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CA12_CONMA
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   25-MAY-2022, entry version 107.
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   FUNCTION, MUTAGENESIS OF GLY-49; SER-52; ASN-53; PRO-54; VAL-55; HIS-57;
RP   LEU-58; 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=20145249; DOI=10.1074/jbc.m109.079012;
RA   Luo S., Akondi K.B., Zhangsun D., Wu Y., Zhu X., Hu Y., Christensen S.,
RA   Dowell C., Daly N.L., Craik D.J., Wang C.I., Lewis R.J., Alewood P.F.,
RA   Michael McIntosh J.;
RT   "Atypical alpha-conotoxin LtIA from Conus litteratus targets a novel
RT   microsite of the alpha3beta2 nicotinic receptor.";
RL   J. Biol. Chem. 285:12355-12366(2010).
RN   [10]
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   [11]
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   [12]
RP   FUNCTION.
RX   PubMed=33523678; DOI=10.1021/acs.jmedchem.0c01973;
RA   Hone A.J., Kaas Q., Kearns I., Hararah F., Gajewiak J., Christensen S.,
RA   Craik D.J., McIntosh J.M.;
RT   "Computational and functional mapping of human and rat alpha6beta4
RT   nicotinic acetylcholine receptors reveals species-specific ligand-binding
RT   motifs.";
RL   J. Med. Chem. 64:1685-1700(2021).
RN   [13]
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   [14]
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   [15]
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/CHRNA3-CHRNB2 > alpha-3-beta-4/CHRNA3-CHRNB4 = alpha-4-beta-
CC       2/CHRNA4-CHRNB2) (PubMed:15005608, PubMed:20145249). Also exhibits
CC       inhibition of D.melanogaster alpha-7/CHRNA7 nAChRs (PubMed:25466886).
CC       In addition, inhibits alpha-6/alpha-3-beta-4 (CHRNA6/CHRNA3-CHRNB4)
CC       nAChR with a higher potency on human (IC(50)=1.49 nM) than on rat
CC       receptors (IC(50)=31.5 nM) (PubMed:33523678). Its binding to alpha-3-
CC       beta-2/CHRNA3-CHRNB2 nAChR is prevented by alpha-conotoxin Lt1a,
CC       suggesting that the two toxins have overlapping binding sites
CC       (PubMed:20145249). In addition, both toxins have distinct nAChR binding
CC       mode (PubMed:20145249). In vivo, inhibits Ehrlich carcinoma growth and
CC       increase mouse survival (PubMed:32272633). These effects are greatly
CC       enhanced when the toxin is applied with the non-selective
CC       cyclooxygenase inhibitor indomethacin (PubMed:32272633).
CC       {ECO:0000269|PubMed:11044728, ECO:0000269|PubMed:15005608,
CC       ECO:0000269|PubMed:15044624, ECO:0000269|PubMed:15929983,
CC       ECO:0000269|PubMed:16964981, ECO:0000269|PubMed:20145249,
CC       ECO:0000269|PubMed:25466886, ECO:0000269|PubMed:32272633,
CC       ECO:0000269|PubMed:33523678, 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}.
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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   AlphaFoldDB; P56636; -.
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: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   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   REGION          52..54
FT                   /note="Ser-Xaa-Pro motif, crucial for potent interaction
FT                   with nAChR"
FT                   /evidence="ECO:0000305|PubMed:20145249"
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 ability to inhibit alpha-
FT                   3-beta-2 nAChR."
FT                   /evidence="ECO:0000269|PubMed:15005608"
FT   MUTAGEN         52
FT                   /note="S->A: 4.9-fold decrease in ability to inhibit alpha-
FT                   3-beta-2 nAChR."
FT                   /evidence="ECO:0000269|PubMed:15005608"
FT   MUTAGEN         53
FT                   /note="N->A: >2700-fold decrease in ability to inhibit
FT                   alpha-3-beta-2 nAChR."
FT                   /evidence="ECO:0000269|PubMed:15005608"
FT   MUTAGEN         54
FT                   /note="P->A: 700-fold decrease in ability to inhibit alpha-
FT                   3-beta-2 nAChR."
FT                   /evidence="ECO:0000269|PubMed:15005608"
FT   MUTAGEN         55
FT                   /note="V->A: 2.5-fold decrease in ability to inhibit 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 ability to inhibit alpha-
FT                   3-beta-2 nAChR."
FT                   /evidence="ECO:0000269|PubMed:15005608"
FT   MUTAGEN         59
FT                   /note="E->A: 4.6-fold decrease in ability to inhibit alpha-
FT                   3-beta-2 nAChR."
FT                   /evidence="ECO:0000269|PubMed:15005608"
FT   MUTAGEN         60
FT                   /note="H->A: About 2700-fold decrease in ability to inhibit
FT                   alpha-3-beta-2 nAChR."
FT                   /evidence="ECO:0000269|PubMed:15005608"
FT   MUTAGEN         61
FT                   /note="S->A: 2.3-fold decrease in ability to inhibit alpha-
FT                   3-beta-2 nAChR."
FT                   /evidence="ECO:0000269|PubMed:15005608"
FT   MUTAGEN         62
FT                   /note="N->A: No change in ability to inhibit 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
 
 
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