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 22-FEB-2023, entry version 112. 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 PTM. RX PubMed=16161170; DOI=10.1002/anie.200502300; RA Kang T.S., Vivekanandan S., Jois S.D., Kini R.M.; RT "Effect of C-terminal amidation on folding and disulfide-pairing of alpha- RT conotoxin ImI."; RL Angew. Chem. Int. Ed. 44:6333-6337(2005). RN [6] 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 [7] 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 [8] 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 [9] 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 [10] 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 [11] 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 [12] 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 [13] 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 [14] 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 [15] 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 (PubMed:18189422). Hydroxylation improves its CC folding but impairs its activity against target receptors CC (PubMed:18189422). {ECO:0000269|PubMed:18189422}. CC -!- PTM: C-terminal amidation facilitates folding and correct disulfide CC pairing. {ECO:0000269|PubMed:16161170}. 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: Negative results: does not inhibit alpha-2-beta-2, CC alpha-4-beta-2, alpha-2-beta-4, alpha-3-beta-4, and alpha-4-beta-4 CC subunits (PubMed:7651351, PubMed:15609996). Has also no effect on CC muscle nAChRs alpha-1-beta-1-delta-epsilon (PubMed:15609996). CC {ECO:0000269|PubMed:15609996, ECO:0000269|PubMed:7651351}. CC -!- SIMILARITY: Belongs to the conotoxin A superfamily. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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 FT alpha-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 //