB; Q9Y3Q4; -.
DR PaxDb; Q9Y3Q4; -.
DR PeptideAtlas; Q9Y3Q4; -.
DR PRIDE; Q9Y3Q4; -.
DR ProteomicsDB; 86060; -.
DR ABCD; Q9Y3Q4; 1 sequenced antibody.
DR Antibodypedia; 26787; 183 antibodies from 31 providers.
DR DNASU; 10021; -.
DR Ensembl; ENST00000261917.4; ENSP00000261917.3; ENSG00000138622.4.
DR GeneID; 10021; -.
DR KEGG; hsa:10021; -.
DR MANE-Select; ENST00000261917.4; ENSP00000261917.3; NM_005477.3; NP_005468.1.
DR UCSC; uc002avp.3; human.
DR CTD; 10021; -.
DR DisGeNET; 10021; -.
DR GeneCards; HCN4; -.
DR GeneReviews; HCN4; -.
DR HGNC; HGNC:16882; HCN4.
DR HPA; ENSG00000138622; Group enriched (brain, heart muscle, testis).
DR MalaCards; HCN4; -.
DR MIM; 163800; phenotype.
DR MIM; 605206; gene.
DR MIM; 613123; phenotype.
DR MIM; 619521; phenotype.
DR neXtProt; NX_Q9Y3Q4; -.
DR OpenTargets; ENSG00000138622; -.
DR Orphanet; 130; Brugada syndrome.
DR Orphanet; 166282; Familial sick sinus syndrome.
DR PharmGKB; PA394; -.
DR VEuPathDB; HostDB:ENSG00000138622; -.
DR eggNOG; KOG0498; Eukaryota.
DR GeneTree; ENSGT00940000154743; -.
DR HOGENOM; CLU_005746_15_0_1; -.
DR InParanoid; Q9Y3Q4; -.
DR OMA; CLPHQMS; -.
DR OrthoDB; 281394at2759; -.
DR PhylomeDB; Q9Y3Q4; -.
DR TreeFam; TF318250; -.
DR PathwayCommons; Q9Y3Q4; -.
DR Reactome; R-HSA-1296061; HCN channels.
DR SignaLink; Q9Y3Q4; -.
DR SIGNOR; Q9Y3Q4; -.
DR BioGRID-ORCS; 10021; 13 hits in 1061 CRISPR screens.
DR ChiTaRS; HCN4; human.
DR EvolutionaryTrace; Q9Y3Q4; -.
DR GeneWiki; HCN4; -.
DR GenomeRNAi; 10021; -.
DR Pharos; Q9Y3Q4; Tclin.
DR PRO; PR:Q9Y3Q4; -.
DR Proteomes; UP000005640; Chromosome 15.
DR RNAct; Q9Y3Q4; protein.
DR Bgee; ENSG00000138622; Expressed in tibialis anterior and 57 other tissues.
DR Genevisible; Q9Y3Q4; 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:BHF-UCL.
DR GO; GO:0031226; C:intrinsic component of plasma membrane; IDA:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:BHF-UCL.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0030552; F:cAMP binding; IEA:UniProtKB-KW.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0005222; F:intracellular cAMP-activated cation channel activity; IDA:UniProtKB.
DR GO; GO:0005249; F:voltage-gated potassium channel activity; IDA:UniProtKB.
DR GO; GO:0086041; F:voltage-gated potassium channel activity involved in SA node cell action potential depolarization; IMP:BHF-UCL.
DR GO; GO:0005248; F:voltage-gated sodium channel activity; IMP:UniProtKB.
DR GO; GO:0008015; P:blood circulation; NAS:ProtInc.
DR GO; GO:0006812; P:cation transport; IDA:BHF-UCL.
DR GO; GO:0071320; P:cellular response to cAMP; IDA:UniProtKB.
DR GO; GO:0071321; P:cellular response to cGMP; IDA:UniProtKB.
DR GO; GO:0086012; P:membrane depolarization during cardiac muscle cell action potential; IC:BHF-UCL.
DR GO; GO:0086046; P:membrane depolarization during SA node cell action potential; IMP:BHF-UCL.
DR GO; GO:0006936; P:muscle contraction; TAS:ProtInc.
DR GO; GO:1990573; P:potassium ion import across plasma membrane; IDA:BHF-UCL.
DR GO; GO:0071805; P:potassium ion transmembrane transport; IDA:UniProtKB.
DR GO; GO:0098909; P:regulation of cardiac muscle cell action potential involved in regulation of contraction; IMP:BHF-UCL.
DR GO; GO:0055117; P:regulation of cardiac muscle contraction; IMP:BHF-UCL.
DR GO; GO:2001257; P:regulation of cation channel activity; IC:ComplexPortal.
DR GO; GO:0002027; P:regulation of heart rate; IMP:UniProtKB.
DR GO; GO:0086091; P:regulation of heart rate by cardiac conduction; IMP:BHF-UCL.
DR GO; GO:0003254; P:regulation of membrane depolarization; IDA:BHF-UCL.
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:0086015; P:SA node cell action potential; IMP:BHF-UCL.
DR GO; GO:0003163; P:sinoatrial node development; NAS:BHF-UCL.
DR GO; GO:0098719; P:sodium ion import across plasma membrane; IDA:BHF-UCL.
DR GO; GO:0035725; P:sodium ion transmembrane transport; IMP:UniProtKB.
DR CDD; cd00038; CAP_ED; 1.
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; IPR003938; K_chnl_volt-dep_EAG/ELK/ERG.
DR InterPro; IPR014710; RmlC-like_jellyroll.
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; Brugada syndrome; cAMP; cAMP-binding; Cell membrane;
KW Disease variant; Epilepsy; Glycoprotein; Ion channel; Ion transport;
KW Ligand-gated ion channel; Membrane; Nucleotide-binding; Phosphoprotein;
KW Potassium; Potassium channel; Potassium transport; Reference proteome;
KW Sodium; Sodium channel; Sodium transport; Transmembrane;
KW Transmembrane helix; Transport; Voltage-gated channel.
FT CHAIN 1..1203
FT /note="Potassium/sodium hyperpolarization-activated cyclic
FT nucleotide-gated channel 4"
FT /id="PRO_0000054117"
FT TOPO_DOM 1..266
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 267..287
FT /note="Helical; Name=Segment S1"
FT /evidence="ECO:0000255"
FT TOPO_DOM 288..293
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 294..314
FT /note="Helical; Name=Segment S2"
FT /evidence="ECO:0000255"
FT TOPO_DOM 315..340
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 341..361
FT /note="Helical; Name=Segment S3"
FT /evidence="ECO:0000255"
FT TOPO_DOM 362..368
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 369..389
FT /note="Helical; Voltage-sensor; Name=Segment S4"
FT /evidence="ECO:0000255"
FT TOPO_DOM 390..420
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 421..441
FT /note="Helical; Name=Segment S5"
FT /evidence="ECO:0000255"
FT TOPO_DOM 442..464
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT INTRAMEM 465..486
FT /note="Pore-forming; Name=Segment H5"
FT /evidence="ECO:0000255"
FT TOPO_DOM 487..496
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 497..517
FT /note="Helical; Name=Segment S6"
FT /evidence="ECO:0000255"
FT TOPO_DOM 518..1203
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 1..182
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 209..260
FT /note="Involved in subunit assembly"
FT /evidence="ECO:0000250"
FT REGION 836..856
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 870..897
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 918..1203
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 106..120
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 121..137
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 159..175
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 918..937
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1027..1041
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1055..1070
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1082..1107
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 659..662
FT /ligand="3',5'-cyclic AMP"
FT /ligand_id="ChEBI:CHEBI:58165"
FT /evidence="ECO:0000269|PubMed:20829353,
FT ECO:0000269|PubMed:22006928"
FT BINDING 669..670
FT /ligand="3',5'-cyclic AMP"
FT /ligand_id="ChEBI:CHEBI:58165"
FT /evidence="ECO:0000269|PubMed:20829353,
FT ECO:0000269|PubMed:22006928"
FT BINDING 710..713
FT /ligand="3',5'-cyclic AMP"
FT /ligand_id="ChEBI:CHEBI:58165"
FT /evidence="ECO:0000269|PubMed:20829353,
FT ECO:0000269|PubMed:22006928"
FT MOD_RES 138
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9JKA7"
FT MOD_RES 1105
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O70507"
FT MOD_RES 1108
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O70507"
FT CARBOHYD 458
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VARIANT 485
FT /note="A -> V (in SSS2; results in a significant reduction
FT of current density compared to wild-type;
FT dbSNP:rs1454748709)"
FT /evidence="ECO:0000269|PubMed:20662977"
FT /id="VAR_066614"
FT VARIANT 550
FT /note="R -> C (in EIG18; associated with disease
FT susceptibility; alters the channel kinetics by causing a
FT leftward shift in the voltage dependence of the channel
FT activation curve; neurons expressing mutant channels
FT present lower current thresholds to firing and higher
FT firing rates)"
FT /evidence="ECO:0000269|PubMed:30127718"
FT /id="VAR_086273"
FT VARIANT 553
FT /note="D -> N (in SSS2; dbSNP:rs104894485)"
FT /evidence="ECO:0000269|PubMed:15123648"
FT /id="VAR_026534"
FT VARIANT 672
FT /note="S -> R (in SSS2; results in decreased affinity for
FT cAMP but does not abolish channel activation; shifts the
FT current activation range to hyperpolarized voltages; slows
FT channel opening and speeds up channel closure;
FT dbSNP:rs104894488)"
FT /evidence="ECO:0000269|PubMed:16407510,
FT ECO:0000269|PubMed:23103389"
FT /id="VAR_026535"
FT CONFLICT 110
FT /note="S -> T (in Ref. 2; CAB52754)"
FT /evidence="ECO:0000305"
FT HELIX 217..221
FT /evidence="ECO:0007829|PDB:6GYN"
FT HELIX 228..233
FT /evidence="ECO:0007829|PDB:6GYN"
FT STRAND 234..236
FT /evidence="ECO:0007829|PDB:6GYN"
FT HELIX 237..248
FT /evidence="ECO:0007829|PDB:6GYN"
FT STRAND 251..253
FT /evidence="ECO:0007829|PDB:6GYN"
FT HELIX 260..285
FT /evidence="ECO:0007829|PDB:6GYN"
FT HELIX 293..312
FT /evidence="ECO:0007829|PDB:6GYN"
FT HELIX 313..315
FT /evidence="ECO:0007829|PDB:6GYN"
FT STRAND 324..327
FT /evidence="ECO:0007829|PDB:6GYO"
FT HELIX 330..340
FT /evidence="ECO:0007829|PDB:6GYN"
FT HELIX 342..349
FT /evidence="ECO:0007829|PDB:6GYN"
FT HELIX 352..363
FT /evidence="ECO:0007829|PDB:6GYN"
FT TURN 365..368
FT /evidence="ECO:0007829|PDB:6GYN"
FT HELIX 372..383
FT /evidence="ECO:0007829|PDB:6GYN"
FT HELIX 384..390
FT /evidence="ECO:0007829|PDB:6GYN"
FT HELIX 391..409
FT /evidence="ECO:0007829|PDB:6GYN"
FT HELIX 413..442
FT /evidence="ECO:0007829|PDB:6GYN"
FT HELIX 450..453
FT /evidence="ECO:0007829|PDB:6GYN"
FT STRAND 457..459
FT /evidence="ECO:0007829|PDB:6GYN"
FT HELIX 461..474
FT /evidence="ECO:0007829|PDB:6GYN"
FT TURN 475..478
FT /evidence="ECO:0007829|PDB:6GYN"
FT STRAND 482..484
FT /evidence="ECO:0007829|PDB:6GYN"
FT HELIX 489..517
FT /evidence="ECO:0007829|PDB:6GYN"
FT TURN 518..520
FT /evidence="ECO:0007829|PDB:6GYN"
FT HELIX 522..540
FT /evidence="ECO:0007829|PDB:3OTF"
FT HELIX 545..559
FT /evidence="ECO:0007829|PDB:3OTF"
FT HELIX 566..571
FT /evidence="ECO:0007829|PDB:3OTF"
FT HELIX 575..585
FT /evidence="ECO:0007829|PDB:3OTF"
FT HELIX 587..591
FT /evidence="ECO:0007829|PDB:3OTF"
FT HELIX 594..597
FT /evidence="ECO:0007829|PDB:3OTF"
FT HELIX 601..608
FT /evidence="ECO:0007829|PDB:3OTF"
FT STRAND 612..616
FT /evidence="ECO:0007829|PDB:3OTF"
FT STRAND 621..623
FT /evidence="ECO:0007829|PDB:3OTF"
FT STRAND 631..637
FT /evidence="ECO:0007829|PDB:3OTF"
FT STRAND 640..643
FT /evidence="ECO:0007829|PDB:3OTF"
FT STRAND 645..647
FT /evidence="ECO:0007829|PDB:3OTF"
FT STRAND 650..652
FT /evidence="ECO:0007829|PDB:3OTF"
FT HELIX 661..665
FT /evidence="ECO:0007829|PDB:3OTF"
FT STRAND 666..668
FT /evidence="ECO:0007829|PDB:4KL1"
FT STRAND 670..677
FT /evidence="ECO:0007829|PDB:3OTF"
FT STRAND 679..685
FT /evidence="ECO:0007829|PDB:3OTF"
FT HELIX 686..695
FT /evidence="ECO:0007829|PDB:3OTF"
FT HELIX 697..699
FT /evidence="ECO:0007829|PDB:3OTF"
FT HELIX 700..712
FT /evidence="ECO:0007829|PDB:3OTF"
SQ SEQUENCE 1203 AA; 129042 MW; 7EFDD2D69CF1F9D9 CRC64;
MDKLPPSMRK RLYSLPQQVG AKAWIMDEEE DAEEEGAGGR QDPSRRSIRL RPLPSPSPSA
AAGGTESRSS ALGAADSEGP ARGAGKSSTN GDCRRFRGSL ASLGSRGGGS GGTGSGSSHG
HLHDSAEERR LIAEGDASPG EDRTPPGLAA EPERPGASAQ PAASPPPPQQ PPQPASASCE
QPSVDTAIKV EGGAAAGDQI LPEAEVRLGQ AGFMQRQFGA MLQPGVNKFS LRMFGSQKAV
EREQERVKSA GFWIIHPYSD FRFYWDLTML LLMVGNLIII PVGITFFKDE NTTPWIVFNV
VSDTFFLIDL VLNFRTGIVV EDNTEIILDP QRIKMKYLKS WFMVDFISSI PVDYIFLIVE
TRIDSEVYKT ARALRIVRFT KILSLLRLLR LSRLIRYIHQ WEEIFHMTYD LASAVVRIVN
LIGMMLLLCH WDGCLQFLVP MLQDFPDDCW VSINNMVNNS WGKQYSYALF KAMSHMLCIG
YGRQAPVGMS DVWLTMLSMI VGATCYAMFI GHATALIQSL DSSRRQYQEK YKQVEQYMSF
HKLPPDTRQR IHDYYEHRYQ GKMFDEESIL GELSEPLREE IINFNCRKLV ASMPLFANAD
PNFVTSMLTK LRFEVFQPGD YIIREGTIGK KMYFIQHGVV SVLTKGNKET KLADGSYFGE
ICLLTRGRRT ASVRADTYCR LYSLSVDNFN EVLEEYPMMR RAFETVALDR LDRIGKKNSI
LLHKVQHDLN SGVFNYQENE IIQQIVQHDR EMAHCAHRVQ AAASATPTPT PVIWTPLIQA
PLQAAAATTS VAIALTHHPR LPAAIFRPPP GSGLGNLGAG QTPRHLKRLQ SLIPSALGSA
SPASSPSQVD TPSSSSFHIQ QLAGFSAPAG LSPLLPSSSS SPPPGACGSP SAPTPSAGVA
ATTIAGFGHF HKALGGSLSS SDSPLLTPLQ PGARSPQAAQ PSPAPPGARG GLGLPEHFLP
PPPSSRSPSS SPGQLGQPPG ELSLGLATGP LSTPETPPRQ PEPPSLVAGA SGGASPVGFT
PRGGLSPPGH SPGPPRTFPS APPRASGSHG SLLLPPASSP PPPQVPQRRG TPPLTPGRLT
QDLKLISASQ PALPQDGAQT LRRASPHSSG ESMAAFPLFP RAGGGSGGSG SSGGLGPPGR
PYGAIPGQHV TLPRKTSSGS LPPPLSLFGA RATSSGGPPL TAGPQREPGA RPEPVRSKLP
SNL
