ID CA12_CONMA Reviewed; 68 AA. AC P56636; DT 15-DEC-1998, integrated into UniProtKB/Swiss-Prot. DT 05-SEP-2006, sequence version 3. DT 02-JUN-2021, entry version 104. DE RecName: Full=Alpha-conotoxin MII {ECO:0000303|PubMed:8631783}; DE Short=Alpha-Ctx MII {ECO:0000303|PubMed:9398298}; DE Short=Alpha-MII {ECO:0000303|PubMed:14701840}; DE Flags: Precursor; OS Conus magus (Magical cone). OC Eukaryota; Metazoa; Spiralia; Lophotrochozoa; Mollusca; Gastropoda; OC Caenogastropoda; Neogastropoda; Conoidea; Conidae; Conus; Pionoconus. OX NCBI_TaxID=6492; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Venom duct; RX PubMed=14701840; DOI=10.1074/jbc.m309654200; RA Santos A.D., McIntosh J.M., Hillyard D.R., Cruz L.J., Olivera B.M.; RT "The A-superfamily of conotoxins: structural and functional divergence."; RL J. Biol. Chem. 279:17596-17606(2004). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 28-68. RC TISSUE=Hepatopancreas; RX PubMed=12114524; DOI=10.1074/jbc.m205102200; RA McIntosh J.M., Dowell C., Watkins M., Garrett J.E., Yoshikami D., RA Olivera B.M.; RT "Alpha-conotoxin GIC from Conus geographus, a novel peptide antagonist of RT nicotinic acetylcholine receptors."; RL J. Biol. Chem. 277:33610-33615(2002). RN [3] RP PROTEIN SEQUENCE OF 49-64, FUNCTION, SYNTHESIS OF 49-64, AMIDATION AT RP CYS-64, DISULFIDE BONDS, MASS SPECTROMETRY, AND SUBCELLULAR LOCATION. RC TISSUE=Venom; RX PubMed=8631783; DOI=10.1074/jbc.271.13.7522; RA Cartier G.E., Yoshikami D., Gray W.R., Luo S., Olivera B.M., McIntosh J.M.; RT "A new alpha-conotoxin which targets alpha3beta2 nicotinic acetylcholine RT receptors."; RL J. Biol. Chem. 271:7522-7528(1996). RN [4] RP FUNCTION ON ALPHA-6 ACHR. RX PubMed=11044728; DOI=10.1016/s0028-3908(00)00144-1; RA Kuryatov A., Olale F., Cooper J., Choi C., Lindstrom J.; RT "Human alpha6 AChR subtypes: subunit composition, assembly, and RT pharmacological responses."; RL Neuropharmacology 39:2570-2590(2000). RN [5] RP FUNCTION, AND MUTAGENESIS OF HIS-57 AND LEU-63. RX PubMed=15044624; DOI=10.1124/mol.65.4.944; RA McIntosh J.M., Azam L., Staheli S., Dowell C., Lindstrom J.M., Kuryatov A., RA Garrett J.E., Marks M.J., Whiteaker P.; RT "Analogs of alpha-conotoxin MII are selective for alpha6-containing RT nicotinic acetylcholine receptors."; RL Mol. Pharmacol. 65:944-952(2004). RN [6] RP FUNCTION ON ALPHA-3-3 AND ALPHA-4-BETA-2 NACHR. RX PubMed=15929983; DOI=10.1074/jbc.m504229200; RA Dutertre S., Nicke A., Lewis R.J.; RT "Beta2 subunit contribution to 4/7 alpha-conotoxin binding to the nicotinic RT acetylcholine receptor."; RL J. Biol. Chem. 280:30460-30468(2005). RN [7] RP FUNCTION ON ALPHA-3-BETA-2 NACHR. RX PubMed=16964981; DOI=10.1021/bi0611715; RA Shiembob D.L., Roberts R.L., Luetje C.W., McIntosh J.M.; RT "Determinants of alpha-conotoxin BuIA selectivity on the nicotinic RT acetylcholine receptor beta subunit."; RL Biochemistry 45:11200-11207(2006). RN [8] RP MUTAGENESIS OF GLY-49; SER-52; ASN-53; PRO-54; VAL-55; HIS-57; LEU-58; RP GLU-59; HIS-60; SER-61; ASN-62 AND LEU-63, AND SYNTHESIS OF 49-64. RX PubMed=15005608; DOI=10.1021/bi036180h; RA Everhart D., Cartier G.E., Malhotra A., Gomes A.V., McIntosh J.M., RA Luetje C.W.; RT "Determinants of potency on alpha-conotoxin MII, a peptide antagonist of RT neuronal nicotinic receptors."; RL Biochemistry 43:2732-2737(2004). 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 FUNCTION. RX PubMed=32272633; DOI=10.3390/md18040193; RA Osipov A.V., Terpinskaya T.I., Yanchanka T., Balashevich T., Zhmak M.N., RA Tsetlin V.I., Utkin Y.N.; RT "Alpha-conotoxins enhance both the in vivo suppression of Ehrlich carcinoma RT growth and in vitro reduction in cell viability elicited by cyclooxygenase RT and lipoxygenase inhibitors."; RL Mar. Drugs 18:1-11(2020). RN [11] RP STRUCTURE BY NMR OF 49-64, DISULFIDE BONDS, AND SYNTHESIS OF 49-64. RX PubMed=9398298; DOI=10.1021/bi971443r; RA Shon K.-J., Koerber S.C., Rivier J.E., Olivera B.M., McIntosh J.M.; RT "Three-dimensional solution structure of alpha-conotoxin MII, an RT alpha3beta2 neuronal nicotinic acetylcholine receptor-targeted ligand."; RL Biochemistry 36:15693-15700(1997). RN [12] RP STRUCTURE BY NMR OF 49-64, AMIDATION AT CYS-64, DISULFIDE BONDS, AND RP SYNTHESIS OF 49-64. RX PubMed=9843366; DOI=10.1021/bi981535w; RA Hill J.M., Oomen C.J., Miranda L.P., Bingham J.-P., Alewood P.F., RA Craik D.J.; RT "Three-dimensional solution structure of alpha-conotoxin MII by NMR RT spectroscopy: effects of solution environment on helicity."; RL Biochemistry 37:15621-15630(1998). RN [13] RP STRUCTURE BY NMR OF 49-64, CYCLIZATION, DISULFIDE BONDS, AND SYNTHESIS OF RP 49-64. RX PubMed=16162671; DOI=10.1073/pnas.0504613102; RA Clark R.J., Fischer H., Dempster L., Daly N.L., Rosengren K.J., Nevin S.T., RA Meunier F.A., Adams D.J., Craik D.J.; RT "Engineering stable peptide toxins by means of backbone cyclization: RT stabilization of the alpha-conotoxin MII."; RL Proc. Natl. Acad. Sci. U.S.A. 102:13767-13772(2005). CC -!- FUNCTION: Alpha-conotoxins bind to the nicotinic acetylcholine CC receptors (nAChR) and inhibit them. This toxin blocks neuronal CC mammalian nAChRs (alpha-6/alpha-3-beta-2-beta-3 (0.39 nM) > alpha-3- CC beta-2 > alpha-3-beta-4 = alpha-4-beta-2). Also exhibits inhibition of CC D.melanogaster alpha-7 nAChRs (PubMed:25466886). In vivo, inhibits CC Ehrlich carcinoma growth and increase mouse survival (PubMed:32272633). CC These effects are greatly enhanced when the toxin is applied with the CC non-selective cyclooxygenase inhibitor indomethacin (PubMed:32272633). CC {ECO:0000269|PubMed:11044728, ECO:0000269|PubMed:15044624, CC ECO:0000269|PubMed:15929983, ECO:0000269|PubMed:16964981, CC ECO:0000269|PubMed:25466886, ECO:0000269|PubMed:32272633, CC ECO:0000269|PubMed:8631783}. CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:8631783}. CC -!- TISSUE SPECIFICITY: Expressed by the venom duct. CC {ECO:0000305|PubMed:8631783}. CC -!- DOMAIN: The cysteine framework is I (CC-C-C). Alpha4/7 pattern. CC {ECO:0000305}. CC -!- MASS SPECTROMETRY: Mass=1710.6; Method=LSI; CC Evidence={ECO:0000269|PubMed:8631783}; CC -!- MISCELLANEOUS: There are currently a number of patents describing the CC use of this peptide in therapeutic applications. 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 PIR; A59046; A59046. DR PDB; 1M2C; NMR; -; A=49-64. DR PDB; 1MII; NMR; -; A=49-64. DR PDB; 2AJW; NMR; -; A=49-64. DR PDB; 2AK0; NMR; -; A=49-64. DR PDBsum; 1M2C; -. DR PDBsum; 1MII; -. DR PDBsum; 2AJW; -. DR PDBsum; 2AK0; -. DR SMR; P56636; -. DR TCDB; 8.B.32.1.1; the nicotinic acetylcholine receptor-targeting alpha-conotoxin (a-conotoxin) family. DR ConoServer; 8; MII precursor. DR EvolutionaryTrace; P56636; -. 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:InterPro. DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW. DR GO; GO:0009405; P:pathogenesis; IEA:InterPro. 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 Direct protein sequencing; Disulfide bond; Ion channel impairing toxin; KW Neurotoxin; Postsynaptic neurotoxin; Secreted; Signal; Toxin. FT SIGNAL 1..21 FT /evidence="ECO:0000255" FT PROPEP 22..48 FT /evidence="ECO:0000269|PubMed:8631783" FT /id="PRO_0000034881" FT PEPTIDE 49..64 FT /note="Alpha-conotoxin MII" FT /evidence="ECO:0000269|PubMed:8631783" FT /id="PRO_0000034882" FT MOD_RES 64 FT /note="Cysteine amide" FT /evidence="ECO:0000269|PubMed:8631783, FT ECO:0000269|PubMed:9843366" FT DISULFID 50..56 FT /evidence="ECO:0000269|PubMed:16162671, FT ECO:0000269|PubMed:9398298, ECO:0000269|PubMed:9843366, FT ECO:0000312|PDB:1M2C, ECO:0000312|PDB:1MII, FT ECO:0000312|PDB:2AJW, ECO:0000312|PDB:2AK0" FT DISULFID 51..64 FT /evidence="ECO:0000269|PubMed:16162671, FT ECO:0000269|PubMed:9398298, ECO:0000269|PubMed:9843366, FT ECO:0000312|PDB:1M2C, ECO:0000312|PDB:1MII, FT ECO:0000312|PDB:2AJW, ECO:0000312|PDB:2AK0" FT MUTAGEN 49 FT /note="G->A: 4.5-fold decrease in inhibition of alpha- FT 3/beta-2 nAChR." FT /evidence="ECO:0000269|PubMed:15005608" FT MUTAGEN 52 FT /note="S->A: 4.9-fold decrease in inhibition of alpha- FT 3/beta-2 nAChR." FT /evidence="ECO:0000269|PubMed:15005608" FT MUTAGEN 53 FT /note="N->A: >2700-fold decrease in inhibition of alpha- FT 3/beta-2 nAChR." FT /evidence="ECO:0000269|PubMed:15005608" FT MUTAGEN 54 FT /note="P->A: 700-fold decrease in inhibition of alpha- FT 3/beta-2 nAChR." FT /evidence="ECO:0000269|PubMed:15005608" FT MUTAGEN 55 FT /note="V->A: 2.5-fold decrease in inhibition of alpha- FT 3/beta-2 nAChR." FT /evidence="ECO:0000269|PubMed:15005608" FT MUTAGEN 57 FT /note="H->A: 2-fold and ~20-fold decrease in ability to FT inhibit alpha-6/alpha-3-beta-2-beta-3 and alpha-3-beta-2, FT respectively. In MII[H9A;L15A]; exhibits preferential loss FT of activity at alpha-3-beta-2 versus alpha-6/alpha-3-beta- FT 2-beta-3 nAChR, making this analog the most selective FT alpha-6 ligand known." FT /evidence="ECO:0000269|PubMed:15005608, FT ECO:0000269|PubMed:15044624" FT MUTAGEN 58 FT /note="L->A: 1.5-fold decrease in inhibition of alpha- FT 3/beta-2 nAChR." FT /evidence="ECO:0000269|PubMed:15005608" FT MUTAGEN 59 FT /note="E->A: 4.6-fold decrease in inhibition of alpha- FT 3/beta-2 nAChR." FT /evidence="ECO:0000269|PubMed:15005608" FT MUTAGEN 60 FT /note="H->A: About 2700-fold decrease in inhibition of FT alpha-3/beta-2 nAChR." FT /evidence="ECO:0000269|PubMed:15005608" FT MUTAGEN 61 FT /note="S->A: 2.3-fold decrease in inhibition of alpha- FT 3/beta-2 nAChR." FT /evidence="ECO:0000269|PubMed:15005608" FT MUTAGEN 62 FT /note="N->A: No change in inhibition of alpha-3/beta-2 FT nAChR." FT /evidence="ECO:0000269|PubMed:15005608" FT MUTAGEN 63 FT /note="L->A: 2.4-fold and 15-fold decrease in ability to FT inhibit alpha-6/alpha-3-beta-2-beta-3 and alpha-3-beta-2, FT respectively. In MII[H9A;L15A]; exhibits preferential loss FT of activity at alpha-3-beta-2 versus alpha-6/alpha-3-beta- FT 2-beta-3 nAChR, making this analog the most selective FT alpha-6 ligand thus far reported." FT /evidence="ECO:0000269|PubMed:15005608, FT ECO:0000269|PubMed:15044624" FT TURN 50..52 FT /evidence="ECO:0007829|PDB:1MII" FT HELIX 54..59 FT /evidence="ECO:0007829|PDB:1M2C" FT HELIX 61..63 FT /evidence="ECO:0007829|PDB:1M2C" SQ SEQUENCE 68 AA; 7357 MW; FBD9AB40E6F277DF CRC64; MGMRMMFTVF LLVVLATTVV SFPSDRASDG RNAAANDKAS DVITLALKGC CSNPVCHLEH SNLCGRRR //