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   27-MAR-2024, entry version 194.
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 CYS-550, CHARACTERIZATION OF VARIANT CYS-550, AND INVOLVEMENT IN
RP   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}.
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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   EMDB; EMD-0093; -.
DR   EMDB; EMD-0094; -.
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   GlyCosmos; Q9Y3Q4; 1 site, No reported glycans.
DR   GlyGen; Q9Y3Q4; 1 site.
DR   iPTMnet; Q9Y3Q4; -.
DR   PhosphoSitePlus; Q9Y3Q4; -.
DR   SwissPalm; Q9Y3Q4; -.
DR   BioMuta; HCN4; -.
DR   DMDM; 38605641; -.
DR   EPD; Q9Y3Q4; -.
DR   jPOST; Q9Y3Q4; -.
DR   MassIVE; Q9Y3Q4; -.
DR   MaxQB; Q9Y3Q4; -.
DR   PaxDb; 9606-ENSP00000261917; -.
DR   PeptideAtlas; Q9Y3Q4; -.
DR   ProteomicsDB; 86060; -.
DR   ABCD; Q9Y3Q4; 1 sequenced antibody.
DR   Antibodypedia; 26787; 205 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   AGR; HGNC:16882; -.
DR   CTD; 10021; -.
DR   DisGeNET; 10021; -.
DR   GeneCards; HCN4; -.
DR   GeneReviews; HCN4; -.
DR   HGNC; HGNC:16882; HCN4.
DR   HPA; ENSG00000138622; Group enriched (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; HFQQATT; -.
DR   OrthoDB; 74296at2759; -.
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 1141 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 59 other cell types or tissues.
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: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: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:0006812; P:monoatomic cation transport; IDA: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: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: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; 1.10.287.70; -; 1.
DR   Gene3D; 1.10.287.630; Helix hairpin bin; 1.
DR   Gene3D; 2.60.120.10; Jelly Rolls; 1.
DR   InterPro; IPR018488; cNMP-bd_CS.
DR   InterPro; IPR000595; cNMP-bd_dom.
DR   InterPro; IPR018490; cNMP-bd_dom_sf.
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   PANTHER; PTHR45689; I[[H]] CHANNEL, ISOFORM E; 1.
DR   PANTHER; PTHR45689:SF4; POTASSIUM_SODIUM HYPERPOLARIZATION-ACTIVATED CYCLIC NUCLEOTIDE-GATED CHANNEL 4; 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; cAMP-binding domain-like; 1.
DR   SUPFAM; SSF81324; Voltage-gated potassium channels; 1.
DR   PROSITE; PS00888; CNMP_BINDING_1; 1.
DR   PROSITE; PS50042; CNMP_BINDING_3; 1.
DR   Genevisible; Q9Y3Q4; HS.
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 (risk factor for EIG18; alters the channel
FT                   kinetics by causing a leftward shift in the voltage
FT                   dependence of the channel activation curve; neurons
FT                   expressing mutant channels present lower current thresholds
FT                   to firing and higher firing rates; dbSNP:rs150691273)"
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
//