UniProt functional annotation for P69747



	UniProt functional annotation for P69747

UniProt code: P69747.

Organism: Conus victoriae (Queen Victoria cone).

Taxonomy: Eukaryota; Metazoa; Spiralia; Lophotrochozoa; Mollusca; Gastropoda; Caenogastropoda; Neogastropoda; Conoidea; Conidae; Conus; Cylinder.

Function: 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 (IC(50)=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). {ECO:0000269|PubMed:17804600, ECO:0000269|PubMed:18945902}.

Function: 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, IC(50)=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) (IC(50)=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) (IC(50)=140 nM) and alpha-6/alpha-3-beta- 4 (CHRNA6/CHRNA3-CHRNB4) (IC(50)=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). {ECO:0000269|PubMed:12779345, ECO:0000269|PubMed:15770155, ECO:0000269|PubMed:17101979, ECO:0000269|PubMed:17804600, ECO:0000269|PubMed:18945902, ECO:0000269|PubMed:19447885, ECO:0000269|PubMed:20533477, ECO:0000269|PubMed:23566299, ECO:0000269|PubMed:23768016, ECO:0000269|PubMed:26948522}.

Subcellular location: Secreted {ECO:0000269|PubMed:15170751}.

Tissue specificity: Expressed by the venom duct. {ECO:0000305|PubMed:15170751}.

Domain: The cysteine framework is I (CC-C-C). Alpha4/7 pattern. {ECO:0000305}.

Ptm: Vc1.1 is described as having no post-translational modifications (except C-terminal amidation), whereas Vc1a contains a hydroxyproline at Pro-55 and a 4-carboxyglutamate at Glu-63 (and a C-terminal amidation) (PubMed:17101979, PubMed:17804600). {ECO:0000305|PubMed:17101979, ECO:0000305|PubMed:17804600}.

Ptm: 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 (IC(50)=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). {ECO:0000269|PubMed:17804600, ECO:0000269|PubMed:18945902}.

Ptm: 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 (IC(50)=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). {ECO:0000269|PubMed:17804600, ECO:0000269|PubMed:18945902}.

Ptm: 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 uM 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). {ECO:0000269|PubMed:26948522}.

Ptm: [C3S]Vc1.1(1-8) mutant is C-terminally amidated. {ECO:0000269|PubMed:26948522}.

Mass spectrometry: Mass=1866.5; Method=Electrospray; Evidence={ECO:0000269|PubMed:15170751};

Mass spectrometry: Mass=1866; Method=Electrospray; Evidence={ECO:0000269|PubMed:16754662};

Pharmaceutical: 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). {ECO:0000305|PubMed:29194563}.

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 (IC(50)=7.2 uM), alpha-3-beta-2/CHRNA3-CHRNB2 (IC(50)=5.5-7.3 uM), alpha-3-beta- 4/CHRNA3-CHRNB4 (IC(50)=4.2 uM), alpha-3-alpha-5-beta-4/CHRNA3-CHRNA5- CHRNB4 (IC(50)>30 uM), alpha-4-beta-2/CHRNA4-CHRNB2 (IC(50)>30 uM), alpha-4-beta-4/CHRNA4-CHRNB4 (IC(50)>30 uM), rat alpha-7/CHRNA7 (IC(50)=7.1 uM) and alpha-1-beta-1-gamma-delta/CHRNA1-CHRNB1-CHRNG- CHRND (IC(50)>30 uM) subunits. {ECO:0000269|PubMed:16754662, ECO:0000269|PubMed:19447885, ECO:0000269|PubMed:32101438}.

Miscellaneous: cVc1.1 is a cyclic peptide with inhibitory activity on alpha-9-alpha-10/CHRNA9-CHRNA10 nAChRs (IC(50)=766 nM) and a high potency at inhibiting HVA calcium channels in mice DRG neurons (IC(50)=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 (IC(50)>17 uM) and a high potency at inhibiting HVA calcium channels in mice DRG neurons (IC(50)=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). {ECO:0000269|PubMed:20533477, ECO:0000269|PubMed:29194563, ECO:0000269|PubMed:29746088}.

Similarity: Belongs to the conotoxin A superfamily. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Conus victoriae (Queen Victoria cone).
Taxonomy:		Eukaryota; Metazoa; Spiralia; Lophotrochozoa; Mollusca; Gastropoda; Caenogastropoda; Neogastropoda; Conoidea; Conidae; Conus; Cylinder.



Function:		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 (IC(50)=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). {ECO:0000269\|PubMed:17804600, ECO:0000269\|PubMed:18945902}.



Function:		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, IC(50)=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) (IC(50)=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) (IC(50)=140 nM) and alpha-6/alpha-3-beta- 4 (CHRNA6/CHRNA3-CHRNB4) (IC(50)=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). {ECO:0000269\|PubMed:12779345, ECO:0000269\|PubMed:15770155, ECO:0000269\|PubMed:17101979, ECO:0000269\|PubMed:17804600, ECO:0000269\|PubMed:18945902, ECO:0000269\|PubMed:19447885, ECO:0000269\|PubMed:20533477, ECO:0000269\|PubMed:23566299, ECO:0000269\|PubMed:23768016, ECO:0000269\|PubMed:26948522}.


Subcellular location:		Secreted {ECO:0000269\|PubMed:15170751}.
Tissue specificity:		Expressed by the venom duct. {ECO:0000305\|PubMed:15170751}.
Domain:		The cysteine framework is I (CC-C-C). Alpha4/7 pattern. {ECO:0000305}.
Ptm:		Vc1.1 is described as having no post-translational modifications (except C-terminal amidation), whereas Vc1a contains a hydroxyproline at Pro-55 and a 4-carboxyglutamate at Glu-63 (and a C-terminal amidation) (PubMed:17101979, PubMed:17804600). {ECO:0000305\|PubMed:17101979, ECO:0000305\|PubMed:17804600}.
Ptm:		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 (IC(50)=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). {ECO:0000269\|PubMed:17804600, ECO:0000269\|PubMed:18945902}.
Ptm:		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 (IC(50)=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). {ECO:0000269\|PubMed:17804600, ECO:0000269\|PubMed:18945902}.
Ptm:		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 uM 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). {ECO:0000269\|PubMed:26948522}.
Ptm:		[C3S]Vc1.1(1-8) mutant is C-terminally amidated. {ECO:0000269\|PubMed:26948522}.
Mass spectrometry:		Mass=1866.5; Method=Electrospray; Evidence={ECO:0000269\|PubMed:15170751};
Mass spectrometry:		Mass=1866; Method=Electrospray; Evidence={ECO:0000269\|PubMed:16754662};
Pharmaceutical:		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). {ECO:0000305\|PubMed:29194563}.
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 (IC(50)=7.2 uM), alpha-3-beta-2/CHRNA3-CHRNB2 (IC(50)=5.5-7.3 uM), alpha-3-beta- 4/CHRNA3-CHRNB4 (IC(50)=4.2 uM), alpha-3-alpha-5-beta-4/CHRNA3-CHRNA5- CHRNB4 (IC(50)>30 uM), alpha-4-beta-2/CHRNA4-CHRNB2 (IC(50)>30 uM), alpha-4-beta-4/CHRNA4-CHRNB4 (IC(50)>30 uM), rat alpha-7/CHRNA7 (IC(50)=7.1 uM) and alpha-1-beta-1-gamma-delta/CHRNA1-CHRNB1-CHRNG- CHRND (IC(50)>30 uM) subunits. {ECO:0000269\|PubMed:16754662, ECO:0000269\|PubMed:19447885, ECO:0000269\|PubMed:32101438}.
Miscellaneous:		cVc1.1 is a cyclic peptide with inhibitory activity on alpha-9-alpha-10/CHRNA9-CHRNA10 nAChRs (IC(50)=766 nM) and a high potency at inhibiting HVA calcium channels in mice DRG neurons (IC(50)=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 (IC(50)>17 uM) and a high potency at inhibiting HVA calcium channels in mice DRG neurons (IC(50)=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). {ECO:0000269\|PubMed:20533477, ECO:0000269\|PubMed:29194563, ECO:0000269\|PubMed:29746088}.
Similarity:		Belongs to the conotoxin A superfamily. {ECO:0000305}.