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Protein

Voltage-dependent calcium channel subunit alpha-2/delta-1

Gene

CACNA2D1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel. Plays an important role in excitation-contraction coupling (By similarity).By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Metal bindingi259Divalent metal cationBy similarity1
Metal bindingi261Divalent metal cationBy similarity1
Metal bindingi263Divalent metal cationBy similarity1

GO - Molecular functioni

  • metal ion binding Source: UniProtKB-KW
  • voltage-gated calcium channel activity Source: BHF-UCL

GO - Biological processi

  • calcium ion transmembrane transport via high voltage-gated calcium channel Source: BHF-UCL
  • calcium ion transport Source: UniProtKB
  • calcium ion transport into cytosol Source: BHF-UCL
  • cardiac conduction Source: Reactome
  • cardiac muscle cell action potential involved in contraction Source: BHF-UCL
  • membrane depolarization during cardiac muscle cell action potential Source: GOC
  • positive regulation of high voltage-gated calcium channel activity Source: BHF-UCL
  • regulation of calcium ion transport Source: BHF-UCL
  • regulation of heart rate by cardiac conduction Source: BHF-UCL
  • regulation of membrane repolarization during action potential Source: BHF-UCL
  • regulation of ventricular cardiac muscle cell membrane repolarization Source: BHF-UCL
Complete GO annotation...

Keywords - Molecular functioni

Calcium channel, Ion channel, Voltage-gated channel

Keywords - Biological processi

Calcium transport, Ion transport, Transport

Keywords - Ligandi

Calcium, Metal-binding

Enzyme and pathway databases

BioCyciZFISH:ENSG00000153956-MONOMER.
ReactomeiR-HSA-5576892. Phase 0 - rapid depolarisation.
R-HSA-5576893. Phase 2 - plateau phase.
R-HSA-5576894. Phase 1 - inactivation of fast Na+ channels.

Protein family/group databases

TCDBi8.A.18.1.1. the ca(2+) channel auxiliary subunit Alpha2Delta types 1-4 (cca-Alpha2Delta) family.

Names & Taxonomyi

Protein namesi
Recommended name:
Voltage-dependent calcium channel subunit alpha-2/delta-1
Alternative name(s):
Voltage-gated calcium channel subunit alpha-2/delta-1
Cleaved into the following 2 chains:
Gene namesi
Name:CACNA2D1
Synonyms:CACNL2A, CCHL2A, MHS3
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 7

Organism-specific databases

HGNCiHGNC:1399. CACNA2D1.

Subcellular locationi

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini25 – 1073ExtracellularSequence analysisAdd BLAST1049
Transmembranei1074 – 1094HelicalSequence analysisAdd BLAST21
Topological domaini1095 – 1103CytoplasmicSequence analysis9

GO - Cellular componenti

  • extracellular exosome Source: UniProtKB
  • L-type voltage-gated calcium channel complex Source: BHF-UCL
  • plasma membrane Source: Reactome
  • sarcoplasmic reticulum Source: Ensembl
  • voltage-gated calcium channel complex Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Membrane

Pathology & Biotechi

Organism-specific databases

DisGeNETi781.
MalaCardsiCACNA2D1.
OpenTargetsiENSG00000153956.
Orphaneti130. Brugada syndrome.
51083. Familial short QT syndrome.
PharmGKBiPA86.

Chemistry databases

ChEMBLiCHEMBL1919.
DrugBankiDB00381. Amlodipine.
DB04838. Cyclandelate.
DB01023. Felodipine.
DB00996. Gabapentin.
DB00308. Ibutilide.
DB00270. Isradipine.
DB00653. Magnesium Sulfate.
DB00622. Nicardipine.
DB01115. Nifedipine.
DB06712. Nilvadipine.
DB00401. Nisoldipine.
DB01054. Nitrendipine.
DB00421. Spironolactone.

Polymorphism and mutation databases

BioMutaiCACNA2D1.
DMDMi262527579.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 24Sequence analysisAdd BLAST24
ChainiPRO_000030463325 – 1103Voltage-dependent calcium channel subunit alpha-2/delta-1Add BLAST1079
ChainiPRO_000000500125 – 956Voltage-dependent calcium channel subunit alpha-2-1By similarityAdd BLAST932
ChainiPRO_0000005002957 – 1103Voltage-dependent calcium channel subunit delta-1By similarityAdd BLAST147

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi92N-linked (GlcNAc...)Sequence analysis1
Modified residuei119PhosphoserineBy similarity1
Glycosylationi136N-linked (GlcNAc...)Sequence analysis1
Glycosylationi184N-linked (GlcNAc...)Sequence analysis1
Glycosylationi324N-linked (GlcNAc...)Sequence analysis1
Glycosylationi348N-linked (GlcNAc...)Sequence analysis1
Disulfide bondi404 ↔ 1059Interchain (between alpha-2-1 and delta-1 chains)
Glycosylationi468N-linked (GlcNAc...)Sequence analysis1
Glycosylationi475N-linked (GlcNAc...)Sequence analysis1
Glycosylationi604N-linked (GlcNAc...)Sequence analysis1
Glycosylationi613N-linked (GlcNAc...)Sequence analysis1
Glycosylationi675N-linked (GlcNAc...)Sequence analysis1
Glycosylationi781N-linked (GlcNAc...)Sequence analysis1
Glycosylationi824N-linked (GlcNAc...)Sequence analysis1
Glycosylationi888N-linked (GlcNAc...)Sequence analysis1
Glycosylationi895N-linked (GlcNAc...)Sequence analysis1
Glycosylationi985N-linked (GlcNAc...)Sequence analysis1
Glycosylationi998N-linked (GlcNAc...)Sequence analysis1

Post-translational modificationi

Proteolytically processed into subunits alpha-2-1 and delta-1 that are disulfide-linked.By similarity

Keywords - PTMi

Disulfide bond, Glycoprotein, Phosphoprotein

Proteomic databases

EPDiP54289.
MaxQBiP54289.
PaxDbiP54289.
PeptideAtlasiP54289.
PRIDEiP54289.

PTM databases

iPTMnetiP54289.
PhosphoSitePlusiP54289.
SwissPalmiP54289.

Expressioni

Tissue specificityi

Isoform 1 is expressed in skeletal muscle. Isoform 2 is expressed in the central nervous system. Isoform 2, isoform 4 and isoform 5 are expressed in neuroblastoma cells. Isoform 3, isoform 4 and isoform 5 are expressed in the aorta.2 Publications

Gene expression databases

BgeeiENSG00000153956.
CleanExiHS_CACNA2D1.
ExpressionAtlasiP54289. baseline and differential.
GenevisibleiP54289. HS.

Organism-specific databases

HPAiHPA008213.
HPA008621.

Interactioni

Subunit structurei

Dimer formed of alpha-2-1 and delta-1 chains; disulfide-linked. Voltage-dependent calcium channels are multisubunit complexes, consisting of alpha-1 (CACNA1), alpha-2 (CACNA2D), beta (CACNB) and delta (CACNA2D) subunits in a 1:1:1:1 ratio (By similarity).By similarity

Protein-protein interaction databases

BioGridi107235. 38 interactors.
IntActiP54289. 8 interactors.
STRINGi9606.ENSP00000349320.

Chemistry databases

BindingDBiP54289.

Structurei

3D structure databases

ProteinModelPortaliP54289.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini253 – 430VWFAPROSITE-ProRule annotationAdd BLAST178
Domaini446 – 556CacheAdd BLAST111

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi259 – 263MIDAS-like motif5

Domaini

The MIDAS-like motif in the VWFA domain binds divalent metal cations and is required to promote trafficking of the alpha-1 (CACNA1) subunit to the plasma membrane by an integrin-like switch.By similarity

Sequence similaritiesi

Contains 1 cache domain.Curated
Contains 1 VWFA domain.PROSITE-ProRule annotation

Keywords - Domaini

Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG2353. Eukaryota.
ENOG410XPDX. LUCA.
GeneTreeiENSGT00530000062904.
HOVERGENiHBG057779.
InParanoidiP54289.
KOiK04858.
OMAiDDYTNQI.
OrthoDBiEOG091G00UY.
PhylomeDBiP54289.
TreeFamiTF315824.

Family and domain databases

Gene3Di3.40.50.410. 1 hit.
InterProiIPR013680. VDCC_a2/dsu.
IPR013608. VWA_N.
IPR002035. VWF_A.
[Graphical view]
PfamiPF08473. VGCC_alpha2. 1 hit.
PF00092. VWA. 1 hit.
PF08399. VWA_N. 1 hit.
[Graphical view]
SMARTiSM00327. VWA. 1 hit.
[Graphical view]
SUPFAMiSSF53300. SSF53300. 1 hit.
PROSITEiPS50234. VWFA. 1 hit.
[Graphical view]

Sequences (5)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 5 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P54289-1) [UniParc]FASTAAdd to basket
Also known as: Alpha-2a

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MAAGCLLALT LTLFQSLLIG PSSEEPFPSA VTIKSWVDKM QEDLVTLAKT
60 70 80 90 100
ASGVNQLVDI YEKYQDLYTV EPNNARQLVE IAARDIEKLL SNRSKALVRL
110 120 130 140 150
ALEAEKVQAA HQWREDFASN EVVYYNAKDD LDPEKNDSEP GSQRIKPVFI
160 170 180 190 200
EDANFGRQIS YQHAAVHIPT DIYEGSTIVL NELNWTSALD EVFKKNREED
210 220 230 240 250
PSLLWQVFGS ATGLARYYPA SPWVDNSRTP NKIDLYDVRR RPWYIQGAAS
260 270 280 290 300
PKDMLILVDV SGSVSGLTLK LIRTSVSEML ETLSDDDFVN VASFNSNAQD
310 320 330 340 350
VSCFQHLVQA NVRNKKVLKD AVNNITAKGI TDYKKGFSFA FEQLLNYNVS
360 370 380 390 400
RANCNKIIML FTDGGEERAQ EIFNKYNKDK KVRVFTFSVG QHNYDRGPIQ
410 420 430 440 450
WMACENKGYY YEIPSIGAIR INTQEYLDVL GRPMVLAGDK AKQVQWTNVY
460 470 480 490 500
LDALELGLVI TGTLPVFNIT GQFENKTNLK NQLILGVMGV DVSLEDIKRL
510 520 530 540 550
TPRFTLCPNG YYFAIDPNGY VLLHPNLQPK PIGVGIPTIN LRKRRPNIQN
560 570 580 590 600
PKSQEPVTLD FLDAELENDI KVEIRNKMID GESGEKTFRT LVKSQDERYI
610 620 630 640 650
DKGNRTYTWT PVNGTDYSLA LVLPTYSFYY IKAKLEETIT QARYSETLKP
660 670 680 690 700
DNFEESGYTF IAPRDYCNDL KISDNNTEFL LNFNEFIDRK TPNNPSCNAD
710 720 730 740 750
LINRVLLDAG FTNELVQNYW SKQKNIKGVK ARFVVTDGGI TRVYPKEAGE
760 770 780 790 800
NWQENPETYE DSFYKRSLDN DNYVFTAPYF NKSGPGAYES GIMVSKAVEI
810 820 830 840 850
YIQGKLLKPA VVGIKIDVNS WIENFTKTSI RDPCAGPVCD CKRNSDVMDC
860 870 880 890 900
VILDDGGFLL MANHDDYTNQ IGRFFGEIDP SLMRHLVNIS VYAFNKSYDY
910 920 930 940 950
QSVCEPGAAP KQGAGHRSAY VPSVADILQI GWWATAAAWS ILQQFLLSLT
960 970 980 990 1000
FPRLLEAVEM EDDDFTASLS KQSCITEQTQ YFFDNDSKSF SGVLDCGNCS
1010 1020 1030 1040 1050
RIFHGEKLMN TNLIFIMVES KGTCPCDTRL LIQAEQTSDG PNPCDMVKQP
1060 1070 1080 1090 1100
RYRKGPDVCF DNNVLEDYTD CGGVSGLNPS LWYIIGIQFL LLWLVSGSTH

RLL
Length:1,103
Mass (Da):124,568
Last modified:November 3, 2009 - v3
Checksum:i0749685DE9DB0700
GO
Isoform 2 (identifier: P54289-2) [UniParc]FASTAAdd to basket
Also known as: Alpha-2b

The sequence of this isoform differs from the canonical sequence as follows:
     531-549: Missing.
     644-644: Y → SKKGKMKD

Show »
Length:1,091
Mass (Da):123,183
Checksum:iDBD649BAC7871934
GO
Isoform 3 (identifier: P54289-3) [UniParc]FASTAAdd to basket
Also known as: Alpha-2c

The sequence of this isoform differs from the canonical sequence as follows:
     531-554: Missing.
     644-644: Y → SKKGKMKD

Show »
Length:1,086
Mass (Da):122,629
Checksum:i55B5E049C472FD0C
GO
Isoform 4 (identifier: P54289-4) [UniParc]FASTAAdd to basket
Also known as: Alpha-2d

The sequence of this isoform differs from the canonical sequence as follows:
     531-554: Missing.

Show »
Length:1,079
Mass (Da):121,889
Checksum:iAFC36093EB8EE8D3
GO
Isoform 5 (identifier: P54289-5) [UniParc]FASTAAdd to basket
Also known as: Alpha-2e

The sequence of this isoform differs from the canonical sequence as follows:
     531-549: Missing.

Show »
Length:1,084
Mass (Da):122,443
Checksum:i972A0FB832A88313
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti99R → S in AAA51903 (PubMed:1309651).Curated1
Sequence conflicti386T → R in AAA51903 (PubMed:1309651).Curated1
Sequence conflicti395D → E in AAA51903 (PubMed:1309651).Curated1
Sequence conflicti635L → I no nucleotide entry (PubMed:8107964).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_0539601019E → D.Corresponds to variant rs9886043dbSNPEnsembl.1
Natural variantiVAR_0350471057D → A.Corresponds to variant rs35131433dbSNPEnsembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_038349531 – 554Missing in isoform 3 and isoform 4. 1 PublicationAdd BLAST24
Alternative sequenceiVSP_038348531 – 549Missing in isoform 2 and isoform 5. 3 PublicationsAdd BLAST19
Alternative sequenceiVSP_038350644Y → SKKGKMKD in isoform 2 and isoform 3. 3 Publications1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M76559 mRNA. Translation: AAA51903.1.
CH471091 Genomic DNA. Translation: EAW76990.1.
BC117468 mRNA. Translation: AAI17469.1.
BC117470 mRNA. Translation: AAI17471.1.
CCDSiCCDS5598.1. [P54289-2]
PIRiJH0565.
RefSeqiNP_000713.2. NM_000722.3. [P54289-2]
XP_005250627.1. XM_005250570.2. [P54289-1]
XP_005250629.1. XM_005250572.2. [P54289-3]
XP_005250630.1. XM_005250573.2. [P54289-5]
XP_005250631.1. XM_005250574.2. [P54289-4]
UniGeneiHs.282151.
Hs.592625.
Hs.743228.

Genome annotation databases

EnsembliENST00000356253; ENSP00000348589; ENSG00000153956. [P54289-1]
ENST00000356860; ENSP00000349320; ENSG00000153956. [P54289-2]
GeneIDi781.
KEGGihsa:781.
UCSCiuc003uhr.2. human. [P54289-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M76559 mRNA. Translation: AAA51903.1.
CH471091 Genomic DNA. Translation: EAW76990.1.
BC117468 mRNA. Translation: AAI17469.1.
BC117470 mRNA. Translation: AAI17471.1.
CCDSiCCDS5598.1. [P54289-2]
PIRiJH0565.
RefSeqiNP_000713.2. NM_000722.3. [P54289-2]
XP_005250627.1. XM_005250570.2. [P54289-1]
XP_005250629.1. XM_005250572.2. [P54289-3]
XP_005250630.1. XM_005250573.2. [P54289-5]
XP_005250631.1. XM_005250574.2. [P54289-4]
UniGeneiHs.282151.
Hs.592625.
Hs.743228.

3D structure databases

ProteinModelPortaliP54289.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi107235. 38 interactors.
IntActiP54289. 8 interactors.
STRINGi9606.ENSP00000349320.

Chemistry databases

BindingDBiP54289.
ChEMBLiCHEMBL1919.
DrugBankiDB00381. Amlodipine.
DB04838. Cyclandelate.
DB01023. Felodipine.
DB00996. Gabapentin.
DB00308. Ibutilide.
DB00270. Isradipine.
DB00653. Magnesium Sulfate.
DB00622. Nicardipine.
DB01115. Nifedipine.
DB06712. Nilvadipine.
DB00401. Nisoldipine.
DB01054. Nitrendipine.
DB00421. Spironolactone.

Protein family/group databases

TCDBi8.A.18.1.1. the ca(2+) channel auxiliary subunit Alpha2Delta types 1-4 (cca-Alpha2Delta) family.

PTM databases

iPTMnetiP54289.
PhosphoSitePlusiP54289.
SwissPalmiP54289.

Polymorphism and mutation databases

BioMutaiCACNA2D1.
DMDMi262527579.

Proteomic databases

EPDiP54289.
MaxQBiP54289.
PaxDbiP54289.
PeptideAtlasiP54289.
PRIDEiP54289.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000356253; ENSP00000348589; ENSG00000153956. [P54289-1]
ENST00000356860; ENSP00000349320; ENSG00000153956. [P54289-2]
GeneIDi781.
KEGGihsa:781.
UCSCiuc003uhr.2. human. [P54289-1]

Organism-specific databases

CTDi781.
DisGeNETi781.
GeneCardsiCACNA2D1.
HGNCiHGNC:1399. CACNA2D1.
HPAiHPA008213.
HPA008621.
MalaCardsiCACNA2D1.
MIMi114204. gene.
neXtProtiNX_P54289.
OpenTargetsiENSG00000153956.
Orphaneti130. Brugada syndrome.
51083. Familial short QT syndrome.
PharmGKBiPA86.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG2353. Eukaryota.
ENOG410XPDX. LUCA.
GeneTreeiENSGT00530000062904.
HOVERGENiHBG057779.
InParanoidiP54289.
KOiK04858.
OMAiDDYTNQI.
OrthoDBiEOG091G00UY.
PhylomeDBiP54289.
TreeFamiTF315824.

Enzyme and pathway databases

BioCyciZFISH:ENSG00000153956-MONOMER.
ReactomeiR-HSA-5576892. Phase 0 - rapid depolarisation.
R-HSA-5576893. Phase 2 - plateau phase.
R-HSA-5576894. Phase 1 - inactivation of fast Na+ channels.

Miscellaneous databases

ChiTaRSiCACNA2D1. human.
GeneWikiiCACNA2D1.
GenomeRNAii781.
PROiP54289.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000153956.
CleanExiHS_CACNA2D1.
ExpressionAtlasiP54289. baseline and differential.
GenevisibleiP54289. HS.

Family and domain databases

Gene3Di3.40.50.410. 1 hit.
InterProiIPR013680. VDCC_a2/dsu.
IPR013608. VWA_N.
IPR002035. VWF_A.
[Graphical view]
PfamiPF08473. VGCC_alpha2. 1 hit.
PF00092. VWA. 1 hit.
PF08399. VWA_N. 1 hit.
[Graphical view]
SMARTiSM00327. VWA. 1 hit.
[Graphical view]
SUPFAMiSSF53300. SSF53300. 1 hit.
PROSITEiPS50234. VWFA. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiCA2D1_HUMAN
AccessioniPrimary (citable) accession number: P54289
Secondary accession number(s): Q17R45
, Q9UD80, Q9UD81, Q9UD82
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: November 3, 2009
Last modified: November 2, 2016
This is version 166 of the entry and version 3 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Miscellaneous

Binds gabapentin, an antiepileptic drug.

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 7
    Human chromosome 7: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.