CA1_CONIM
ID CA1_CONIM Reviewed; 17 AA.
AC P50983; Q8I6R4;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 16-JAN-2004, sequence version 2.
DT 25-MAY-2022, entry version 110.
DE RecName: Full=Alpha-conotoxin ImI {ECO:0000303|PubMed:15609996, ECO:0000303|PubMed:8206995};
DE Short=Alpha-CTx ImI {ECO:0000303|PubMed:12384509};
DE Flags: Precursor; Fragment;
OS Conus imperialis (Imperial cone).
OC Eukaryota; Metazoa; Spiralia; Lophotrochozoa; Mollusca; Gastropoda;
OC Caenogastropoda; Neogastropoda; Conoidea; Conidae; Conus; Stephanoconus.
OX NCBI_TaxID=35631;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], SYNTHESIS OF 5-16, FUNCTION, AND
RP MUTAGENESIS OF PRO-10.
RC TISSUE=Venom duct;
RX PubMed=12384509; DOI=10.1074/jbc.m204565200;
RA Ellison M.A., McIntosh J.M., Olivera B.M.;
RT "Alpha-conotoxins ImI and ImII: similar alpha 7 nicotinic receptor
RT antagonists act at different sites.";
RL J. Biol. Chem. 278:757-764(2003).
RN [2]
RP PROTEIN SEQUENCE OF 5-16, FUNCTION, SYNTHESIS OF 5-16, DISULFIDE BONDS,
RP SUBCELLULAR LOCATION, AMIDATION AT CYS-16, AND MASS SPECTROMETRY.
RC TISSUE=Venom;
RX PubMed=8206995; DOI=10.1016/s0021-9258(19)89452-8;
RA McIntosh J.M., Yoshikami D., Mahe E., Nielsen D.B., Rivier J.E., Gray W.R.,
RA Olivera B.M.;
RT "A nicotinic acetylcholine receptor ligand of unique specificity, alpha-
RT conotoxin ImI.";
RL J. Biol. Chem. 269:16733-16739(1994).
RN [3]
RP FUNCTION, AND SYNTHESIS OF 5-16.
RX PubMed=7651351;
RA Johnson D.S., Martinez J., Elgoyhen A.B., Heinemann S.F., McIntosh J.M.;
RT "Alpha-conotoxin ImI exhibits subtype-specific nicotinic acetylcholine
RT receptor blockade: preferential inhibition of homomeric alpha 7 and alpha 9
RT receptors.";
RL Mol. Pharmacol. 48:194-199(1995).
RN [4]
RP FUNCTION, SYNTHESIS OF 5-16, 3D-STRUCTURE MODELING, AND SUBUNIT.
RX PubMed=15609996; DOI=10.1021/bi048918g;
RA Ellison M., Gao F., Wang H.L., Sine S.M., McIntosh J.M., Olivera B.M.;
RT "Alpha-conotoxins ImI and ImII target distinct regions of the human alpha7
RT nicotinic acetylcholine receptor and distinguish human nicotinic receptor
RT subtypes.";
RL Biochemistry 43:16019-16026(2004).
RN [5]
RP SYNTHESIS OF 5-16, 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 [6]
RP FUNCTION ON ALPHA-7 AND ALPHA-3-BETA-4, AND SYNTHESIS OF 5-16.
RX PubMed=19131337; DOI=10.1074/jbc.m806136200;
RA Armishaw C., Jensen A.A., Balle T., Clark R.J., Harpsoee K., Skonberg C.,
RA Liljefors T., Stroemgaard K.;
RT "Rational design of alpha-conotoxin analogues targeting alpha7 nicotinic
RT acetylcholine receptors: improved antagonistic activity by incorporation of
RT proline derivatives.";
RL J. Biol. Chem. 284:9498-9512(2009).
RN [7]
RP DISULFIDE BONDS (RIBBON FORM), 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 [8]
RP FUNCTION.
RX PubMed=25466886; DOI=10.1096/fj.14-262733;
RA Heghinian M.D., Mejia M., Adams D.J., Godenschwege T.A., Mari F.;
RT "Inhibition of cholinergic pathways in Drosophila melanogaster by alpha-
RT conotoxins.";
RL FASEB J. 29:1011-1018(2015).
RN [9]
RP STRUCTURE BY NMR OF 5-16, AND DISULFIDE BONDS.
RX PubMed=10194298; DOI=10.1021/bi9826254;
RA Rogers J.P., Luginbuehl P., Shen G.S., McCabe R.T., Stevens R.C.,
RA Wemmer D.E.;
RT "NMR solution structure of alpha-conotoxin ImI and comparison to other
RT conotoxins specific for neuronal nicotinic acetylcholine receptors.";
RL Biochemistry 38:3874-3882(1999).
RN [10]
RP STRUCTURE BY NMR OF 5-16, AND DISULFIDE BONDS.
RX PubMed=10350614; DOI=10.1016/s0167-4838(99)00065-5;
RA Gouda H., Hirono S.;
RT "Solution structure of alpha-conotoxin ImI determined by two-dimensional
RT NMR spectroscopy.";
RL Biochim. Biophys. Acta 1431:384-394(1999).
RN [11]
RP STRUCTURE BY NMR OF 5-16, AND DISULFIDE BONDS.
RX PubMed=10050774; DOI=10.1016/s0014-5793(99)00069-1;
RA Maslennikov I.V., Shenkarev Z.O., Zhmak M.N., Ivanov V.T., Methfessel C.,
RA Tsetlin V.I., Arseniev A.S.;
RT "NMR spatial structure of alpha-conotoxin ImI reveals a common scaffold in
RT snail and snake toxins recognizing neuronal nicotinic acetylcholine
RT receptors.";
RL FEBS Lett. 444:275-280(1999).
RN [12]
RP STRUCTURE BY NMR OF 5-16, AND DISULFIDE BONDS.
RX PubMed=10431825; DOI=10.1016/s0014-5793(99)00831-5;
RA Lamthanh H., Jegou-Matheron C., Servent D., Menez A., Lancelin J.-M.;
RT "Minimal conformation of the alpha-conotoxin ImI for the alpha7 neuronal
RT nicotinic acetylcholine receptor recognition: correlated CD, NMR and
RT binding studies.";
RL FEBS Lett. 454:293-298(1999).
RN [13]
RP STRUCTURE BY NMR OF 5-16, AND DISULFIDE BONDS.
RX PubMed=10395477; DOI=10.1021/jm990114p;
RA Gehrmann J., Daly N.L., Alewood P.F., Craik D.J.;
RT "Solution structure of alpha-conotoxin ImI by 1H nuclear magnetic
RT resonance.";
RL J. Med. Chem. 42:2364-2372(1999).
RN [14]
RP MUTAGENESIS OF ASP-9; ARG-11 AND ARG-15, STRUCTURE BY NMR OF 5-16 OF THESE
RP THREE MUTANTS, AND DISULFIDE BONDS.
RX PubMed=11124036; DOI=10.1006/jmbi.2000.4247;
RA Rogers J.P., Luginbuhl P., Pemberton K., Harty P., Wemmer D.E.,
RA Stevens R.C.;
RT "Structure-activity relationships in a peptidic alpha7 nicotinic
RT acetylcholine receptor antagonist.";
RL J. Mol. Biol. 304:911-926(2000).
CC -!- FUNCTION: Alpha-conotoxins act on postsynaptic membranes, they bind to
CC the nicotinic acetylcholine receptors (nAChR) and thus inhibit them.
CC This toxin blocks neuronal alpha-3-beta-2/CHRNA3-CHRNB2 (human and
CC rat), alpha-7/CHRNA7 (human and rat), and alpha-3-beta-4/CHRNA3-CHRNB4
CC (human) nAChRs (PubMed:8206995, PubMed:15609996, PubMed:19131337). Acts
CC voltage-independently (PubMed:15609996). Competes with alpha-
CC bungarotoxin for binding to the receptor (PubMed:12384509,
CC PubMed:15609996). Binds to a different site than alpha-conotoxin ImII
CC (PubMed:15609996). Is highly active against the neuromuscular receptor
CC in frog (PubMed:8206995). Also exhibits inhibition of D.melanogaster
CC alpha-7 nAChRs (PubMed:25466886). {ECO:0000269|PubMed:12384509,
CC ECO:0000269|PubMed:15609996, ECO:0000269|PubMed:19131337,
CC ECO:0000269|PubMed:25466886, ECO:0000269|PubMed:8206995}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:8206995}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom duct. {ECO:0000305}.
CC -!- DOMAIN: The cysteine framework is I (CC-C-C). Alpha4/3 pattern.
CC {ECO:0000305}.
CC -!- PTM: Not hydroxylated; hydroxylation improves its folding but impairs
CC its activity against target receptors. {ECO:0000269|PubMed:18189422}.
CC -!- MASS SPECTROMETRY: Mass=1351.48; Method=Unknown; Note=Monoisotopic
CC mass.; Evidence={ECO:0000269|PubMed:8206995};
CC -!- MISCELLANEOUS: This toxin is a substrate for a multienzyme complex that
CC regulates its folding and assembly. This complex is composed of
CC protein-disulfide isomerase (PDI), peptidyl-prolyl cis-trans isomerase
CC (PPI) and immunoglobulin-binding protein (BiP). PDI catalyzes the
CC oxidation and reduction of disulfide bonds. Oxidative folding rates are
CC further increased in the presence of PPI with the maximum effect
CC observed in the presence of both enzymes. In contrast, BiP is only
CC observed to assist folding in the presence of microsomes, suggesting
CC that additional cofactors are involved. This toxin has been observed in
CC the venom as globular (disulfide pattern C1-C3 and C2-C4) and ribbon
CC form (C1-C4 and C2-C3). {ECO:0000269|PubMed:22891240}.
CC -!- MISCELLANEOUS: Does not inhibit alpha-2-beta-2, alpha-4-beta-2, alpha-
CC 2-beta-4, alpha-3-beta-4, and alpha-4-beta-4 subunits (PubMed:7651351,
CC PubMed:15609996). Has also no effect on muscle nAChRs alpha-1-beta-1-
CC delta-epsilon (PubMed:15609996). {ECO:0000269|PubMed:15609996,
CC ECO:0000269|PubMed:7651351}.
CC -!- SIMILARITY: Belongs to the conotoxin A superfamily. {ECO:0000305}.
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DR EMBL; AY159318; AAN78128.1; -; Genomic_DNA.
DR PIR; A53709; A53709.
DR PDB; 1CNL; NMR; -; A=5-16.
DR PDB; 1E74; NMR; -; A=5-14.
DR PDB; 1E75; NMR; -; A=5-16.
DR PDB; 1E76; NMR; -; A=5-16.
DR PDB; 1G2G; NMR; -; A=5-16.
DR PDB; 1IM1; NMR; -; A=5-16.
DR PDB; 1IMI; NMR; -; A=5-16.
DR PDB; 2BC7; NMR; -; A=5-16.
DR PDB; 2BC8; NMR; -; A=5-16.
DR PDB; 2BYP; X-ray; 2.07 A; F/G/H/I/J=5-16.
DR PDB; 2C9T; X-ray; 2.25 A; K/M/O/P/Q/R/S/T=5-16.
DR PDB; 2IGU; NMR; -; A=5-16.
DR PDB; 2MOA; NMR; -; A=5-16.
DR PDBsum; 1CNL; -.
DR PDBsum; 1E74; -.
DR PDBsum; 1E75; -.
DR PDBsum; 1E76; -.
DR PDBsum; 1G2G; -.
DR PDBsum; 1IM1; -.
DR PDBsum; 1IMI; -.
DR PDBsum; 2BC7; -.
DR PDBsum; 2BC8; -.
DR PDBsum; 2BYP; -.
DR PDBsum; 2C9T; -.
DR PDBsum; 2IGU; -.
DR PDBsum; 2MOA; -.
DR AlphaFoldDB; P50983; -.
DR SMR; P50983; -.
DR DIP; DIP-61127N; -.
DR IntAct; P50983; 1.
DR ConoServer; 93; ImI precursor.
DR EvolutionaryTrace; P50983; -.
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; IPR018072; Conotoxin_a-typ_CS.
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; Toxin.
FT PROPEP <1..4
FT /evidence="ECO:0000269|PubMed:8206995"
FT /id="PRO_0000273426"
FT PEPTIDE 5..16
FT /note="Alpha-conotoxin ImI"
FT /evidence="ECO:0000269|PubMed:8206995"
FT /id="PRO_0000034877"
FT SITE 9
FT /note="Important for binding to human alpha-7 nAChR"
FT /evidence="ECO:0000305|PubMed:15609996"
FT SITE 10
FT /note="Important for binding to human alpha-7 nAChR"
FT /evidence="ECO:0000305|PubMed:15609996"
FT SITE 11
FT /note="Important for binding to human alpha-7 nAChR"
FT /evidence="ECO:0000305|PubMed:15609996"
FT SITE 13
FT /note="Important for binding to human alpha-7 nAChR"
FT /evidence="ECO:0000305|PubMed:15609996"
FT SITE 14
FT /note="Important for binding to human alpha-7 nAChR"
FT /evidence="ECO:0000305|PubMed:15609996"
FT MOD_RES 16
FT /note="Cysteine amide"
FT /evidence="ECO:0000269|PubMed:8206995"
FT DISULFID 6..16
FT /note="In Imi-ribbon form; alternate"
FT /evidence="ECO:0000269|PubMed:22891240"
FT DISULFID 6..12
FT /note="In Imi-globular form; alternate"
FT /evidence="ECO:0000269|PubMed:10050774,
FT ECO:0000269|PubMed:10194298, ECO:0000269|PubMed:10350614,
FT ECO:0000269|PubMed:10395477, ECO:0000269|PubMed:10431825,
FT ECO:0000269|PubMed:11124036"
FT DISULFID 7..16
FT /note="In Imi-globular form; alternate"
FT /evidence="ECO:0000269|PubMed:10050774,
FT ECO:0000269|PubMed:10194298, ECO:0000269|PubMed:10350614,
FT ECO:0000269|PubMed:10395477, ECO:0000269|PubMed:10431825,
FT ECO:0000269|PubMed:11124036"
FT DISULFID 7..12
FT /note="In Imi-ribbon form; alternate"
FT /evidence="ECO:0000269|PubMed:22891240"
FT MUTAGEN 9
FT /note="D->L: Reduction of toxicity."
FT /evidence="ECO:0000269|PubMed:11124036"
FT MUTAGEN 10
FT /note="P->R: Loss of ability to compete with alpha-
FT bungarotoxin."
FT /evidence="ECO:0000269|PubMed:12384509"
FT MUTAGEN 11
FT /note="R->L: Reduction of toxicity."
FT /evidence="ECO:0000269|PubMed:11124036"
FT MUTAGEN 15
FT /note="R->E: No loss of activity."
FT /evidence="ECO:0000269|PubMed:11124036"
FT NON_TER 1
FT HELIX 6..8
FT /evidence="ECO:0007829|PDB:2BYP"
FT TURN 10..12
FT /evidence="ECO:0007829|PDB:2BYP"
FT HELIX 13..15
FT /evidence="ECO:0007829|PDB:2BYP"
SQ SEQUENCE 17 AA; 1938 MW; 9590D9CEA50279CF CRC64;
IVRRGCCSDP RCAWRCG
