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Protein

Alpha-conotoxin Vc1A

Gene
N/A
Organism
Conus victoriae (Queen Victoria cone)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Alpha-conotoxins act on postsynaptic membranes, they bind to the nicotinic acetylcholine receptors (nAChR) and thus inhibit them. This toxin (native toxin Vc1a; hydroxylated and gamma-carboxylated) blocks alpha-9-alpha-10/CHRNA9-CHRNA10 nAChRs (IC50=62.9 nM) (PubMed:17804600). In contrast to the non-post-translationally modified analog Vc1.1, Vc1a does not inhibit high voltage-activated (HVA) calcium channel currents (PubMed:18945902). In vivo, in contrast to Vc1.1, Vc1a does not show analgesic effects in rat models of neuropathic pain (PubMed:17804600).2 Publications
The synthetic peptide Vc1.1 (a non-hydroxylated and non-gamma-carboxylated analog of Vc1a) has two types of targets. It blocks alpha-9-alpha-10/CHRNA9-CHRNA10 nAChRs (on rat receptors, IC50=19-109 nM) (with preference for rat over human receptors) and inhibits high voltage-activated (HVA) calcium channel (Cav2.2, Cav2.3) currents by acting on GABA(B) receptors (GABBR1 and GABBR2) (IC50=1.7 nM) (PubMed:17101979, PubMed:17804600, PubMed:18945902, PubMed:19447885, PubMed:23566299, PubMed:26948522, PubMed:20533477, PubMed:23768016). It also shows moderate inhibition on alpha-6/alpha-3-beta-2-beta-3 (CHRNA6/CHRNA3-CHRNB2-CHRNB3) (IC50=140 nM) and alpha-6/alpha-3-beta-4 (CHRNA6/CHRNA3-CHRNB4) (IC50=980 nM) (PubMed:17101979). On alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR, it most likely interacts with the alpha-10+/alpha-9-interface of the receptor (PubMed:23566299). In vivo, it acts as a powerful analgesic in rat models of neuropathic pain (PubMed:17804600).10 Publications

Miscellaneous

The synthetic peptide Vc1.1 (a non-hydroxylated and non-gamma-carboxylated analog of Vc1a) shows weak inhibition on nAChRs composed of alpha-3-alpha-5-beta-2/CHRNA3-CHRNA5-CHRNB2 (IC50=7.2 µM), alpha-3-beta-2/CHRNA3-CHRNB2 (IC50=5.5-7.3 µM), alpha-3-beta-4/CHRNA3-CHRNB4 (IC50=4.2 µM), alpha-3-alpha-5-beta-4/CHRNA3-CHRNA5-CHRNB4 (IC50>30 µM), alpha-4-beta-2/CHRNA4-CHRNB2 (IC50>30 µM), alpha-4-beta-4/CHRNA4-CHRNB4 (IC50>30 µM), rat alpha-7/CHRNA7 (IC50=7.1 µM) and alpha-1-beta-1-gamma-delta/CHRNA1-CHRNB1-CHRNG-CHRND (IC50>30 µM) subunits.2 Publications
cVc1.1 is a cyclic peptide with inhibitory activity on alpha-9-alpha-10/CHRNA9-CHRNA10 nAChRs (IC50=766 nM) and a high potency at inhibiting HVA calcium channels in mice DRG neurons (IC50=0.3 nM) (PubMed:20533477). Toxin cVc1.1[D11A; E14A] is a cyclic peptide with a very low inhibitory activity on alpha-9-alpha-10/CHRNA9-CHRNA10 nAChRs (IC50>17 µM) and a high potency at inhibiting HVA calcium channels in mice DRG neurons (IC50=3.3 nM) (PubMed:29746088). Both of them show antinociceptive actions, with greater efficacy in a model of animal chronic visceral hypersensitivity (CVH) (PubMed:29194563, PubMed:29746088).3 Publications

GO - Molecular functioni

Keywordsi

Molecular functionAcetylcholine receptor inhibiting toxin, Ion channel impairing toxin, Neurotoxin, Postsynaptic neurotoxin, Toxin

Names & Taxonomyi

Protein namesi
Recommended name:
Alpha-conotoxin Vc1A1 Publication
Short name:
Alpha-Vc1A
Alternative name(s):
ACV11 Publication
Vc1.11 Publication
OrganismiConus victoriae (Queen Victoria cone)
Taxonomic identifieri319920 [NCBI]
Taxonomic lineageiEukaryotaMetazoaLophotrochozoaMolluscaGastropodaCaenogastropodaNeogastropodaConoideaConidaeConusCylinder

Organism-specific databases

ConoServeri499 VcIA precursor

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Secreted

Pathology & Biotechi

Pharmaceutical usei

Failed in phase II clinical trial. Was tested by Metabolic under the name ACV1 to treat neuropathic pain.1 Publication
Cyclic versions of Vc1.1 evoke significant anti-nociceptive actions in animal model of chronic visceral hypersensitivity (CVH), suggesting that they could be novel candidates for treatment of chronic visceral pain (CVP).1 Publication

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi50G → A or D: Vc1.1; No change in potency of inhibition of rat alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR. No change in potency of inhibition of HVA calcium channels in rat/mouse DRG neurons. 2 Publications1
Mutagenesisi50G → K: Vc1.1; No change in potency of inhibition of rat alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR. Decrease in potency of inhibition of HVA calcium channels in rat/mouse DRG neurons. 2 Publications1
Mutagenesisi52C → S in [C3S]Vc1.1(1-8); Shows similar potency of inhibition of HVA calcium currents. Shows 95% inhibition of human alpha-7/CHRNA7, but no inhibition of human alpha-9-alpha-10/CHRNA9-CHRNA10 AChR. 1 Publication1
Mutagenesisi53S → A: Vc1.1; 2.5-fold decrease in potency of inhibition of rat alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR. Decrease in potency of inhibition of HVA calcium channels in rat/mouse DRG neurons. 2 Publications1
Mutagenesisi53S → D: Vc1.1; 1.7-fold decrease in potency of inhibition of rat alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR. No change in potency of inhibition of HVA calcium channels in rat/mouse DRG neurons. 2 Publications1
Mutagenesisi53S → K: Vc1.1; 1.7-fold increase in potency of inhibition of rat alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR. No change in potency of inhibition of HVA calcium channels in rat/mouse DRG neurons. 2-fold increase in potency of inhibition of rat alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR; when associated with A-58. 2 Publications1
Mutagenesisi54D → A or K: Vc1.1; Almost complete loss of potency of inhibition of rat alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR. Decrease in potency of inhibition of HVA calcium channels in rat/mouse DRG neurons. 2 Publications1
Mutagenesisi55P → A, D or K: Vc1.1; Almost complete loss of potency of inhibition of rat alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR. Decrease in potency of inhibition of HVA calcium channels in rat/mouse DRG neurons. 2 Publications1
Mutagenesisi56R → A, D or K: Vc1.1; Almost complete loss of potency of inhibition of rat alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR. Decrease in potency of inhibition of HVA calcium channels in rat/mouse DRG neurons. 2 Publications1
Mutagenesisi58 – 65Missing in [C3S]Vc1.1(1-8); Shows similar potency of inhibition of HVA calcium currents. Shows 95% inhibition of human alpha-7/CHRNA7, but no inhibition of human alpha-9-alpha-10/CHRNA9-CHRNA10 AChR. 1 Publication8
Mutagenesisi58N → A: Vc1.1; 2.2-fold increase in potency of inhibition of rat alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR. 30-fold increase in potency of inhibition of rat alpha-3-beta-2/CHRNA3-CHRNB2 nAChR. Decrease in potency of inhibition of HVA calcium channels in rat/mouse DRG neurons. 2-fold increase in potency of inhibition of rat alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR; when associated with K-53. 2 Publications1
Mutagenesisi58N → D: Vc1.1; No change in potency of inhibition of rat alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR. No change in potency of inhibition of HVA calcium channels in rat/mouse DRG neurons. 2 Publications1
Mutagenesisi58N → G: Vc1.1; 1.9-fold increase in potency of inhibition of rat alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR. 1 Publication1
Mutagenesisi58N → I: Vc1.1; 1.7-fold increase in potency of inhibition of rat alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR. 25-fold increase in potency of inhibition of rat alpha-3-beta-2/CHRNA3-CHRNB2 nAChR. 7-fold increase in potency of inhibition of rat alpha-7/CHRNA7 nAChR. 1 Publication1
Mutagenesisi58N → K: Vc1.1; Complete loss of potency of inhibition of rat alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR. No change in potency of inhibition of HVA calcium channels in rat/mouse DRG neurons. 2 Publications1
Mutagenesisi58N → L: Vc1.1; 1.7-fold increase in potency of inhibition of rat alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR. 2-fold increase in potency of inhibition of rat alpha-3-beta-2/CHRNA3-CHRNB2 nAChR. 1 Publication1
Mutagenesisi59Y → A or K: Vc1.1; No change in potency of inhibition of rat alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR. Decrease in potency of inhibition of HVA calcium channels in rat/mouse DRG neurons. 2 Publications1
Mutagenesisi59Y → D: Vc1.1; 5-fold decrease in potency of inhibition of rat alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR. Decrease in potency of inhibition of HVA calcium channels in rat/mouse DRG neurons. 2 Publications1
Mutagenesisi60D → A: Vc1.1; 5-fold decrease in potency of inhibition of rat alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR. No change in potency of inhibition of HVA calcium channels in rat/mouse DRG neurons. Toxin cVc1.1[D11A; E14A]; important decrease in potency of inhibition of alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR. Very potent in inhibition of HVA calcium channels in mouse DRG neurons. 2 Publications1
Mutagenesisi60D → K: Vc1.1; 5-fold decrease in potency of inhibition of rat alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR. No change in potency of inhibition of HVA calcium channels in rat/mouse DRG neurons. 2 Publications1
Mutagenesisi61H → A: Vc1.1; 10-fold decrease in potency of inhibition of rat alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR. Decrease in potency of inhibition of HVA calcium channels in rat/mouse DRG neurons. 2 Publications1
Mutagenesisi61H → D or K: Vc1.1; About 4.1-fold decrease in potency of inhibition of rat alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR. Decrease in potency of inhibition of HVA calcium channels in rat/mouse DRG neurons. 2 Publications1
Mutagenesisi62P → A: Vc1.1; 3.3-fold decrease in potency of inhibition of rat alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR. Decrease in potency of inhibition of HVA calcium channels in rat/mouse DRG neurons. 2 Publications1
Mutagenesisi62P → D or K: Vc1.1; Complete loss of potency of inhibition of rat alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR. Decrease in potency of inhibition of HVA calcium channels in rat/mouse DRG neurons. 2 Publications1
Mutagenesisi63E → A: Vc1.1; About 3.3-fold decrease in potency of inhibition of rat alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR. No change in potency of inhibition of HVA calcium channels in rat/mouse DRG neurons. Toxin cVc1.1[D11A; E14A]; important decrease in potency of inhibition of alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR. Very potent in inhibition of HVA calcium channels in mouse DRG neurons. 2 Publications1
Mutagenesisi63E → D: Vc1.1; About 2-fold decrease in potency of inhibition of rat alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR. No change in potency of inhibition of HVA calcium channels in rat/mouse DRG neurons. 2 Publications1
Mutagenesisi63E → K: Vc1.1; About 3-fold decrease in potency of inhibition of rat alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR. Decrease in potency of inhibition of HVA calcium channels in rat/mouse DRG neurons. 2 Publications1
Mutagenesisi64I → A: Vc1.1; 5-fold decrease in potency of inhibition of rat alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR. No change in potency of inhibition of HVA calcium channels in rat/mouse DRG neurons. 2 Publications1
Mutagenesisi64I → D: Vc1.1; Complete loss of potency of inhibition of rat alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR. No change in potency of inhibition of HVA calcium channels in rat/mouse DRG neurons. 2 Publications1
Mutagenesisi64I → K: Vc1.1; 2.5-fold decrease in potency of inhibition of rat alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR. Decrease in potency of inhibition of HVA calcium channels in rat/mouse DRG neurons. 2 Publications1
Mutagenesisi66G → GGAAGG: Toxin cVc1.1[D11A; E14A]; important decrease in potency of inhibition of alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR. Very potent in inhibition of HVA calcium channels in mouse DRG neurons. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 25Sequence analysisAdd BLAST25
PropeptideiPRO_000003489626 – 47CuratedAdd BLAST22
PeptideiPRO_000003489750 – 65Alpha-conotoxin Vc1A1 PublicationAdd BLAST16

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi51 ↔ 573 PublicationsImported
Disulfide bondi52 ↔ 653 PublicationsImported
Modified residuei554-hydroxyproline1 Publication1
Modified residuei634-carboxyglutamate1 Publication1
Modified residuei65Cysteine amide1 Publication1

Post-translational modificationi

Vc1.1 is described as having no post-translational modifications (except C-terminal amidation), whereas Vc1a contains an hydroxyproline at Pro-55 and a 4-carboxyglutamate at Glu-63 (and a C-terminal amidation) (PubMed:17101979, PubMed:17804600).2 Publications
Hydroxylation of Pro-55 is not important for inhibition of alpha-9-alpha-10/CHRNA9-CHRNA10 nAChRs, since [P6O]Vc1.1 (Pro-55 hydroxylated) shows similar inhibition than native toxin (IC50=99.1 nM) (PubMed:17804600). In contrast, hydroxylation of Pro-55 seems to impair inhibition of HVA calcium channel currents, since [P6O]Vc1.1 has no effect on HVA calcium channel currents (PubMed:18945902). In vivo, hydroxylation of Pro-55 seems to induce the loss of analgesic effects in rat models of neuropathic pain, since [P6O]Vc1.1 has no effect on mechanical allodynia (PubMed:17804600).2 Publications
Gamma-carboxylation of Glu-63 is not important for inhibition of alpha-9-alpha-10/CHRNA9-CHRNA10 nAChRs, since [E14gamma]Vc1.1 (carboxyglutamate at Glu-63) shows similar inhibition than native toxin (IC50=65.3 nM) (PubMed:17804600). In contrast, gamma-carboxylation of Glu-63 seems to impair inhibition of HVA calcium channel currents, since [E14gamma]Vc1.1 has no effect on HVA calcium channel currents (PubMed:18945902).2 Publications
Non-native isomers 'ribbon' (with disulfide connectivity C1-C4; C2-C3) and 'beads' (with disulfide connectivity C1-C2; C3-C4) of Vc1.1 also inhibit HVA calcium channel currents in rat DRG neurons (20-30% inhibition at 1 µM toxin) (PubMed:26948522). It has been shown that both reduced and alkylated Vc1.1 have no effect on HVA calcium channel currents. The observed activity can be attributed to specific isomers (PubMed:26948522).1 Publication
[C3S]Vc1.11-8 mutant is C-terminally amidated.1 Publication

Keywords - PTMi

Amidation, Cleavage on pair of basic residues, Disulfide bond, Gamma-carboxyglutamic acid, Hydroxylation

Expressioni

Tissue specificityi

Expressed by the venom duct.1 Publication

Structurei

Secondary structure

166
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliP69747
SMRiP69747
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP69747

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni54 – 56Key region for inhibition of alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR1 Publication3
Regioni60 – 64Key region for inhibition of alpha-9-alpha-10/CHRNA9-CHRNA10 nAChR1 Publication5

Domaini

The cysteine framework is I (CC-C-C). Alpha4/7 pattern.Curated

Sequence similaritiesi

Belongs to the conotoxin A superfamily.Curated

Keywords - Domaini

Signal

Family and domain databases

InterProiView protein in InterPro
IPR009958 Conotoxin_a-typ
IPR018072 Conotoxin_a-typ_CS
PfamiView protein in Pfam
PF07365 Toxin_8, 1 hit
PROSITEiView protein in PROSITE
PS60014 ALPHA_CONOTOXIN, 1 hit

Sequencei

Sequence statusi: Complete.

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

P69747-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MGMRMMFTVF LLVVLATTVV SSTSGRREFR GRNAAAKASD LVSLTDKKRG
60
CCSDPRCNYD HPEICG
Length:66
Mass (Da):7,258
Last modified:April 26, 2005 - v1
Checksum:iC55B0951D5E7A28D
GO

Mass spectrometryi

Molecular mass is 1866.5 Da from positions 50 - 65. Determined by ESI. 1 Publication
Molecular mass is 1866 Da from positions 50 - 65. Determined by ESI. 1 Publication

Similar proteinsi

Cross-referencesi

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2H8SNMR-A50-65[»]
2MFXNMR-A50-65[»]
2MFYNMR-A50-65[»]
2MG6NMR-A50-65[»]
2N07NMR-X50-65[»]
4TTLX-ray1.70A50-65[»]
6CGXNMR-A50-65[»]
ProteinModelPortaliP69747
SMRiP69747
ModBaseiSearch...
MobiDBiSearch...

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Organism-specific databases

ConoServeri499 VcIA precursor

Miscellaneous databases

EvolutionaryTraceiP69747

Family and domain databases

InterProiView protein in InterPro
IPR009958 Conotoxin_a-typ
IPR018072 Conotoxin_a-typ_CS
PfamiView protein in Pfam
PF07365 Toxin_8, 1 hit
PROSITEiView protein in PROSITE
PS60014 ALPHA_CONOTOXIN, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiCA1A_CONVC
AccessioniPrimary (citable) accession number: P69747
Entry historyiIntegrated into UniProtKB/Swiss-Prot: April 26, 2005
Last sequence update: April 26, 2005
Last modified: November 7, 2018
This is version 59 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programAnimal Toxin Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Pharmaceutical

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  2. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health

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