CA1_CONGE
ID CA1_CONGE Reviewed; 64 AA.
AC X5I9Y2; P01519;
DT 23-FEB-2022, integrated into UniProtKB/Swiss-Prot.
DT 11-JUN-2014, sequence version 1.
DT 03-AUG-2022, entry version 24.
DE RecName: Full=Alpha-conotoxin GI {ECO:0000303|PubMed:7014556};
DE AltName: Full=G1;
DE Flags: Precursor;
OS Conus geographus (Geography cone) (Nubecula geographus).
OC Eukaryota; Metazoa; Spiralia; Lophotrochozoa; Mollusca; Gastropoda;
OC Caenogastropoda; Neogastropoda; Conoidea; Conidae; Conus; Gastridium.
OX NCBI_TaxID=6491;
RN [1] {ECO:0000312|EMBL:BAO65577.1}
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Venom duct;
RX PubMed=24662800; DOI=10.1038/ncomms4521;
RA Dutertre S., Jin A.-H., Vetter I., Hamilton B., Sunagar K., Lavergne V.,
RA Dutertre V., Fry B.G., Antunes A., Venter D.J., Alewood P.F., Lewis R.J.;
RT "Evolution of separate predation- and defence-evoked venoms in carnivorous
RT cone snails.";
RL Nat. Commun. 5:3521-3521(2014).
RN [2]
RP PROTEIN SEQUENCE OF 50-62, AMIDATION AT CYS-62, SUBCELLULAR LOCATION, AND
RP PROBABLE AMIDATION AT CYS-62.
RX PubMed=7014556; DOI=10.1016/s0021-9258(19)69313-0;
RA Gray W.R., Luque A., Olivera B.M., Barrett J., Cruz L.J.;
RT "Peptide toxins from Conus geographus venom.";
RL J. Biol. Chem. 256:4734-4740(1981).
RN [3]
RP DISULFIDE BONDS, AND SYNTHESIS OF 50-62.
RX PubMed=7152021; DOI=10.1016/0014-5793(82)80820-x;
RA Nishiuchi Y., Sakakibara S.;
RT "Primary and secondary structure of conotoxin GI, a neurotoxic
RT tridecapeptide from a marine snail.";
RL FEBS Lett. 148:260-262(1982).
RN [4]
RP DISULFIDE BONDS, AND SYNTHESIS OF 50-62.
RX PubMed=6466616; DOI=10.1021/bi00307a040;
RA Gray W.R., Luque F.A., Galyean R., Atherton E., Sheppard R.C., Stone B.L.,
RA Reyes A., Alford J., McIntosh M., Olivera B.M., Cruz L.J., Rivier J.;
RT "Conotoxin GI: disulfide bridges, synthesis, and preparation of iodinated
RT derivatives.";
RL Biochemistry 23:2796-2802(1984).
RN [5]
RP COMPARISON WITH ALPHA-CONOTOXIN SI AND ALPHA-CONOTOXIN MI.
RX PubMed=7947815; DOI=10.1021/bi00251a014;
RA Hann R.M., Pagan O.R., Eterovic V.A.;
RT "The alpha-conotoxins GI and MI distinguish between the nicotinic
RT acetylcholine receptor agonist sites while SI does not.";
RL Biochemistry 33:14058-14063(1994).
RN [6]
RP PHARMACOLOGICAL CHARACTERIZATION ON MOUSE MUSCLE-DERIVED BC3H-1 CELLS AND
RP TORPEDO ELECTRIC ORGAN.
RX PubMed=7623764;
RA Groebe D.R., Dumm J.M., Levitan E.S., Abramson S.N.;
RT "Alpha-conotoxins selectively inhibit one of the two acetylcholine binding
RT sites of nicotinic receptors.";
RL Mol. Pharmacol. 48:105-111(1995).
RN [7]
RP MUTAGENESIS OF ARG-58.
RX PubMed=9174364; DOI=10.1021/bi970195w;
RA Groebe D.R., Gray W.R., Abramson S.N.;
RT "Determinants involved in the affinity of alpha-conotoxins GI and SI for
RT the muscle subtype of nicotinic acetylcholine receptors.";
RL Biochemistry 36:6469-6474(1997).
RN [8]
RP SYNTHESIS OF 50-62, AND ROLE OF HYDROXYLATION.
RX PubMed=18189422; DOI=10.1021/bi701934m;
RA Lopez-Vera E., Walewska A., Skalicky J.J., Olivera B.M., Bulaj G.;
RT "Role of hydroxyprolines in the in vitro oxidative folding and biological
RT activity of conotoxins.";
RL Biochemistry 47:1741-1751(2008).
RN [9]
RP DISULFIDE BONDS, AND FOLDING.
RC TISSUE=Venom;
RX PubMed=22891240; DOI=10.1074/jbc.m112.366781;
RA Safavi-Hemami H., Gorasia D.G., Steiner A.M., Williamson N.A., Karas J.A.,
RA Gajewiak J., Olivera B.M., Bulaj G., Purcell A.W.;
RT "Modulation of conotoxin structure and function is achieved through a
RT multienzyme complex in the venom glands of cone snails.";
RL J. Biol. Chem. 287:34288-34303(2012).
RN [10]
RP FUNCTION, AND MUTAGENESIS OF GLU-50; ASN-53; PRO-54; GLY-57; ARG-58;
RP HIS-59; TYR-60 AND SER-61.
RX PubMed=30551685; DOI=10.3390/md16120507;
RA Ning J., Li R., Ren J., Zhangsun D., Zhu X., Wu Y., Luo S.;
RT "Alanine-scanning mutagenesis of alpha-conotoxin GI reveals the residues
RT crucial for activity at the muscle acetylcholine receptor.";
RL Mar. Drugs 16:0-0(2018).
RN [11]
RP SYNTHESIS OF 50-62 AS GLOBULAR AND RIBBON ISOMER, AND FUNCTION.
RX PubMed=34062129; DOI=10.1016/j.bcp.2021.114638;
RA Tae H.S., Gao B., Jin A.H., Alewood P.F., Adams D.J.;
RT "Globular and ribbon isomers of Conus geographus alpha-conotoxins
RT antagonize human nicotinic acetylcholine receptors.";
RL Biochem. Pharmacol. 190:114638-114638(2021).
RN [12]
RP X-RAY CRYSTALLOGRAPHY (1.2 ANGSTROMS) OF 50-62, AND DISULFIDE BONDS.
RX PubMed=8784187; DOI=10.1021/bi960820h;
RA Guddat L.W., Martin J.A., Shan L., Edmundson A.B., Gray W.R.;
RT "Three-dimensional structure of the alpha-conotoxin GI at 1.2-A
RT resolution.";
RL Biochemistry 35:11329-11335(1996).
RN [13]
RP STRUCTURE BY NMR OF 50-62, AND DISULFIDE BONDS.
RX PubMed=2765514; DOI=10.1021/bi00437a050;
RA Kobayashi Y., Ohkubo T., Kyogoku Y., Nishiuchi Y., Sakakibara S., Braun W.,
RA Go N.;
RT "Solution conformation of conotoxin GI determined by 1H nuclear magnetic
RT resonance spectroscopy and distance geometry calculations.";
RL Biochemistry 28:4853-4860(1989).
RN [14]
RP STRUCTURE BY NMR OF 50-62, AND DISULFIDE BONDS.
RX PubMed=2775719; DOI=10.1021/bi00439a026;
RA Pardi A., Galdes A., Florance J., Maniconte D.;
RT "Solution structures of alpha-conotoxin G1 determined by two-dimensional
RT NMR spectroscopy.";
RL Biochemistry 28:5494-5501(1989).
RN [15]
RP STRUCTURE BY NMR OF 50-62, AND DISULFIDE BONDS.
RX PubMed=9660176; DOI=10.1046/j.1432-1327.1998.2540238.x;
RA Maslennikov I.V., Sobol A.G., Gladky K.V., Lugovskoy A.A., Ostrovsky A.G.,
RA Tsetlin V.I., Ivanov V.T., Arseniev A.S.;
RT "Two distinct structures of alpha-conotoxin GI in aqueous solution.";
RL Eur. J. Biochem. 254:238-247(1998).
RN [16]
RP STRUCTURE BY NMR OF 50-62, AND DISULFIDE BONDS.
RX PubMed=9571060; DOI=10.1006/jmbi.1998.1701;
RA Gehrmann J., Alewood P.F., Craik D.J.;
RT "Structure determination of the three disulfide bond isomers of alpha-
RT conotoxin GI: a model for the role of disulfide bonds in structural
RT stability.";
RL J. Mol. Biol. 278:401-415(1998).
RN [17]
RP STRUCTURE BY NMR OF 50-62 OF AN ANTITOXIC ANALOG, AND DISULFIDE BONDS.
RX PubMed=10508392; DOI=10.1021/bi990558n;
RA Mok K.H., Han K.H.;
RT "NMR solution conformation of an antitoxic analogue of alpha-conotoxin GI:
RT identification of a common nicotinic acetylcholine receptor alpha(1)-
RT subunit binding surface for small ligands and alpha-conotoxins.";
RL Biochemistry 38:11895-11904(1999).
CC -!- FUNCTION: Alpha-conotoxins act on postsynaptic membranes, they bind to
CC the nicotinic acetylcholine receptors (nAChR) and thus inhibit them.
CC Both globular (with C1-C3; C2-C4 disulfide pattern) and ribbon (C1-C4;
CC C2-C3) isomers reversibly inhibit mammalian muscle-type alpha-1-beta-1-
CC delta-epsilon/CHRNA1-CHRNB1-CHRND-CHRNE nAChRs (IC(50)=5.86-19.9 nM and
CC IC(50)=701 nM, respectively) (PubMed:30551685, PubMed:34062129). The
CC higher affinity site is the alpha/delta site on mouse muscle-derived
CC BC3H-1 receptor, and the other site (alpha/gamma site) on nicotinic
CC receptors from Torpedo californica electric organ (PubMed:7623764).
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:7014556}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom duct.
CC {ECO:0000305|PubMed:7014556}.
CC -!- DOMAIN: The cysteine framework is I (CC-C-C). Alpha3/5 pattern.
CC {ECO:0000305}.
CC -!- PTM: Not hydroxylated; hydroxylation, on a synthetic hydroxylated GI,
CC improves its folding but impairs its activity against target receptors.
CC -!- MISCELLANEOUS: Both globular (with C1-C3; C2-C4 disulfide pattern) and
CC ribbon (C1-C4; C2-C3) isomers show no or very weak inhibitory activity
CC on alpha-3-beta-2/CHRNA3-CHRNB2, alpha-3-beta-4/CHRNA3-CHRNB4, alpha-4-
CC beta-2/CHRNA4-CHRNB2, alpha-7/CHRNA7, and alpha-9-alpha-10/CHRNA9-
CC CHRNA10. {ECO:0000269|PubMed:30551685, ECO:0000269|PubMed:34062129}.
CC -!- MISCELLANEOUS: This toxin is a substrate for a cone snail multienzyme
CC complex that regulates its folding and assembly. This complex is
CC composed of protein-disulfide isomerase (PDI), peptidyl-prolyl cis-
CC trans isomerase (PPI) and immunoglobulin-binding protein (BiP). PDI
CC catalyzes the oxidation and reduction of disulfide bonds. Oxidative
CC folding rates are further increased in the presence of PPI with the
CC maximum effect observed in the presence of both enzymes. In contrast,
CC BiP is only observed to assist folding in the presence of microsomes,
CC suggesting that additional cofactors are involved. This toxin has been
CC only observed in the globular form (disulfide pattern C1-C3 and C2-C4).
CC {ECO:0000269|PubMed:22891240}.
CC -!- SIMILARITY: Belongs to the conotoxin A superfamily. {ECO:0000305}.
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DR EMBL; AB910809; BAO65577.1; -; mRNA.
DR PIR; A01782; NTKNAG.
DR PDB; 1NOT; X-ray; 1.20 A; A=50-62.
DR PDB; 1QS3; NMR; -; A=51-61.
DR PDB; 1XGA; NMR; -; A=50-62.
DR PDB; 1XGB; NMR; -; A=50-62.
DR PDB; 1XGC; NMR; -; A=50-62.
DR PDB; 2FR9; NMR; -; A=50-60.
DR PDB; 2FRB; NMR; -; A=50-62.
DR PDBsum; 1NOT; -.
DR PDBsum; 1QS3; -.
DR PDBsum; 1XGA; -.
DR PDBsum; 1XGB; -.
DR PDBsum; 1XGC; -.
DR PDBsum; 2FR9; -.
DR PDBsum; 2FRB; -.
DR ConoServer; 74; GI.
DR ConoServer; 22; GIA.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0035792; C:host cell postsynaptic membrane; IEA:UniProtKB-KW.
DR GO; GO:0030550; F:acetylcholine receptor inhibitor activity; IEA:UniProtKB-KW.
DR GO; GO:0099106; F:ion channel regulator activity; IEA:UniProtKB-KW.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR InterPro; IPR009958; Conotoxin_a-typ.
DR InterPro; IPR018072; Conotoxin_a-typ_CS.
DR Pfam; PF07365; Toxin_8; 1.
DR PROSITE; PS60014; ALPHA_CONOTOXIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylcholine receptor inhibiting toxin; Amidation;
KW Cleavage on pair of basic residues; Direct protein sequencing;
KW Disulfide bond; Ion channel impairing toxin; Neurotoxin;
KW Postsynaptic neurotoxin; Secreted; Signal; Toxin.
FT SIGNAL 1..21
FT /evidence="ECO:0000255"
FT PROPEP 22..49
FT /evidence="ECO:0000305|PubMed:7014556"
FT /id="PRO_0000454094"
FT PEPTIDE 50..62
FT /note="Alpha-conotoxin GI"
FT /evidence="ECO:0000269|PubMed:7014556"
FT /id="PRO_0000034874"
FT SITE 60
FT /note="Key residue that binds to three hydrophobic amino
FT acids of the delta subunit of muscle-type acetylcholine
FT receptor"
FT /evidence="ECO:0000305|PubMed:30551685"
FT MOD_RES 62
FT /note="Cysteine amide"
FT /evidence="ECO:0000269|PubMed:7014556"
FT DISULFID 51..56
FT /evidence="ECO:0000269|PubMed:10508392,
FT ECO:0000269|PubMed:22891240, ECO:0000269|PubMed:2765514,
FT ECO:0000269|PubMed:2775719, ECO:0000269|PubMed:6466616,
FT ECO:0000269|PubMed:7152021, ECO:0000269|PubMed:8784187,
FT ECO:0000269|PubMed:9571060, ECO:0000269|PubMed:9660176"
FT DISULFID 52..62
FT /evidence="ECO:0000269|PubMed:10508392,
FT ECO:0000269|PubMed:22891240, ECO:0000269|PubMed:2765514,
FT ECO:0000269|PubMed:2775719, ECO:0000269|PubMed:6466616,
FT ECO:0000269|PubMed:7152021, ECO:0000269|PubMed:8784187,
FT ECO:0000269|PubMed:9571060, ECO:0000269|PubMed:9660176"
FT MUTAGEN 50
FT /note="E->A: 3-fold increase in inhibitory potency towards
FT mouse muscle-type acetylcholine receptor. No increase in
FT inhibitory potency towards alpha-3-beta-2/CHRNA3-CHRNB2,
FT alpha-3-beta-4/CHRNA3-CHRNB4, alpha-4-beta-4/CHRNA4-CHRNB4,
FT alpha-7/CHRNA7, and alpha-9-alpha-10/CHRNA9-CHRNA10
FT nAChRs."
FT /evidence="ECO:0000269|PubMed:30551685"
FT MUTAGEN 53
FT /note="N->A: No significant change in inhibitory potency
FT towards mouse muscle-type acetylcholine receptor."
FT /evidence="ECO:0000269|PubMed:30551685"
FT MUTAGEN 54
FT /note="P->A: 10-fold decrease in inhibitory potency towards
FT mouse muscle-type acetylcholine receptor. 2-fold increase
FT in inhibitory potency towards rat alpha-9-alpha-10/CHRNA9-
FT CHRNA10 nAChRs. No increase in inhibitory potency towards
FT alpha-3-beta-2/CHRNA3-CHRNB2, alpha-3-beta-4/CHRNA3-CHRNB4,
FT alpha-4-beta-4/CHRNA4-CHRNB4, and alpha-7/CHRNA7 nAChRs."
FT /evidence="ECO:0000269|PubMed:30551685"
FT MUTAGEN 57
FT /note="G->A: 30-fold decrease in inhibitory potency towards
FT mouse muscle-type acetylcholine receptor. 2-fold increase
FT in inhibitory potency towards rat alpha-9-alpha-10/CHRNA9-
FT CHRNA10 nAChRs. No increase in inhibitory potency towards
FT alpha-3-beta-2/CHRNA3-CHRNB2, alpha-3-beta-4/CHRNA3-CHRNB4,
FT alpha-4-beta-4/CHRNA4-CHRNB4, and alpha-7/CHRNA7 nAChRs."
FT /evidence="ECO:0000269|PubMed:30551685"
FT MUTAGEN 58
FT /note="R->A: 8.5-fold decrease in inhibitory potency
FT towards mouse muscle-type acetylcholine receptor. No
FT increase in inhibitory potency towards alpha-3-beta-
FT 2/CHRNA3-CHRNB2, alpha-3-beta-4/CHRNA3-CHRNB4, alpha-4-
FT beta-4/CHRNA4-CHRNB4, alpha-7/CHRNA7, and alpha-9-alpha-
FT 10/CHRNA9-CHRNA10 nAChRs. Decrease in affinity for both
FT alpha/delta and alpha/gamma sites on BC3H-50 receptors and
FT loss of affinity for both alpha/delta and alpha/gamma sites
FT on Torpedo receptors."
FT /evidence="ECO:0000269|PubMed:30551685,
FT ECO:0000269|PubMed:9174364"
FT MUTAGEN 59
FT /note="H->A: No significant change in inhibitory potency
FT towards mouse muscle-type acetylcholine receptor."
FT /evidence="ECO:0000269|PubMed:30551685"
FT MUTAGEN 60
FT /note="Y->A: 65-fold decrease in inhibitory potency towards
FT mouse muscle-type acetylcholine receptor. No increase in
FT inhibitory potency towards alpha-3-beta-2/CHRNA3-CHRNB2,
FT alpha-3-beta-4/CHRNA3-CHRNB4, alpha-4-beta-4/CHRNA4-CHRNB4,
FT alpha-7/CHRNA7, and alpha-9-alpha-10/CHRNA9-CHRNA10
FT nAChRs."
FT /evidence="ECO:0000269|PubMed:30551685"
FT MUTAGEN 61
FT /note="S->A: No significant change in inhibitory potency
FT towards mouse muscle-type acetylcholine receptor."
FT /evidence="ECO:0000269|PubMed:30551685"
FT HELIX 54..59
FT /evidence="ECO:0007829|PDB:1NOT"
SQ SEQUENCE 64 AA; 7094 MW; A15D550E4BA7E140 CRC64;
MGMRMMFTVF LLVVLATTVV SFPSERASDG RDDTAKDEGS DMDKLVEKKE CCNPACGRHY
SCGR
