HCN2_HUMAN
ID HCN2_HUMAN Reviewed; 889 AA.
AC Q9UL51; O60742; O60743; O75267; Q9UBS2;
DT 28-FEB-2003, integrated into UniProtKB/Swiss-Prot.
DT 13-JUN-2006, sequence version 3.
DT 03-AUG-2022, entry version 180.
DE RecName: Full=Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2;
DE AltName: Full=Brain cyclic nucleotide-gated channel 2;
DE Short=BCNG-2;
GN Name=HCN2; Synonyms=BCNG2;
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, AND SUBCELLULAR LOCATION.
RX PubMed=10524219; DOI=10.1016/s0167-4781(99)00092-5;
RA Vaccari T., Moroni A., Rocchi M., Gorza L., Bianchi M.E., Beltrame M.,
RA DiFrancesco D.;
RT "The human gene coding for HCN2, a pacemaker channel of the heart.";
RL Biochim. Biophys. Acta 1446:419-425(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], FUNCTION, ACTIVITY REGULATION,
RP SUBCELLULAR LOCATION, AND TISSUE 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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E.,
RA Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A.,
RA Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S.,
RA Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A.,
RA Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J.,
RA Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M.,
RA Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W.,
RA Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V.,
RA Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D.,
RA McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I.,
RA Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L.,
RA Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A.,
RA She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J.,
RA Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 147-743, 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 [5]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [6]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 470-672 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 [7]
RP VARIANT EIG17 LYS-515, CHARACTERIZATION OF VARIANT EIG17 LYS-515, AND
RP INVOLVEMENT IN EIG17.
RX PubMed=22131395; DOI=10.1523/jneurosci.3727-11.2011;
RA DiFrancesco J.C., Barbuti A., Milanesi R., Coco S., Bucchi A., Bottelli G.,
RA Ferrarese C., Franceschetti S., Terragni B., Baruscotti M., DiFrancesco D.;
RT "Recessive loss-of-function mutation in the pacemaker HCN2 channel causing
RT increased neuronal excitability in a patient with idiopathic generalized
RT epilepsy.";
RL J. Neurosci. 31:17327-17337(2011).
RN [8]
RP VARIANT FEB2 LEU-126, CHARACTERIZATION OF VARIANT FEB2 LEU-126, AND
RP INVOLVEMENT IN FEB2.
RX PubMed=24324597; DOI=10.1371/journal.pone.0080376;
RA Nakamura Y., Shi X., Numata T., Mori Y., Inoue R., Lossin C., Baram T.Z.,
RA Hirose S.;
RT "Novel HCN2 mutation contributes to febrile seizures by shifting the
RT channel's kinetics in a temperature-dependent manner.";
RL PLoS ONE 8:e80376-e80376(2013).
RN [9]
RP VARIANTS EIG17 MET-246; TRP-632 AND CYS-756, CHARACTERIZATION OF VARIANTS
RP EIG17 MET-246; TRP-632 AND CYS-756, INVOLVEMENT IN EIG17, AND
RP CHARACTERIZATION OF VARIANTS LYS-280 AND THR-705.
RX PubMed=29064616; DOI=10.1002/humu.23357;
RA Li M., Maljevic S., Phillips A.M., Petrovski S., Hildebrand M.S.,
RA Burgess R., Mount T., Zara F., Striano P., Schubert J., Thiele H.,
RA Nuernberg P., Wong M., Weisenberg J.L., Thio L.L., Lerche H.,
RA Scheffer I.E., Berkovic S.F., Petrou S., Reid C.A.;
RT "Gain-of-function HCN2 variants in genetic epilepsy.";
RL Hum. Mutat. 39:202-209(2018).
RN [10]
RP VARIANT VAL-418.
RX PubMed=29463886; DOI=10.1038/s41380-018-0020-x;
RA Eising E., Carrion-Castillo A., Vino A., Strand E.A., Jakielski K.J.,
RA Scerri T.S., Hildebrand M.S., Webster R., Ma A., Mazoyer B., Francks C.,
RA Bahlo M., Scheffer I.E., Morgan A.T., Shriberg L.D., Fisher S.E.;
RT "A set of regulatory genes co-expressed in embryonic human brain is
RT implicated in disrupted speech development.";
RL Mol. Psychiatry 24:1065-1078(2019).
CC -!- FUNCTION: Hyperpolarization-activated ion channel exhibiting weak
CC selectivity for potassium over sodium ions. Contributes to the native
CC pacemaker currents in heart (If) and in neurons (Ih). Can also
CC transport ammonium in the distal nephron. Produces a large
CC instantaneous current. Modulated by intracellular chloride ions and pH;
CC acidic pH shifts the activation to more negative voltages (By
CC similarity). {ECO:0000250, ECO:0000269|PubMed:10228147,
CC ECO:0000269|PubMed:10524219}.
CC -!- ACTIVITY REGULATION: Activated by cAMP, and at 10-100 times higher
CC concentrations, also by cGMP. cAMP binding causes a conformation change
CC that leads to the assembly of an active tetramer and channel opening.
CC Channel activity is modulated by intracellular chloride ions and pH;
CC acidic pH shifts the activation to more negative voltages.
CC {ECO:0000269|PubMed:10228147, ECO:0000269|PubMed:22006928}.
CC -!- SUBUNIT: The potassium channel is composed of a homo- or
CC heterotetrameric complex of pore-forming subunits. Heterotetramer with
CC HCN1. Forms an obligate 4:4 complex with accessory subunit PEX5L.
CC Interacts with KCNE2 (By similarity). Homotetramer. {ECO:0000250,
CC ECO:0000269|PubMed:22006928}.
CC -!- INTERACTION:
CC Q9UL51; Q9UL51: HCN2; NbExp=2; IntAct=EBI-1751885, EBI-1751885;
CC Q9UL51; Q4ACU6-1: Shank3; Xeno; NbExp=3; IntAct=EBI-1751885, EBI-16201983;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:10228147,
CC ECO:0000269|PubMed:10524219}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:10228147, ECO:0000269|PubMed:10524219}.
CC -!- TISSUE SPECIFICITY: Highly expressed throughout the brain. Detected at
CC low levels in heart. {ECO:0000269|PubMed:10228147,
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.
CC -!- PTM: Phosphorylation at Ser-668 by PRKG2 shifts the voltage-dependence
CC to more negative voltages, hence counteracting the stimulatory effect
CC of cGMP on gating. {ECO:0000250}.
CC -!- DISEASE: Epilepsy, idiopathic generalized 17 (EIG17) [MIM:602477]: A
CC form of idiopathic generalized epilepsy, a disorder characterized by
CC recurring generalized seizures in the absence of detectable brain
CC lesions and/or metabolic abnormalities. Generalized seizures arise
CC diffusely and simultaneously from both hemispheres of the brain.
CC Seizure types include juvenile myoclonic seizures, absence seizures,
CC and generalized tonic-clonic seizures. Both autosomal dominant and
CC autosomal recessive EIG17 inheritance have been reported.
CC {ECO:0000269|PubMed:22131395, ECO:0000269|PubMed:29064616}.
CC Note=Disease susceptibility is associated with variants affecting the
CC gene represented in this entry.
CC -!- DISEASE: Febrile seizures, familial, 2 (FEB2) [MIM:602477]: Seizures
CC associated with febrile episodes in childhood without any evidence of
CC intracranial infection or defined pathologic or traumatic cause. It is
CC a common condition, affecting 2-5% of children aged 3 months to 5
CC years. The majority are simple febrile seizures (generally defined as
CC generalized onset, single seizures with a duration of less than 30
CC minutes). Complex febrile seizures are characterized by focal onset,
CC duration greater than 30 minutes, and/or more than one seizure in a 24
CC hour period. The likelihood of developing epilepsy following simple
CC febrile seizures is low. Complex febrile seizures are associated with a
CC moderately increased incidence of epilepsy. FEB2 transmission pattern
CC is consistent with autosomal dominant inheritance.
CC {ECO:0000269|PubMed:24324597}. Note=The disease is caused by variants
CC 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; AF065164; AAC28444.2; -; mRNA.
DR EMBL; AJ012582; CAB42602.1; -; mRNA.
DR EMBL; AJ133727; CAB42630.1; -; Genomic_DNA.
DR EMBL; AJ133728; CAB42630.1; JOINED; Genomic_DNA.
DR EMBL; AJ133729; CAB42630.1; JOINED; Genomic_DNA.
DR EMBL; AJ133730; CAB42630.1; JOINED; Genomic_DNA.
DR EMBL; AJ133731; CAB42630.1; JOINED; Genomic_DNA.
DR EMBL; AJ133732; CAB42630.1; JOINED; Genomic_DNA.
DR EMBL; AJ133733; CAB42630.1; JOINED; Genomic_DNA.
DR EMBL; AJ133734; CAB42630.1; JOINED; Genomic_DNA.
DR EMBL; AC004449; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC005559; AAC33280.2; -; Genomic_DNA.
DR EMBL; AF064877; AAC39760.1; -; mRNA.
DR CCDS; CCDS12035.1; -.
DR RefSeq; NP_001185.3; NM_001194.3.
DR PDB; 2MPF; NMR; -; A=521-672.
DR PDB; 3U10; X-ray; 2.30 A; A=470-672.
DR PDBsum; 2MPF; -.
DR PDBsum; 3U10; -.
DR AlphaFoldDB; Q9UL51; -.
DR BMRB; Q9UL51; -.
DR SMR; Q9UL51; -.
DR BioGRID; 107081; 11.
DR ComplexPortal; CPX-143; HCN2 channel complex.
DR DIP; DIP-52285N; -.
DR IntAct; Q9UL51; 8.
DR STRING; 9606.ENSP00000251287; -.
DR BindingDB; Q9UL51; -.
DR ChEMBL; CHEMBL1795172; -.
DR DrugBank; DB02527; Cyclic adenosine monophosphate.
DR DrugBank; DB02315; Cyclic GMP.
DR DrugBank; DB09083; Ivabradine.
DR DrugCentral; Q9UL51; -.
DR GuidetoPHARMACOLOGY; 401; -.
DR TCDB; 1.A.1.5.11; the voltage-gated ion channel (vic) superfamily.
DR GlyGen; Q9UL51; 2 sites, 1 O-linked glycan (1 site).
DR iPTMnet; Q9UL51; -.
DR PhosphoSitePlus; Q9UL51; -.
DR BioMuta; HCN2; -.
DR DMDM; 108935843; -.
DR jPOST; Q9UL51; -.
DR MassIVE; Q9UL51; -.
DR MaxQB; Q9UL51; -.
DR PaxDb; Q9UL51; -.
DR PeptideAtlas; Q9UL51; -.
DR PRIDE; Q9UL51; -.
DR ProteomicsDB; 84951; -.
DR Antibodypedia; 22327; 227 antibodies from 32 providers.
DR DNASU; 610; -.
DR Ensembl; ENST00000251287.3; ENSP00000251287.1; ENSG00000099822.3.
DR GeneID; 610; -.
DR KEGG; hsa:610; -.
DR MANE-Select; ENST00000251287.3; ENSP00000251287.1; NM_001194.4; NP_001185.3.
DR UCSC; uc002lpe.3; human.
DR CTD; 610; -.
DR DisGeNET; 610; -.
DR GeneCards; HCN2; -.
DR HGNC; HGNC:4846; HCN2.
DR HPA; ENSG00000099822; Tissue enriched (brain).
DR MIM; 602477; phenotype.
DR MIM; 602781; gene.
DR neXtProt; NX_Q9UL51; -.
DR OpenTargets; ENSG00000099822; -.
DR PharmGKB; PA78; -.
DR VEuPathDB; HostDB:ENSG00000099822; -.
DR eggNOG; KOG0498; Eukaryota.
DR GeneTree; ENSGT00940000156523; -.
DR HOGENOM; CLU_005746_15_1_1; -.
DR InParanoid; Q9UL51; -.
DR OMA; PRMMRRF; -.
DR OrthoDB; 281394at2759; -.
DR PhylomeDB; Q9UL51; -.
DR TreeFam; TF318250; -.
DR PathwayCommons; Q9UL51; -.
DR Reactome; R-HSA-1296061; HCN channels.
DR SignaLink; Q9UL51; -.
DR SIGNOR; Q9UL51; -.
DR BioGRID-ORCS; 610; 15 hits in 1032 CRISPR screens.
DR ChiTaRS; HCN2; human.
DR GeneWiki; HCN2; -.
DR GenomeRNAi; 610; -.
DR Pharos; Q9UL51; Tclin.
DR PRO; PR:Q9UL51; -.
DR Proteomes; UP000005640; Chromosome 19.
DR RNAct; Q9UL51; protein.
DR Bgee; ENSG00000099822; Expressed in C1 segment of cervical spinal cord and 140 other tissues.
DR Genevisible; Q9UL51; 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:0005887; C:integral component of plasma membrane; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0008076; C:voltage-gated potassium channel complex; TAS:ProtInc.
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:0005248; F:voltage-gated sodium channel activity; IMP:UniProtKB.
DR GO; GO:0007267; P:cell-cell signaling; TAS: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: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: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: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; cAMP; cAMP-binding; Cell membrane; Disease variant; Epilepsy;
KW Glycoprotein; Ion channel; Ion transport; Ligand-gated ion channel;
KW Membrane; Methylation; Nucleotide-binding; Phosphoprotein; Potassium;
KW Potassium channel; Potassium transport; Reference proteome; Sodium;
KW Sodium channel; Sodium transport; Transmembrane; Transmembrane helix;
KW Transport; Voltage-gated channel.
FT CHAIN 1..889
FT /note="Potassium/sodium hyperpolarization-activated cyclic
FT nucleotide-gated channel 2"
FT /id="PRO_0000054111"
FT TOPO_DOM 1..215
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 216..236
FT /note="Helical; Name=Segment S1"
FT /evidence="ECO:0000255"
FT TOPO_DOM 237..240
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 241..261
FT /note="Helical; Name=Segment S2"
FT /evidence="ECO:0000255"
FT TOPO_DOM 262..288
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 289..309
FT /note="Helical; Name=Segment S3"
FT /evidence="ECO:0000255"
FT TOPO_DOM 310..317
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 318..338
FT /note="Helical; Voltage-sensor; Name=Segment S4"
FT /evidence="ECO:0000255"
FT TOPO_DOM 339..369
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 370..390
FT /note="Helical; Name=Segment S5"
FT /evidence="ECO:0000255"
FT TOPO_DOM 391..413
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT INTRAMEM 414..435
FT /note="Pore-forming; Name=Segment H5"
FT /evidence="ECO:0000255"
FT TOPO_DOM 436..440
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 441..461
FT /note="Helical; Name=Segment S6"
FT /evidence="ECO:0000255"
FT TOPO_DOM 462..889
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 1..159
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 158..209
FT /note="Involved in subunit assembly"
FT /evidence="ECO:0000250"
FT REGION 754..889
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 15..59
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 756..788
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 608..611
FT /ligand="3',5'-cyclic AMP"
FT /ligand_id="ChEBI:CHEBI:58165"
FT /evidence="ECO:0000269|PubMed:22006928"
FT BINDING 618..619
FT /ligand="3',5'-cyclic AMP"
FT /ligand_id="ChEBI:CHEBI:58165"
FT /evidence="ECO:0000269|PubMed:22006928"
FT BINDING 659..662
FT /ligand="3',5'-cyclic AMP"
FT /ligand_id="ChEBI:CHEBI:58165"
FT /evidence="ECO:0000269|PubMed:22006928"
FT MOD_RES 146
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O88703"
FT MOD_RES 161
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9JKA9"
FT MOD_RES 668
FT /note="Phosphoserine; by PKG/PRKG2"
FT /evidence="ECO:0000250|UniProtKB:O88703"
FT MOD_RES 754
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9JKA9"
FT MOD_RES 756
FT /note="Omega-N-methylarginine"
FT /evidence="ECO:0000250|UniProtKB:O88703"
FT MOD_RES 771
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O88703"
FT MOD_RES 779
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O88703"
FT MOD_RES 786
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O88703"
FT MOD_RES 866
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O88703"
FT MOD_RES 868
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O88703"
FT CARBOHYD 407
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VARIANT 126
FT /note="S -> L (in FEB2; affects channel activity resulting
FT in faster kinetics and increased current density at higher
FT temperature compared to wild type)"
FT /evidence="ECO:0000269|PubMed:24324597"
FT /id="VAR_086190"
FT VARIANT 246
FT /note="V -> M (in EIG17; associated with disease
FT susceptibility; gain-of-function variant; affects channel
FT activity resulting in a depolarizing shift in activation
FT and faster activation kinetics compared to controls)"
FT /evidence="ECO:0000269|PubMed:29064616"
FT /id="VAR_086191"
FT VARIANT 280
FT /note="E -> K (does not affect channel activity;
FT dbSNP:rs114790896)"
FT /evidence="ECO:0000269|PubMed:29064616"
FT /id="VAR_086192"
FT VARIANT 418
FT /note="L -> V (de novo variant found in a patient with
FT childhood apraxia of speech; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:29463886"
FT /id="VAR_081530"
FT VARIANT 515
FT /note="E -> K (in EIG17; associated with disease
FT susceptibility; causes a large negative shift of the
FT activation curve; homomeric mutant channels transfected
FT into rat cortical neurons lower the threshold of action
FT potential firing and strongly increase cell excitability
FT when compared with wild-type channels)"
FT /evidence="ECO:0000269|PubMed:22131395"
FT /id="VAR_086193"
FT VARIANT 527
FT /note="R -> Q (in dbSNP:rs55687900)"
FT /id="VAR_061106"
FT VARIANT 632
FT /note="S -> W (in EIG17; associated with disease
FT susceptibility; gain-of-function variant; affects channel
FT activity resulting in a depolarizing shift in activation
FT and faster activation kinetics compared to controls)"
FT /evidence="ECO:0000269|PubMed:29064616"
FT /id="VAR_086194"
FT VARIANT 705
FT /note="A -> T (does not affect channel activity;
FT dbSNP:rs200188844)"
FT /evidence="ECO:0000269|PubMed:29064616"
FT /id="VAR_086195"
FT VARIANT 756
FT /note="R -> C (in EIG17; unknown pathological significance;
FT does not affect channel activity)"
FT /evidence="ECO:0000269|PubMed:29064616"
FT /id="VAR_086196"
FT CONFLICT 17..20
FT /note="TPAP -> SPTT (in Ref. 1; AAC28444)"
FT /evidence="ECO:0000305"
FT CONFLICT 29
FT /note="A -> R (in Ref. 1; AAC28444)"
FT /evidence="ECO:0000305"
FT CONFLICT 32
FT /note="Q -> K (in Ref. 1; AAC28444)"
FT /evidence="ECO:0000305"
FT CONFLICT 294
FT /note="D -> V (in Ref. 4; AAC39760)"
FT /evidence="ECO:0000305"
FT CONFLICT 713
FT /note="L -> F (in Ref. 4; AAC39760)"
FT /evidence="ECO:0000305"
FT CONFLICT 849
FT /note="G -> R (in Ref. 2; CAB42602/CAB42630)"
FT /evidence="ECO:0000305"
FT HELIX 471..489
FT /evidence="ECO:0007829|PDB:3U10"
FT HELIX 494..508
FT /evidence="ECO:0007829|PDB:3U10"
FT HELIX 515..520
FT /evidence="ECO:0007829|PDB:3U10"
FT HELIX 524..534
FT /evidence="ECO:0007829|PDB:3U10"
FT HELIX 536..540
FT /evidence="ECO:0007829|PDB:3U10"
FT TURN 543..547
FT /evidence="ECO:0007829|PDB:3U10"
FT HELIX 550..557
FT /evidence="ECO:0007829|PDB:3U10"
FT STRAND 561..565
FT /evidence="ECO:0007829|PDB:3U10"
FT STRAND 570..572
FT /evidence="ECO:0007829|PDB:3U10"
FT STRAND 576..578
FT /evidence="ECO:0007829|PDB:2MPF"
FT STRAND 580..586
FT /evidence="ECO:0007829|PDB:3U10"
FT STRAND 589..592
FT /evidence="ECO:0007829|PDB:3U10"
FT STRAND 598..601
FT /evidence="ECO:0007829|PDB:3U10"
FT STRAND 606..608
FT /evidence="ECO:0007829|PDB:3U10"
FT HELIX 610..614
FT /evidence="ECO:0007829|PDB:3U10"
FT STRAND 619..626
FT /evidence="ECO:0007829|PDB:3U10"
FT STRAND 628..634
FT /evidence="ECO:0007829|PDB:3U10"
FT HELIX 635..644
FT /evidence="ECO:0007829|PDB:3U10"
FT HELIX 646..661
FT /evidence="ECO:0007829|PDB:3U10"
FT TURN 662..664
FT /evidence="ECO:0007829|PDB:3U10"
FT HELIX 668..670
FT /evidence="ECO:0007829|PDB:3U10"
SQ SEQUENCE 889 AA; 96950 MW; 4B263E0C06C2A47D CRC64;
MDARGGGGRP GESPGATPAP GPPPPPPPAP PQQQPPPPPP PAPPPGPGPA PPQHPPRAEA
LPPEAADEGG PRGRLRSRDS SCGRPGTPGA ASTAKGSPNG ECGRGEPQCS PAGPEGPARG
PKVSFSCRGA ASGPAPGPGP AEEAGSEEAG PAGEPRGSQA SFMQRQFGAL LQPGVNKFSL
RMFGSQKAVE REQERVKSAG AWIIHPYSDF RFYWDFTMLL FMVGNLIIIP VGITFFKDET
TAPWIVFNVV SDTFFLMDLV LNFRTGIVIE DNTEIILDPE KIKKKYLRTW FVVDFVSSIP
VDYIFLIVEK GIDSEVYKTA RALRIVRFTK ILSLLRLLRL SRLIRYIHQW EEIFHMTYDL
ASAVMRICNL ISMMLLLCHW DGCLQFLVPM LQDFPRNCWV SINGMVNHSW SELYSFALFK
AMSHMLCIGY GRQAPESMTD IWLTMLSMIV GATCYAMFIG HATALIQSLD SSRRQYQEKY
KQVEQYMSFH KLPADFRQKI HDYYEHRYQG KMFDEDSILG ELNGPLREEI VNFNCRKLVA
SMPLFANADP NFVTAMLTKL KFEVFQPGDY IIREGTIGKK MYFIQHGVVS VLTKGNKEMK
LSDGSYFGEI CLLTRGRRTA SVRADTYCRL YSLSVDNFNE VLEEYPMMRR AFETVAIDRL
DRIGKKNSIL LHKVQHDLNS GVFNNQENAI IQEIVKYDRE MVQQAELGQR VGLFPPPPPP
PQVTSAIATL QQAAAMSFCP QVARPLVGPL ALGSPRLVRR PPPGPAPAAA SPGPPPPASP
PGAPASPRAP RTSPYGGLPA APLAGPALPA RRLSRASRPL SASQPSLPHG APGPAASTRP
ASSSTPRLGP TPAARAAAPS PDRRDSASPG AAGGLDPQDS ARSRLSSNL
