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 03-AUG-2022, entry version 200.
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; DOI=10.1016/s0021-9258(17)31796-9;
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 DEE69, VARIANTS DEE69 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 DEE69 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: Developmental and epileptic encephalopathy 69 (DEE69)
CC [MIM:618285]: A form of epileptic encephalopathy, a heterogeneous group
CC of severe early-onset epilepsies characterized by refractory seizures,
CC neurodevelopmental impairment, and poor prognosis. Development is
CC normal prior to seizure onset, after which cognitive and motor delays
CC become apparent. DEE69 is an autosomal dominant form characterized by
CC refractory seizures, hypotonia, and profoundly impaired development
CC often associated with macrocephaly, hyperkinetic movements, and
CC contractures. The disorder can sometimes result in early death. Some
CC patients may have a favorable seizure response to topiramate
CC medication. {ECO:0000269|PubMed:30343943}. Note=The disease is caused
CC by variants affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the calcium channel alpha-1 subunit (TC
CC 1.A.1.11) family. CACNA1E subfamily. {ECO:0000305}.
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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 AlphaFoldDB; Q15878; -.
DR SMR; Q15878; -.
DR BioGRID; 107231; 3.
DR IntAct; Q15878; 2.
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; DB00228; Enflurane.
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; 126 antibodies from 20 providers.
DR DNASU; 777; -.
DR Ensembl; ENST00000358338.7; ENSP00000351101.6; ENSG00000198216.13. [Q15878-2]
DR Ensembl; ENST00000367567.8; ENSP00000356539.5; ENSG00000198216.13. [Q15878-3]
DR Ensembl; ENST00000367570.5; ENSP00000356542.1; ENSG00000198216.13. [Q15878-3]
DR Ensembl; ENST00000367573.7; ENSP00000356545.2; ENSG00000198216.13. [Q15878-1]
DR Ensembl; ENST00000621551.3; ENSP00000483914.1; ENSG00000198216.13. [Q15878-1]
DR Ensembl; ENST00000621791.4; ENSP00000481619.1; ENSG00000198216.13. [Q15878-2]
DR GeneID; 777; -.
DR KEGG; hsa:777; -.
DR MANE-Select; ENST00000367573.7; ENSP00000356545.2; NM_001205293.3; NP_001192222.1.
DR UCSC; uc001gow.5; human. [Q15878-1]
DR CTD; 777; -.
DR DisGeNET; 777; -.
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 VEuPathDB; HostDB:ENSG00000198216; -.
DR eggNOG; KOG2301; Eukaryota.
DR GeneTree; ENSGT00940000155601; -.
DR HOGENOM; CLU_000540_1_0_1; -.
DR InParanoid; Q15878; -.
DR OMA; PRINHRE; -.
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 SignaLink; Q15878; -.
DR SIGNOR; Q15878; -.
DR BioGRID-ORCS; 777; 10 hits in 1058 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 middle temporal gyrus and 118 other tissues.
DR ExpressionAtlas; Q15878; baseline and differential.
DR Genevisible; Q15878; HS.
DR GO; GO:0043025; C:neuronal cell body; IBA:GO_Central.
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; IBA:GO_Central.
DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR GO; GO:0008331; F:high voltage-gated calcium channel activity; IBA:GO_Central.
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:0098703; P:calcium ion import across plasma membrane; IBA:GO_Central.
DR GO; GO:0007268; P:chemical synaptic transmission; IBA:GO_Central.
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 variant; Disulfide bond; Epilepsy; Glycoprotein;
KW Ion channel; Ion transport; Membrane; Metal-binding; Phosphoprotein;
KW Reference proteome; Repeat; Transmembrane; Transmembrane helix; Transport;
KW 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 REGION 1..38
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 374..391
FT /note="Binding to the beta subunit"
FT /evidence="ECO:0000250"
FT REGION 729..774
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 851..984
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1103..1125
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1970..2170
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 2206..2225
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 2263..2295
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 17..31
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 745..765
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 950..982
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1970..1996
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 2005..2019
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 2020..2034
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 2065..2122
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 2123..2156
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 426
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000305"
FT BINDING 428
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000305"
FT BINDING 430
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000305"
FT BINDING 432
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="1"
FT /evidence="ECO:0000305"
FT BINDING 1752
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000305"
FT BINDING 1758
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000305"
FT BINDING 1763
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /ligand_label="2"
FT /evidence="ECO:0000305"
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 DEE69; dbSNP:rs1553286282)"
FT /evidence="ECO:0000269|PubMed:30343943"
FT /id="VAR_081838"
FT VARIANT 348
FT /note="G -> R (in DEE69)"
FT /evidence="ECO:0000269|PubMed:30343943"
FT /id="VAR_081839"
FT VARIANT 352
FT /note="G -> R (in DEE69; dbSNP:rs886039323)"
FT /evidence="ECO:0000269|PubMed:30343943"
FT /id="VAR_081840"
FT VARIANT 603
FT /note="I -> L (in DEE69; gain-of-function variant affecting
FT channel activity; results in hyperpolarizing shift in half
FT activation voltage; dbSNP:rs778291283)"
FT /evidence="ECO:0000269|PubMed:30343943"
FT /id="VAR_081841"
FT VARIANT 690
FT /note="G -> D (in DEE69; dbSNP:rs1361083258)"
FT /evidence="ECO:0000269|PubMed:30343943"
FT /id="VAR_081842"
FT VARIANT 698
FT /note="F -> S (in DEE69; gain-of-function variant affecting
FT channel activity; shifts the voltage dependence of
FT 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 DEE69)"
FT /evidence="ECO:0000269|PubMed:30343943"
FT /id="VAR_081844"
FT VARIANT 701
FT /note="I -> V (in DEE69; gain-of-function variant affecting
FT channel activity; shifts the voltage dependence of
FT 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 DEE69; dbSNP:rs12131800)"
FT /evidence="ECO:0000269|PubMed:30343943"
FT /id="VAR_081846"
FT VARIANT 702
FT /note="A -> T (in DEE69; gain-of-function variant affecting
FT channel activity; shifts the voltage dependence of
FT 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 DEE69; 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 DEE69; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:30343943"
FT /id="VAR_081849"
FT VARIANT 1422
FT /note="I -> F (in DEE69)"
FT /evidence="ECO:0000269|PubMed:30343943"
FT /id="VAR_081850"
FT VARIANT 1425
FT /note="T -> N (in DEE69)"
FT /evidence="ECO:0000269|PubMed:30343943"
FT /id="VAR_081851"
FT VARIANT 1430
FT /note="G -> R (in DEE69; dbSNP:rs1553345844)"
FT /evidence="ECO:0000269|PubMed:30343943"
FT /id="VAR_081852"
FT VARIANT 1720
FT /note="A -> G (in DEE69)"
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:0007829|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
