GenomeNet

Database: UniProt/SWISS-PROT
Entry: CAC1E_HUMAN
LinkDB: CAC1E_HUMAN
Original site: CAC1E_HUMAN 
ID   CAC1E_HUMAN             Reviewed;        2313 AA.
AC   Q15878; B1AM12; B1AM13; B1AM14; Q14580; Q14581;
DT   15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
DT   14-OCT-2008, sequence version 3.
DT   07-OCT-2020, entry version 192.
DE   RecName: Full=Voltage-dependent R-type calcium channel subunit alpha-1E;
DE   AltName: Full=Brain calcium channel II;
DE            Short=BII;
DE   AltName: Full=Calcium channel, L type, alpha-1 polypeptide, isoform 6;
DE   AltName: Full=Voltage-gated calcium channel subunit alpha Cav2.3;
GN   Name=CACNA1E; Synonyms=CACH6, CACNL1A6;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT THR-1955.
RC   TISSUE=Brain;
RX   PubMed=7536609;
RA   Schneider T., Wei X., Olcese R., Costantin J.L., Neely A., Palade P.,
RA   Perez-Reyes E., Qin N., Zhou J., Crawford G.D., Smith R.G., Appel S.H.,
RA   Stefani E., Birnbaumer M.;
RT   "Molecular analysis and functional expression of the human type E neuronal
RT   Ca2+ channel alpha 1 subunit.";
RL   Recept. Channels 2:255-270(1994).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2 AND 3).
RC   TISSUE=Hippocampus;
RX   PubMed=8071363;
RA   Williams M.E., Marubio L.M., Deal C.R., Hans M., Brust P.F.,
RA   Philipson L.H., Miller R.J., Johnson E.C., Harpold M.M., Ellis S.B.;
RT   "Structure and functional characterization of neuronal alpha 1E calcium
RT   channel subtypes.";
RL   J. Biol. Chem. 269:22347-22357(1994).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=16710414; DOI=10.1038/nature04727;
RA   Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA   Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA   Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA   Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA   Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA   Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA   Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA   Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA   Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA   Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA   Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA   Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA   Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA   Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA   Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA   Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA   Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA   Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA   Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA   McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA   Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA   Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA   Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA   Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA   Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA   White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA   Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA   Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA   Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT   "The DNA sequence and biological annotation of human chromosome 1.";
RL   Nature 441:315-321(2006).
RN   [4]
RP   INTERACTION WITH EFHC1.
RX   PubMed=15258581; DOI=10.1038/ng1393;
RA   Suzuki T., Delgado-Escueta A.V., Aguan K., Alonso M.E., Shi J., Hara Y.,
RA   Nishida M., Numata T., Medina M.T., Takeuchi T., Morita R., Bai D.,
RA   Ganesh S., Sugimoto Y., Inazawa J., Bailey J.N., Ochoa A., Jara-Prado A.,
RA   Rasmussen A., Ramos-Peek J., Cordova S., Rubio-Donnadieu F., Inoue Y.,
RA   Osawa M., Kaneko S., Oguni H., Mori Y., Yamakawa K.;
RT   "Mutations in EFHC1 cause juvenile myoclonic epilepsy.";
RL   Nat. Genet. 36:842-849(2004).
RN   [5]
RP   FUNCTION, INVOLVEMENT IN EIEE69, VARIANTS EIEE69 PRO-228; ARG-348; ARG-352;
RP   LEU-603; ASP-690; SER-698; THR-700; VAL-701; PRO-702; THR-702;
RP   829-ARG--CYS-2313 DEL; 1389-ARG--CYS-2313 DEL; PHE-1422; ASN-1425; ARG-1430
RP   AND GLY-1720, AND CHARACTERIZATION OF VARIANTS EIEE69 LEU-603; SER-698;
RP   VAL-701 AND THR-702.
RX   PubMed=30343943; DOI=10.1016/j.ajhg.2018.09.006;
RG   Task Force for Neonatal Genomics;
RG   Deciphering Developmental Disorders Study;
RA   Helbig K.L., Lauerer R.J., Bahr J.C., Souza I.A., Myers C.T., Uysal B.,
RA   Schwarz N., Gandini M.A., Huang S., Keren B., Mignot C., Afenjar A.,
RA   Billette de Villemeur T., Heron D., Nava C., Valence S., Buratti J.,
RA   Fagerberg C.R., Soerensen K.P., Kibaek M., Kamsteeg E.J., Koolen D.A.,
RA   Gunning B., Schelhaas H.J., Kruer M.C., Fox J., Bakhtiari S., Jarrar R.,
RA   Padilla-Lopez S., Lindstrom K., Jin S.C., Zeng X., Bilguvar K.,
RA   Papavasileiou A., Xing Q., Zhu C., Boysen K., Vairo F., Lanpher B.C.,
RA   Klee E.W., Tillema J.M., Payne E.T., Cousin M.A., Kruisselbrink T.M.,
RA   Wick M.J., Baker J., Haan E., Smith N., Sadeghpour A., Davis E.E.,
RA   Katsanis N., Corbett M.A., MacLennan A.H., Gecz J., Biskup S., Goldmann E.,
RA   Rodan L.H., Kichula E., Segal E., Jackson K.E., Asamoah A., Dimmock D.,
RA   McCarrier J., Botto L.D., Filloux F., Tvrdik T., Cascino G.D.,
RA   Klingerman S., Neumann C., Wang R., Jacobsen J.C., Nolan M.A., Snell R.G.,
RA   Lehnert K., Sadleir L.G., Anderlid B.M., Kvarnung M., Guerrini R.,
RA   Friez M.J., Lyons M.J., Leonhard J., Kringlen G., Casas K., El Achkar C.M.,
RA   Smith L.A., Rotenberg A., Poduri A., Sanchis-Juan A., Carss K.J.,
RA   Rankin J., Zeman A., Raymond F.L., Blyth M., Kerr B., Ruiz K., Urquhart J.,
RA   Hughes I., Banka S., Hedrich U.B.S., Scheffer I.E., Helbig I.,
RA   Zamponi G.W., Lerche H., Mefford H.C.;
RT   "De novo pathogenic variants in CACNA1E cause developmental and epileptic
RT   encephalopathy with contractures, macrocephaly, and dyskinesias.";
RL   Am. J. Hum. Genet. 103:666-678(2018).
RN   [6]
RP   X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 1867-1885.
RX   PubMed=18400181; DOI=10.1016/j.str.2008.01.011;
RA   Mori M.X., Vander Kooi C.W., Leahy D.J., Yue D.T.;
RT   "Crystal structure of the CaV2 IQ domain in complex with Ca2+/calmodulin:
RT   high-resolution mechanistic implications for channel regulation by Ca2+.";
RL   Structure 16:607-620(2008).
CC   -!- FUNCTION: Voltage-sensitive calcium channels (VSCC) mediate the entry
CC       of calcium ions into excitable cells (PubMed:30343943). They are also
CC       involved in a variety of calcium-dependent processes, including muscle
CC       contraction, hormone or neurotransmitter release, gene expression, cell
CC       motility, cell division and cell death. The isoform alpha-1E gives rise
CC       to R-type calcium currents. R-type calcium channels belong to the
CC       'high-voltage activated' (HVA) group and are blocked by nickel. They
CC       are however insensitive to dihydropyridines (DHP). Calcium channels
CC       containing alpha-1E subunit could be involved in the modulation of
CC       firing patterns of neurons which is important for information
CC       processing. {ECO:0000269|PubMed:30343943}.
CC   -!- SUBUNIT: Interacts with EFHC1. Voltage-dependent calcium channels are
CC       multisubunit complexes, consisting of alpha-1, alpha-2, beta and delta
CC       subunits in a 1:1:1:1 ratio. The channel activity is directed by the
CC       pore-forming and voltage-sensitive alpha-1 subunit. In many cases, this
CC       subunit is sufficient to generate voltage-sensitive calcium channel
CC       activity. The auxiliary subunits beta and alpha-2/delta linked by a
CC       disulfide bridge regulate the channel activity.
CC       {ECO:0000269|PubMed:15258581}.
CC   -!- SUBCELLULAR LOCATION: Membrane; Multi-pass membrane protein.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=3;
CC       Name=1; Synonyms=Alpha-1E;
CC         IsoId=Q15878-1; Sequence=Displayed;
CC       Name=2; Synonyms=Alpha-1E-1;
CC         IsoId=Q15878-2; Sequence=VSP_000937, VSP_024817;
CC       Name=3; Synonyms=Alpha-1E-3;
CC         IsoId=Q15878-3; Sequence=VSP_024817;
CC   -!- TISSUE SPECIFICITY: Expressed in neuronal tissues and in kidney.
CC   -!- DOMAIN: Each of the four internal repeats contains five hydrophobic
CC       transmembrane segments (S1, S2, S3, S5, S6) and one positively charged
CC       transmembrane segment (S4). S4 segments probably represent the voltage-
CC       sensor and are characterized by a series of positively charged amino
CC       acids at every third position.
CC   -!- DISEASE: Epileptic encephalopathy, early infantile, 69 (EIEE69)
CC       [MIM:618285]: A form of epileptic encephalopathy, a heterogeneous group
CC       of severe childhood onset epilepsies characterized by refractory
CC       seizures, neurodevelopmental impairment, and poor prognosis.
CC       Development is normal prior to seizure onset, after which cognitive and
CC       motor delays become apparent. EIEE69 is an autosomal dominant form
CC       characterized by early-onset refractory seizures, hypotonia, and
CC       profoundly impaired development often associated with macrocephaly,
CC       hyperkinetic movements, and contractures. The disorder can sometimes
CC       result in early death. Some patients may have a favorable seizure
CC       response to topiramate medication. {ECO:0000269|PubMed:30343943}.
CC       Note=The disease is caused by mutations affecting the gene represented
CC       in this entry.
CC   -!- SIMILARITY: Belongs to the calcium channel alpha-1 subunit (TC
CC       1.A.1.11) family. CACNA1E subfamily. {ECO:0000305}.
DR   EMBL; L27745; AAA72125.1; -; mRNA.
DR   EMBL; L29384; AAA59204.1; -; mRNA.
DR   EMBL; L29385; AAA59205.1; -; mRNA.
DR   EMBL; AL161734; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AL359270; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AL160059; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AL590998; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   CCDS; CCDS53443.1; -. [Q15878-3]
DR   CCDS; CCDS55664.1; -. [Q15878-1]
DR   CCDS; CCDS55665.1; -. [Q15878-2]
DR   PIR; A54972; A54972.
DR   PIR; B54972; B54972.
DR   RefSeq; NP_000712.2; NM_000721.3. [Q15878-3]
DR   RefSeq; NP_001192222.1; NM_001205293.1. [Q15878-1]
DR   RefSeq; NP_001192223.1; NM_001205294.1. [Q15878-2]
DR   PDB; 3BXL; X-ray; 2.30 A; B=1867-1887.
DR   PDBsum; 3BXL; -.
DR   SMR; Q15878; -.
DR   BioGRID; 107231; 2.
DR   IntAct; Q15878; 1.
DR   STRING; 9606.ENSP00000356545; -.
DR   BindingDB; Q15878; -.
DR   ChEMBL; CHEMBL1687682; -.
DR   DrugBank; DB13746; Bioallethrin.
DR   DrugBank; DB11148; Butamben.
DR   DrugBank; DB11093; Calcium citrate.
DR   DrugBank; DB11348; Calcium Phosphate.
DR   DrugBank; DB14481; Calcium phosphate dihydrate.
DR   DrugBank; DB00153; Ergocalciferol.
DR   DrugBank; DB00555; Lamotrigine.
DR   DrugBank; DB00421; Spironolactone.
DR   DrugBank; DB00273; Topiramate.
DR   GuidetoPHARMACOLOGY; 534; -.
DR   GlyGen; Q15878; 3 sites.
DR   iPTMnet; Q15878; -.
DR   PhosphoSitePlus; Q15878; -.
DR   BioMuta; CACNA1E; -.
DR   DMDM; 209572758; -.
DR   EPD; Q15878; -.
DR   jPOST; Q15878; -.
DR   MassIVE; Q15878; -.
DR   MaxQB; Q15878; -.
DR   PaxDb; Q15878; -.
DR   PeptideAtlas; Q15878; -.
DR   PRIDE; Q15878; -.
DR   ProteomicsDB; 60800; -. [Q15878-1]
DR   ProteomicsDB; 60801; -. [Q15878-2]
DR   ProteomicsDB; 60802; -. [Q15878-3]
DR   Antibodypedia; 34433; 115 antibodies.
DR   Ensembl; ENST00000358338; ENSP00000351101; ENSG00000198216. [Q15878-2]
DR   Ensembl; ENST00000367567; ENSP00000356539; ENSG00000198216. [Q15878-3]
DR   Ensembl; ENST00000367570; ENSP00000356542; ENSG00000198216. [Q15878-3]
DR   Ensembl; ENST00000367573; ENSP00000356545; ENSG00000198216. [Q15878-1]
DR   Ensembl; ENST00000621551; ENSP00000483914; ENSG00000198216. [Q15878-1]
DR   Ensembl; ENST00000621791; ENSP00000481619; ENSG00000198216. [Q15878-2]
DR   GeneID; 777; -.
DR   KEGG; hsa:777; -.
DR   UCSC; uc001gow.5; human. [Q15878-1]
DR   CTD; 777; -.
DR   DisGeNET; 777; -.
DR   EuPathDB; HostDB:ENSG00000198216.10; -.
DR   GeneCards; CACNA1E; -.
DR   HGNC; HGNC:1392; CACNA1E.
DR   HPA; ENSG00000198216; Tissue enriched (brain).
DR   MalaCards; CACNA1E; -.
DR   MIM; 601013; gene.
DR   MIM; 618285; phenotype.
DR   neXtProt; NX_Q15878; -.
DR   OpenTargets; ENSG00000198216; -.
DR   PharmGKB; PA26009; -.
DR   eggNOG; KOG2301; Eukaryota.
DR   GeneTree; ENSGT00940000155601; -.
DR   HOGENOM; CLU_000540_1_0_1; -.
DR   InParanoid; Q15878; -.
DR   KO; K04852; -.
DR   OMA; GQFQEHQ; -.
DR   OrthoDB; 172471at2759; -.
DR   PhylomeDB; Q15878; -.
DR   TreeFam; TF312805; -.
DR   PathwayCommons; Q15878; -.
DR   Reactome; R-HSA-112308; Presynaptic depolarization and calcium channel opening.
DR   Reactome; R-HSA-422356; Regulation of insulin secretion.
DR   BioGRID-ORCS; 777; 4 hits in 861 CRISPR screens.
DR   ChiTaRS; CACNA1E; human.
DR   EvolutionaryTrace; Q15878; -.
DR   GeneWiki; R-type_calcium_channel; -.
DR   GenomeRNAi; 777; -.
DR   Pharos; Q15878; Tchem.
DR   PRO; PR:Q15878; -.
DR   Proteomes; UP000005640; Chromosome 1.
DR   RNAct; Q15878; protein.
DR   Bgee; ENSG00000198216; Expressed in caudate nucleus and 88 other tissues.
DR   ExpressionAtlas; Q15878; baseline and differential.
DR   Genevisible; Q15878; HS.
DR   GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR   GO; GO:0045202; C:synapse; IEA:GOC.
DR   GO; GO:0005891; C:voltage-gated calcium channel complex; TAS:ProtInc.
DR   GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR   GO; GO:0005245; F:voltage-gated calcium channel activity; IDA:MGI.
DR   GO; GO:0022843; F:voltage-gated cation channel activity; IDA:UniProtKB.
DR   GO; GO:0070509; P:calcium ion import; IBA:GO_Central.
DR   GO; GO:0006816; P:calcium ion transport; IBA:GO_Central.
DR   GO; GO:0007268; P:chemical synaptic transmission; IBA:GO_Central.
DR   GO; GO:0051899; P:membrane depolarization; TAS:Reactome.
DR   GO; GO:0050796; P:regulation of insulin secretion; TAS:Reactome.
DR   GO; GO:0034765; P:regulation of ion transmembrane transport; IEA:UniProtKB-KW.
DR   Gene3D; 1.20.120.350; -; 4.
DR   InterPro; IPR002048; EF_hand_dom.
DR   InterPro; IPR031649; GPHH_dom.
DR   InterPro; IPR005821; Ion_trans_dom.
DR   InterPro; IPR014873; VDCC_a1su_IQ.
DR   InterPro; IPR005449; VDCC_R_a1su.
DR   InterPro; IPR002077; VDCCAlpha1.
DR   InterPro; IPR027359; Volt_channel_dom_sf.
DR   PANTHER; PTHR45628:SF5; PTHR45628:SF5; 1.
DR   Pfam; PF08763; Ca_chan_IQ; 1.
DR   Pfam; PF16905; GPHH; 1.
DR   Pfam; PF00520; Ion_trans; 4.
DR   PRINTS; PR00167; CACHANNEL.
DR   PRINTS; PR01633; RVDCCALPHA1.
DR   SMART; SM01062; Ca_chan_IQ; 1.
DR   PROSITE; PS50222; EF_HAND_2; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Alternative splicing; Calcium; Calcium channel;
KW   Calcium transport; Disease mutation; Disulfide bond; Epilepsy;
KW   Glycoprotein; Ion channel; Ion transport; Membrane; Metal-binding;
KW   Phosphoprotein; Polymorphism; Reference proteome; Repeat; Transmembrane;
KW   Transmembrane helix; Transport; Voltage-gated channel.
FT   CHAIN           1..2313
FT                   /note="Voltage-dependent R-type calcium channel subunit
FT                   alpha-1E"
FT                   /id="PRO_0000053938"
FT   TOPO_DOM        1..89
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        90..108
FT                   /note="Helical; Name=S1 of repeat I"
FT   TOPO_DOM        109..127
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        128..146
FT                   /note="Helical; Name=S2 of repeat I"
FT   TOPO_DOM        147..158
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        159..173
FT                   /note="Helical; Name=S3 of repeat I"
FT   TOPO_DOM        174..185
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        186..205
FT                   /note="Helical; Name=S4 of repeat I"
FT   TOPO_DOM        206..223
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        224..244
FT                   /note="Helical; Name=S5 of repeat I"
FT   TOPO_DOM        245..326
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        327..350
FT                   /note="Helical; Name=S6 of repeat I"
FT   TOPO_DOM        351..476
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        477..496
FT                   /note="Helical; Name=S1 of repeat II"
FT   TOPO_DOM        497..509
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        510..529
FT                   /note="Helical; Name=S2 of repeat II"
FT   TOPO_DOM        530..538
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        539..557
FT                   /note="Helical; Name=S3 of repeat II"
FT   TOPO_DOM        558..567
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        568..586
FT                   /note="Helical; Name=S4 of repeat II"
FT   TOPO_DOM        587..605
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        606..625
FT                   /note="Helical; Name=S5 of repeat II"
FT   TOPO_DOM        626..678
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        679..703
FT                   /note="Helical; Name=S6 of repeat II"
FT   TOPO_DOM        704..1148
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        1149..1165
FT                   /note="Helical; Name=S1 of repeat III"
FT   TOPO_DOM        1166..1189
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        1190..1209
FT                   /note="Helical; Name=S2 of repeat III"
FT   TOPO_DOM        1210..1217
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        1218..1240
FT                   /note="Helical; Name=S3 of repeat III"
FT   TOPO_DOM        1241..1254
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        1255..1272
FT                   /note="Helical; Name=S4 of repeat III"
FT   TOPO_DOM        1273..1291
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        1292..1311
FT                   /note="Helical; Name=S5 of repeat III"
FT   TOPO_DOM        1312..1398
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        1399..1422
FT                   /note="Helical; Name=S6 of repeat III"
FT   TOPO_DOM        1423..1479
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        1480..1498
FT                   /note="Helical; Name=S1 of repeat IV"
FT   TOPO_DOM        1499..1513
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        1514..1533
FT                   /note="Helical; Name=S2 of repeat IV"
FT   TOPO_DOM        1534..1541
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        1542..1560
FT                   /note="Helical; Name=S3 of repeat IV"
FT   TOPO_DOM        1561..1571
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        1572..1590
FT                   /note="Helical; Name=S4 of repeat IV"
FT   TOPO_DOM        1591..1609
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        1610..1629
FT                   /note="Helical; Name=S5 of repeat IV"
FT   TOPO_DOM        1630..1698
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        1699..1724
FT                   /note="Helical; Name=S6 of repeat IV"
FT   TOPO_DOM        1725..2313
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   REPEAT          76..354
FT                   /note="I"
FT   REPEAT          462..706
FT                   /note="II"
FT   REPEAT          1140..1426
FT                   /note="III"
FT   REPEAT          1463..1726
FT                   /note="IV"
FT   DOMAIN          1739..1774
FT                   /note="EF-hand"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   CA_BIND         426..437
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   CA_BIND         1752..1763
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00448"
FT   REGION          374..391
FT                   /note="Binding to the beta subunit"
FT                   /evidence="ECO:0000250"
FT   COMPBIAS        716..721
FT                   /note="Poly-Glu"
FT   COMPBIAS        748..753
FT                   /note="Poly-Arg"
FT   COMPBIAS        767..772
FT                   /note="Poly-Arg"
FT   COMPBIAS        1228..1231
FT                   /note="Poly-Val"
FT   COMPBIAS        2284..2288
FT                   /note="Poly-Arg"
FT   SITE            309
FT                   /note="Calcium ion selectivity and permeability"
FT                   /evidence="ECO:0000250"
FT   SITE            657
FT                   /note="Calcium ion selectivity and permeability"
FT                   /evidence="ECO:0000250"
FT   SITE            1372
FT                   /note="Calcium ion selectivity and permeability"
FT                   /evidence="ECO:0000250"
FT   SITE            1663
FT                   /note="Calcium ion selectivity and permeability"
FT                   /evidence="ECO:0000250"
FT   MOD_RES         14
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q61290"
FT   MOD_RES         19
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q61290"
FT   MOD_RES         427
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q61290"
FT   MOD_RES         440
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000250|UniProtKB:Q61290"
FT   MOD_RES         736
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q07652"
FT   MOD_RES         745
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q61290"
FT   MOD_RES         793
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q07652"
FT   MOD_RES         815
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q61290"
FT   MOD_RES         855
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q61290"
FT   MOD_RES         947
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q07652"
FT   MOD_RES         1097
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q07652"
FT   MOD_RES         2094
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q61290"
FT   MOD_RES         2113
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q07652"
FT   CARBOHYD        254
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        1566
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        1571
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   VAR_SEQ         748..766
FT                   /note="Missing (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:8071363"
FT                   /id="VSP_000937"
FT   VAR_SEQ         1967..2009
FT                   /note="Missing (in isoform 2 and isoform 3)"
FT                   /evidence="ECO:0000303|PubMed:8071363"
FT                   /id="VSP_024817"
FT   VARIANT         228
FT                   /note="L -> P (in EIEE69; dbSNP:rs1553286282)"
FT                   /evidence="ECO:0000269|PubMed:30343943"
FT                   /id="VAR_081838"
FT   VARIANT         348
FT                   /note="G -> R (in EIEE69)"
FT                   /evidence="ECO:0000269|PubMed:30343943"
FT                   /id="VAR_081839"
FT   VARIANT         352
FT                   /note="G -> R (in EIEE69; dbSNP:rs886039323)"
FT                   /evidence="ECO:0000269|PubMed:30343943"
FT                   /id="VAR_081840"
FT   VARIANT         603
FT                   /note="I -> L (in EIEE69; gain-of-function variant
FT                   affecting channel activity; results in hyperpolarizing
FT                   shift in half activation voltage; dbSNP:rs778291283)"
FT                   /evidence="ECO:0000269|PubMed:30343943"
FT                   /id="VAR_081841"
FT   VARIANT         690
FT                   /note="G -> D (in EIEE69; dbSNP:rs1361083258)"
FT                   /evidence="ECO:0000269|PubMed:30343943"
FT                   /id="VAR_081842"
FT   VARIANT         698
FT                   /note="F -> S (in EIEE69; gain-of-function variant
FT                   affecting channel activity; shifts the voltage dependence
FT                   of activation toward more negative potentials and slows the
FT                   fast inactivation time course; dbSNP:rs869312920)"
FT                   /evidence="ECO:0000269|PubMed:30343943"
FT                   /id="VAR_081843"
FT   VARIANT         700
FT                   /note="A -> T (in EIEE69)"
FT                   /evidence="ECO:0000269|PubMed:30343943"
FT                   /id="VAR_081844"
FT   VARIANT         701
FT                   /note="I -> V (in EIEE69; gain-of-function variant
FT                   affecting channel activity; shifts the voltage dependence
FT                   of activation toward more negative potentials and slows the
FT                   fast inactivation time course)"
FT                   /evidence="ECO:0000269|PubMed:30343943"
FT                   /id="VAR_081845"
FT   VARIANT         702
FT                   /note="A -> P (in EIEE69; dbSNP:rs12131800)"
FT                   /evidence="ECO:0000269|PubMed:30343943"
FT                   /id="VAR_081846"
FT   VARIANT         702
FT                   /note="A -> T (in EIEE69; gain-of-function variant
FT                   affecting channel activity; shifts the voltage dependence
FT                   of activation toward more negative potentials and slows the
FT                   fast inactivation time course; dbSNP:rs12131800)"
FT                   /evidence="ECO:0000269|PubMed:30343943"
FT                   /id="VAR_081847"
FT   VARIANT         829..2313
FT                   /note="Missing (in EIEE69; unknown pathological
FT                   significance)"
FT                   /evidence="ECO:0000269|PubMed:30343943"
FT                   /id="VAR_081848"
FT   VARIANT         859
FT                   /note="D -> E (in dbSNP:rs35737760)"
FT                   /id="VAR_031912"
FT   VARIANT         1389..2313
FT                   /note="Missing (in EIEE69; unknown pathological
FT                   significance)"
FT                   /evidence="ECO:0000269|PubMed:30343943"
FT                   /id="VAR_081849"
FT   VARIANT         1422
FT                   /note="I -> F (in EIEE69)"
FT                   /evidence="ECO:0000269|PubMed:30343943"
FT                   /id="VAR_081850"
FT   VARIANT         1425
FT                   /note="T -> N (in EIEE69)"
FT                   /evidence="ECO:0000269|PubMed:30343943"
FT                   /id="VAR_081851"
FT   VARIANT         1430
FT                   /note="G -> R (in EIEE69; dbSNP:rs1553345844)"
FT                   /evidence="ECO:0000269|PubMed:30343943"
FT                   /id="VAR_081852"
FT   VARIANT         1720
FT                   /note="A -> G (in EIEE69)"
FT                   /evidence="ECO:0000269|PubMed:30343943"
FT                   /id="VAR_081853"
FT   VARIANT         1955
FT                   /note="A -> T (in dbSNP:rs704326)"
FT                   /evidence="ECO:0000269|PubMed:7536609"
FT                   /id="VAR_046996"
FT   CONFLICT        648
FT                   /note="M -> I (in Ref. 1; AAA72125)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        836..838
FT                   /note="LAL -> WP (in Ref. 1; AAA72125)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        2077
FT                   /note="R -> P (in Ref. 2; AAA59204/AAA59205)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        2084
FT                   /note="G -> R (in Ref. 2; AAA59204/AAA59205)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        2206
FT                   /note="C -> W (in Ref. 2; AAA59204/AAA59205)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        2219
FT                   /note="S -> R (in Ref. 2; AAA59204/AAA59205)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        2245
FT                   /note="G -> V (in Ref. 2; AAA59204/AAA59205)"
FT                   /evidence="ECO:0000305"
FT   HELIX           1868..1882
FT                   /evidence="ECO:0000244|PDB:3BXL"
SQ   SEQUENCE   2313 AA;  261731 MW;  CCC7F309C27C42F1 CRC64;
     MARFGEAVVA RPGSGDGDSD QSRNRQGTPV PASGQAAAYK QTKAQRARTM ALYNPIPVRQ
     NCFTVNRSLF IFGEDNIVRK YAKKLIDWPP FEYMILATII ANCIVLALEQ HLPEDDKTPM
     SRRLEKTEPY FIGIFCFEAG IKIVALGFIF HKGSYLRNGW NVMDFIVVLS GILATAGTHF
     NTHVDLRTLR AVRVLRPLKL VSGIPSLQIV LKSIMKAMVP LLQIGLLLFF AILMFAIIGL
     EFYSGKLHRA CFMNNSGILE GFDPPHPCGV QGCPAGYECK DWIGPNDGIT QFDNILFAVL
     TVFQCITMEG WTTVLYNTND ALGATWNWLY FIPLIIIGSF FVLNLVLGVL SGEFAKERER
     VENRRAFMKL RRQQQIEREL NGYRAWIDKA EEVMLAEENK NAGTSALEVL RRATIKRSRT
     EAMTRDSSDE HCVDISSVGT PLARASIKSA KVDGVSYFRH KERLLRISIR HMVKSQVFYW
     IVLSLVALNT ACVAIVHHNQ PQWLTHLLYY AEFLFLGLFL LEMSLKMYGM GPRLYFHSSF
     NCFDFGVTVG SIFEVVWAIF RPGTSFGISV LRALRLLRIF KITKYWASLR NLVVSLMSSM
     KSIISLLFLL FLFIVVFALL GMQLFGGRFN FNDGTPSANF DTFPAAIMTV FQILTGEDWN
     EVMYNGIRSQ GGVSSGMWSA IYFIVLTLFG NYTLLNVFLA IAVDNLANAQ ELTKDEQEEE
     EAFNQKHALQ KAKEVSPMSA PNMPSIERDR RRRHHMSMWE PRSSHLRERR RRHHMSVWEQ
     RTSQLRKHMQ MSSQEALNRE EAPTMNPLNP LNPLSSLNPL NAHPSLYRRP RAIEGLALGL
     ALEKFEEERI SRGGSLKGDG GDRSSALDNQ RTPLSLGQRE PPWLARPCHG NCDPTQQEAG
     GGEAVVTFED RARHRQSQRR SRHRRVRTEG KESSSASRSR SASQERSLDE AMPTEGEKDH
     ELRGNHGAKE PTIQEERAQD LRRTNSLMVS RGSGLAGGLD EADTPLVLPH PELEVGKHVV
     LTEQEPEGSS EQALLGNVQL DMGRVISQSE PDLSCITANT DKATTESTSV TVAIPDVDPL
     VDSTVVHISN KTDGEASPLK EAEIREDEEE VEKKKQKKEK RETGKAMVPH SSMFIFSTTN
     PIRRACHYIV NLRYFEMCIL LVIAASSIAL AAEDPVLTNS ERNKVLRYFD YVFTGVFTFE
     MVIKMIDQGL ILQDGSYFRD LWNILDFVVV VGALVAFALA NALGTNKGRD IKTIKSLRVL
     RVLRPLKTIK RLPKLKAVFD CVVTSLKNVF NILIVYKLFM FIFAVIAVQL FKGKFFYCTD
     SSKDTEKECI GNYVDHEKNK MEVKGREWKR HEFHYDNIIW ALLTLFTVST GEGWPQVLQH
     SVDVTEEDRG PSRSNRMEMS IFYVVYFVVF PFFFVNIFVA LIIITFQEQG DKMMEECSLE
     KNERACIDFA ISAKPLTRYM PQNRHTFQYR VWHFVVSPSF EYTIMAMIAL NTVVLMMKYY
     SAPCTYELAL KYLNIAFTMV FSLECVLKVI AFGFLNYFRD TWNIFDFITV IGSITEIILT
     DSKLVNTSGF NMSFLKLFRA ARLIKLLRQG YTIRILLWTF VQSFKALPYV CLLIAMLFFI
     YAIIGMQVFG NIKLDEESHI NRHNNFRSFF GSLMLLFRSA TGEAWQEIML SCLGEKGCEP
     DTTAPSGQNE NERCGTDLAY VYFVSFIFFC SFLMLNLFVA VIMDNFEYLT RDSSILGPHH
     LDEFVRVWAE YDRAACGRIH YTEMYEMLTL MSPPLGLGKR CPSKVAYKRL VLMNMPVAED
     MTVHFTSTLM ALIRTALDIK IAKGGADRQQ LDSELQKETL AIWPHLSQKM LDLLVPMPKA
     SDLTVGKIYA AMMIMDYYKQ SKVKKQRQQL EEQKNAPMFQ RMEPSSLPQE IIANAKALPY
     LQQDPVSGLS GRSGYPSMSP LSPQDIFQLA CMDPADDGQF QERQSLEPEV SELKSVQPSN
     HGIYLPSDTQ EHAGSGRASS MPRLTVDPQV VTDPSSMRRS FSTIRDKRSN SSWLEEFSME
     RSSENTYKSR RRSYHSSLRL SAHRLNSDSG HKSDTHRSGG RERGRSKERK HLLSPDVSRC
     NSEERGTQAD WESPERRQSR SPSEGRSQTP NRQGTGSLSE SSIPSVSDTS TPRRSRRQLP
     PVPPKPRPLL SYSSLIRHAG SISPPADGSE EGSPLTSQAL ESNNACLTES SNSPHPQQSQ
     HASPQRYISE PYLALHEDSH ASDCGEEETL TFEAAVATSL GRSNTIGSAP PLRHSWQMPN
     GHYRRRRRGG PGPGMMCGAV NNLLSDTEED DKC
//
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