ID CA2D1_HUMAN Reviewed; 1103 AA. AC P54289; Q17R45; Q9UD80; Q9UD81; Q9UD82; DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot. DT 03-NOV-2009, sequence version 3. DT 22-APR-2020, entry version 193. DE RecName: Full=Voltage-dependent calcium channel subunit alpha-2/delta-1; DE AltName: Full=Voltage-gated calcium channel subunit alpha-2/delta-1; DE Contains: DE RecName: Full=Voltage-dependent calcium channel subunit alpha-2-1; DE Contains: DE RecName: Full=Voltage-dependent calcium channel subunit delta-1; DE Flags: Precursor; GN Name=CACNA2D1; Synonyms=CACNL2A, CCHL2A, MHS3; 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 2), AND TISSUE SPECIFICITY. RX PubMed=1309651; DOI=10.1016/0896-6273(92)90109-q; RA Williams M.E., Feldman D.H., McCue A.F., Brenner R., Velicelebi G., RA Ellis S.B., Harpold M.M.; RT "Structure and functional expression of alpha 1, alpha 2, and beta subunits RT of a novel human neuronal calcium channel subtype."; RL Neuron 8:71-84(1992). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Cerebellum; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] OF 528-648 (ISOFORMS 1; 2; 3; 4 AND 5), TISSUE RP SPECIFICITY, AND ALTERNATIVE SPLICING. RC TISSUE=Neuroblastoma; RX PubMed=8107964; DOI=10.1016/0028-3908(93)90004-m; RA Brust P.F., Simerson S., McCue A.F., Deal C.R., Schoonmaker S., RA Williams M.E., Velicelebi G., Johnson E.C., Harpold M.M., Ellis S.B.; RT "Human neuronal voltage-dependent calcium channels: studies on subunit RT structure and role in channel assembly."; RL Neuropharmacology 32:1089-1102(1993). RN [5] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-136; ASN-324 AND ASN-675. RC TISSUE=Plasma; RX PubMed=16335952; DOI=10.1021/pr0502065; RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E., Moore R.J., RA Smith R.D.; RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction, RT hydrazide chemistry, and mass spectrometry."; RL J. Proteome Res. 4:2070-2080(2005). RN [6] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-348; ASN-475 AND ASN-824. RC TISSUE=Liver; RX PubMed=19159218; DOI=10.1021/pr8008012; RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.; RT "Glycoproteomics analysis of human liver tissue by combination of multiple RT enzyme digestion and hydrazide chemistry."; RL J. Proteome Res. 8:651-661(2009). RN [7] RP INTERCHAIN DISULFIDE BOND, AND SUBUNIT. RX PubMed=22054663; DOI=10.1016/j.ceca.2011.10.002; RA Calderon-Rivera A., Andrade A., Hernandez-Hernandez O., RA Gonzalez-Ramirez R., Sandoval A., Rivera M., Gomora J.C., Felix R.; RT "Identification of a disulfide bridge essential for structure and function RT of the voltage-gated Ca(2+) channel alpha(2)delta-1 auxiliary subunit."; RL Cell Calcium 51:22-30(2012). CC -!- FUNCTION: The alpha-2/delta subunit of voltage-dependent calcium CC channels regulates calcium current density and activation/inactivation CC kinetics of the calcium channel. Plays an important role in excitation- CC contraction coupling (By similarity). {ECO:0000250}. CC -!- SUBUNIT: Dimer formed of alpha-2-1 and delta-1 chains; disulfide- CC linked. Voltage-dependent calcium channels are multisubunit complexes, CC consisting of alpha-1 (CACNA1), alpha-2 (CACNA2D), beta (CACNB) and CC delta (CACNA2D) subunits in a 1:1:1:1 ratio (By similarity). CC {ECO:0000250}. CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000305}; Single-pass type I CC membrane protein {ECO:0000305}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=5; CC Name=1; Synonyms=Alpha-2a; CC IsoId=P54289-1; Sequence=Displayed; CC Name=2; Synonyms=Alpha-2b; CC IsoId=P54289-2; Sequence=VSP_038348, VSP_038350; CC Name=3; Synonyms=Alpha-2c; CC IsoId=P54289-3; Sequence=VSP_038349, VSP_038350; CC Name=4; Synonyms=Alpha-2d; CC IsoId=P54289-4; Sequence=VSP_038349; CC Name=5; Synonyms=Alpha-2e; CC IsoId=P54289-5; Sequence=VSP_038348; CC -!- TISSUE SPECIFICITY: Isoform 1 is expressed in skeletal muscle. Isoform CC 2 is expressed in the central nervous system. Isoform 2, isoform 4 and CC isoform 5 are expressed in neuroblastoma cells. Isoform 3, isoform 4 CC and isoform 5 are expressed in the aorta. {ECO:0000269|PubMed:1309651, CC ECO:0000269|PubMed:8107964}. CC -!- DOMAIN: The MIDAS-like motif in the VWFA domain binds divalent metal CC cations and is required to promote trafficking of the alpha-1 (CACNA1) CC subunit to the plasma membrane by an integrin-like switch. CC {ECO:0000250}. CC -!- PTM: Proteolytically processed into subunits alpha-2-1 and delta-1 that CC are disulfide-linked. {ECO:0000250}. CC -!- MISCELLANEOUS: Binds gabapentin, an antiepileptic drug. CC -!- SIMILARITY: Belongs to the calcium channel subunit alpha-2/delta CC family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; M76559; AAA51903.1; -; mRNA. DR EMBL; CH471091; EAW76990.1; -; Genomic_DNA. DR EMBL; BC117468; AAI17469.1; -; mRNA. DR EMBL; BC117470; AAI17471.1; -; mRNA. DR CCDS; CCDS5598.1; -. [P54289-2] DR PIR; JH0565; JH0565. DR RefSeq; NP_000713.2; NM_000722.3. [P54289-2] DR RefSeq; XP_005250627.1; XM_005250570.2. DR RefSeq; XP_005250629.1; XM_005250572.2. [P54289-3] DR RefSeq; XP_005250630.1; XM_005250573.2. [P54289-5] DR RefSeq; XP_005250631.1; XM_005250574.2. [P54289-4] DR SMR; P54289; -. DR BioGrid; 107235; 52. DR ComplexPortal; CPX-3192; Skeletal muscle VGCC complex. DR ComplexPortal; CPX-3195; Cardiac muscle VGCC complex. DR CORUM; P54289; -. DR IntAct; P54289; 31. DR STRING; 9606.ENSP00000349320; -. DR BindingDB; P54289; -. DR ChEMBL; CHEMBL1919; -. DR DrugBank; DB13746; Bioallethrin. DR DrugBank; DB11148; Butamben. DR DrugBank; DB04838; Cyclandelate. DR DrugBank; DB00153; Ergocalciferol. DR DrugBank; DB01023; Felodipine. DR DrugBank; DB00996; Gabapentin. DR DrugBank; DB08872; Gabapentin enacarbil. DR DrugBank; DB00308; Ibutilide. DR DrugBank; DB00270; Isradipine. DR DrugBank; DB00653; Magnesium sulfate. DR DrugBank; DB00622; Nicardipine. DR DrugBank; DB01115; Nifedipine. DR DrugBank; DB06712; Nilvadipine. DR DrugBank; DB00401; Nisoldipine. DR DrugBank; DB01054; Nitrendipine. DR DrugBank; DB00230; Pregabalin. DR DrugBank; DB00421; Spironolactone. DR DrugCentral; P54289; -. DR TCDB; 8.A.18.1.1; the ca(2+) channel auxiliary subunit Alpha2Delta types 1-4 (cca-Alpha2Delta) family. DR GlyConnect; 1895; -. DR iPTMnet; P54289; -. DR PhosphoSitePlus; P54289; -. DR SwissPalm; P54289; -. DR BioMuta; CACNA2D1; -. DR DMDM; 262527579; -. DR EPD; P54289; -. DR jPOST; P54289; -. DR MassIVE; P54289; -. DR MaxQB; P54289; -. DR PaxDb; P54289; -. DR PeptideAtlas; P54289; -. DR PRIDE; P54289; -. DR ProteomicsDB; 56675; -. [P54289-1] DR ProteomicsDB; 56676; -. [P54289-2] DR ProteomicsDB; 56677; -. [P54289-3] DR ProteomicsDB; 56678; -. [P54289-4] DR ProteomicsDB; 56679; -. [P54289-5] DR Antibodypedia; 2200; 259 antibodies. DR Ensembl; ENST00000356253; ENSP00000348589; ENSG00000153956. [P54289-1] DR Ensembl; ENST00000356860; ENSP00000349320; ENSG00000153956. [P54289-2] DR GeneID; 781; -. DR KEGG; hsa:781; -. DR UCSC; uc003uhr.2; human. [P54289-1] DR CTD; 781; -. DR DisGeNET; 781; -. DR GeneCards; CACNA2D1; -. DR GeneReviews; CACNA2D1; -. DR HGNC; HGNC:1399; CACNA2D1. DR HPA; ENSG00000153956; Tissue enhanced (skeletal). DR MalaCards; CACNA2D1; -. DR MIM; 114204; gene. DR neXtProt; NX_P54289; -. DR OpenTargets; ENSG00000153956; -. DR Orphanet; 130; Brugada syndrome. DR Orphanet; 51083; Familial short QT syndrome. DR PharmGKB; PA86; -. DR eggNOG; KOG2353; Eukaryota. DR eggNOG; ENOG410XPDX; LUCA. DR GeneTree; ENSGT00940000155209; -. DR HOGENOM; CLU_004660_0_0_1; -. DR InParanoid; P54289; -. DR KO; K04858; -. DR OMA; FRRQTSY; -. DR PhylomeDB; P54289; -. DR TreeFam; TF315824; -. DR Reactome; R-HSA-5576892; Phase 0 - rapid depolarisation. DR Reactome; R-HSA-5576893; Phase 2 - plateau phase. DR ChiTaRS; CACNA2D1; human. DR GeneWiki; CACNA2D1; -. DR GenomeRNAi; 781; -. DR Pharos; P54289; Tclin. DR PRO; PR:P54289; -. DR Proteomes; UP000005640; Chromosome 7. DR RNAct; P54289; protein. DR Bgee; ENSG00000153956; Expressed in biceps brachii and 203 other tissues. DR ExpressionAtlas; P54289; baseline and differential. DR Genevisible; P54289; HS. DR GO; GO:0005623; C:cell; IEA:GOC. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:1990454; C:L-type voltage-gated calcium channel complex; IDA:BHF-UCL. DR GO; GO:0005886; C:plasma membrane; TAS:Reactome. DR GO; GO:0016529; C:sarcoplasmic reticulum; IEA:Ensembl. DR GO; GO:0005891; C:voltage-gated calcium channel complex; IDA:UniProtKB. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0005245; F:voltage-gated calcium channel activity; IDA:BHF-UCL. DR GO; GO:0098703; P:calcium ion import across plasma membrane; ISS:BHF-UCL. DR GO; GO:0061577; P:calcium ion transmembrane transport via high voltage-gated calcium channel; ISS:BHF-UCL. DR GO; GO:0006816; P:calcium ion transport; IDA:UniProtKB. DR GO; GO:0060402; P:calcium ion transport into cytosol; ISS:BHF-UCL. DR GO; GO:0061337; P:cardiac conduction; TAS:Reactome. DR GO; GO:0086002; P:cardiac muscle cell action potential involved in contraction; IMP:BHF-UCL. DR GO; GO:1904646; P:cellular response to amyloid-beta; IGI:ARUK-UCL. DR GO; GO:0086048; P:membrane depolarization during bundle of His cell action potential; IMP:BHF-UCL. DR GO; GO:1901843; P:positive regulation of high voltage-gated calcium channel activity; ISS:BHF-UCL. DR GO; GO:1902514; P:regulation of calcium ion transmembrane transport via high voltage-gated calcium channel; IGI:ARUK-UCL. DR GO; GO:0051924; P:regulation of calcium ion transport; IDA:BHF-UCL. DR GO; GO:0086091; P:regulation of heart rate by cardiac conduction; IMP:BHF-UCL. DR GO; GO:0098903; P:regulation of membrane repolarization during action potential; ISS:BHF-UCL. DR GO; GO:0060307; P:regulation of ventricular cardiac muscle cell membrane repolarization; IMP:BHF-UCL. DR Gene3D; 3.40.50.410; -; 1. DR InterPro; IPR013680; VDCC_a2/dsu. DR InterPro; IPR013608; VWA_N. DR InterPro; IPR002035; VWF_A. DR InterPro; IPR036465; vWFA_dom_sf. DR Pfam; PF08473; VGCC_alpha2; 1. DR Pfam; PF00092; VWA; 1. DR Pfam; PF08399; VWA_N; 1. DR SMART; SM00327; VWA; 1. DR SUPFAM; SSF53300; SSF53300; 1. DR PROSITE; PS50234; VWFA; 1. PE 1: Evidence at protein level; KW Alternative splicing; Calcium; Calcium channel; Calcium transport; KW Disulfide bond; Glycoprotein; Ion channel; Ion transport; Membrane; KW Metal-binding; Phosphoprotein; Polymorphism; Reference proteome; Signal; KW Transmembrane; Transmembrane helix; Transport; Voltage-gated channel. FT SIGNAL 1..24 FT /evidence="ECO:0000255" FT CHAIN 25..1103 FT /note="Voltage-dependent calcium channel subunit alpha- FT 2/delta-1" FT /id="PRO_0000304633" FT CHAIN 25..956 FT /note="Voltage-dependent calcium channel subunit alpha-2-1" FT /evidence="ECO:0000250" FT /id="PRO_0000005001" FT CHAIN 957..1103 FT /note="Voltage-dependent calcium channel subunit delta-1" FT /evidence="ECO:0000250" FT /id="PRO_0000005002" FT TOPO_DOM 25..1073 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 1074..1094 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 1095..1103 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT DOMAIN 253..430 FT /note="VWFA" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00219" FT DOMAIN 446..556 FT /note="Cache" FT MOTIF 259..263 FT /note="MIDAS-like motif" FT METAL 259 FT /note="Divalent metal cation" FT /evidence="ECO:0000250" FT METAL 261 FT /note="Divalent metal cation" FT /evidence="ECO:0000250" FT METAL 263 FT /note="Divalent metal cation" FT /evidence="ECO:0000250" FT MOD_RES 119 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P54290" FT CARBOHYD 92 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 136 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 184 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 324 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 348 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 468 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 475 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 604 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 613 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 675 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 781 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 824 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 888 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 895 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 985 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 998 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 404..1059 FT /note="Interchain (between alpha-2-1 and delta-1 chains)" FT VAR_SEQ 531..554 FT /note="Missing (in isoform 3 and isoform 4)" FT /evidence="ECO:0000303|PubMed:8107964" FT /id="VSP_038349" FT VAR_SEQ 531..549 FT /note="Missing (in isoform 2 and isoform 5)" FT /evidence="ECO:0000303|PubMed:1309651, FT ECO:0000303|PubMed:15489334, ECO:0000303|PubMed:8107964" FT /id="VSP_038348" FT VAR_SEQ 644 FT /note="Y -> SKKGKMKD (in isoform 2 and isoform 3)" FT /evidence="ECO:0000303|PubMed:1309651, FT ECO:0000303|PubMed:15489334, ECO:0000303|PubMed:8107964" FT /id="VSP_038350" FT VARIANT 1019 FT /note="E -> D (in dbSNP:rs9886043)" FT /id="VAR_053960" FT VARIANT 1057 FT /note="D -> A (in dbSNP:rs35131433)" FT /id="VAR_035047" FT CONFLICT 99 FT /note="R -> S (in Ref. 1; AAA51903)" FT /evidence="ECO:0000305" FT CONFLICT 386 FT /note="T -> R (in Ref. 1; AAA51903)" FT /evidence="ECO:0000305" FT CONFLICT 395 FT /note="D -> E (in Ref. 1; AAA51903)" FT /evidence="ECO:0000305" FT CONFLICT 635 FT /note="L -> I (in Ref. 4; no nucleotide entry)" FT /evidence="ECO:0000305" SQ SEQUENCE 1103 AA; 124568 MW; 0749685DE9DB0700 CRC64; MAAGCLLALT LTLFQSLLIG PSSEEPFPSA VTIKSWVDKM QEDLVTLAKT ASGVNQLVDI YEKYQDLYTV EPNNARQLVE IAARDIEKLL SNRSKALVRL ALEAEKVQAA HQWREDFASN EVVYYNAKDD LDPEKNDSEP GSQRIKPVFI EDANFGRQIS YQHAAVHIPT DIYEGSTIVL NELNWTSALD EVFKKNREED PSLLWQVFGS ATGLARYYPA SPWVDNSRTP NKIDLYDVRR RPWYIQGAAS PKDMLILVDV SGSVSGLTLK LIRTSVSEML ETLSDDDFVN VASFNSNAQD VSCFQHLVQA NVRNKKVLKD AVNNITAKGI TDYKKGFSFA FEQLLNYNVS RANCNKIIML FTDGGEERAQ EIFNKYNKDK KVRVFTFSVG QHNYDRGPIQ WMACENKGYY YEIPSIGAIR INTQEYLDVL GRPMVLAGDK AKQVQWTNVY LDALELGLVI TGTLPVFNIT GQFENKTNLK NQLILGVMGV DVSLEDIKRL TPRFTLCPNG YYFAIDPNGY VLLHPNLQPK PIGVGIPTIN LRKRRPNIQN PKSQEPVTLD FLDAELENDI KVEIRNKMID GESGEKTFRT LVKSQDERYI DKGNRTYTWT PVNGTDYSLA LVLPTYSFYY IKAKLEETIT QARYSETLKP DNFEESGYTF IAPRDYCNDL KISDNNTEFL LNFNEFIDRK TPNNPSCNAD LINRVLLDAG FTNELVQNYW SKQKNIKGVK ARFVVTDGGI TRVYPKEAGE NWQENPETYE DSFYKRSLDN DNYVFTAPYF NKSGPGAYES GIMVSKAVEI YIQGKLLKPA VVGIKIDVNS WIENFTKTSI RDPCAGPVCD CKRNSDVMDC VILDDGGFLL MANHDDYTNQ IGRFFGEIDP SLMRHLVNIS VYAFNKSYDY QSVCEPGAAP KQGAGHRSAY VPSVADILQI GWWATAAAWS ILQQFLLSLT FPRLLEAVEM EDDDFTASLS KQSCITEQTQ YFFDNDSKSF SGVLDCGNCS RIFHGEKLMN TNLIFIMVES KGTCPCDTRL LIQAEQTSDG PNPCDMVKQP RYRKGPDVCF DNNVLEDYTD CGGVSGLNPS LWYIIGIQFL LLWLVSGSTH RLL //