CM3A_CONGE
ID CM3A_CONGE Reviewed; 75 AA.
AC P01523; X5IG12;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT 11-DEC-2019, sequence version 3.
DT 25-MAY-2022, entry version 120.
DE RecName: Full=Mu-conotoxin GIIIA {ECO:0000303|PubMed:1654319, ECO:0000303|PubMed:2410412};
DE AltName: Full=G3.9 {ECO:0000303|PubMed:15924437};
DE AltName: Full=Geographutoxin I {ECO:0000303|PubMed:2338142, ECO:0000303|PubMed:6852238};
DE Short=GTx-I {ECO:0000303|PubMed:2338142, ECO:0000303|PubMed:6852238};
DE AltName: Full=Myotoxin I;
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]
RP NUCLEOTIDE SEQUENCE [MRNA], AND IDENTIFICATION BY MASS SPECTROMETRY.
RC TISSUE=Venom, and 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 NUCLEOTIDE SEQUENCE [MRNA] OF 2-75.
RC TISSUE=Venom duct;
RX PubMed=15924437; DOI=10.1021/bi047541b;
RA Corpuz G.P., Jacobsen R.B., Jimenez E.C., Watkins M., Walker C.,
RA Colledge C., Garrett J.E., McDougal O., Li W., Gray W.R., Hillyard D.R.,
RA Rivier J., McIntosh J.M., Cruz L.J., Olivera B.M.;
RT "Definition of the M-conotoxin superfamily: characterization of novel
RT peptides from molluscivorous Conus venoms.";
RL Biochemistry 44:8176-8186(2005).
RN [3]
RP PROTEIN SEQUENCE OF 52-73, FUNCTION, AND BIOASSAY.
RC TISSUE=Venom;
RX PubMed=2410412; DOI=10.1016/s0021-9258(17)39364-x;
RA Cruz L.J., Gray W.R., Olivera B.M., Zeikus R.D., Kerr L., Yoshikami D.,
RA Moczydlowski E.;
RT "Conus geographus toxins that discriminate between neuronal and muscle
RT sodium channels.";
RL J. Biol. Chem. 260:9280-9288(1985).
RN [4]
RP PROTEIN SEQUENCE OF 52-73, AND SUBCELLULAR LOCATION.
RC TISSUE=Venom;
RX PubMed=6852238; DOI=10.1016/0014-5793(82)80620-0;
RA Sato S., Nakamura H., Ohizumi Y., Kobayashi J., Hirata Y.;
RT "The amino acid sequences of homologous hydroxyproline-containing myotoxins
RT from the marine snail Conus geographus venom.";
RL FEBS Lett. 155:277-280(1983).
RN [5]
RP DISULFIDE BONDS.
RX PubMed=2338142; DOI=10.1016/0014-5793(90)80756-9;
RA Hidaka Y., Sato K., Nakamura H., Kobayashi J., Ohizumi Y., Simonishi Y.;
RT "Disulfide pairings in geographutoxin I, a peptide neurotoxin from Conus
RT geographus.";
RL FEBS Lett. 264:29-32(1990).
RN [6]
RP FUNCTION, AND MUTAGENESIS OF ARG-52; ASP-53; ASP-63; ARG-64 AND ARG-70.
RX PubMed=1654319; DOI=10.1016/s0021-9258(19)47329-8;
RA Sato K., Ishida Y., Wakamatsu K., Kato R., Honda H., Ohizumi Y.,
RA Nakamura H., Ohya M., Lancelin J.M., Kohda D.;
RT "Active site of mu-conotoxin GIIIA, a peptide blocker of muscle sodium
RT channels.";
RL J. Biol. Chem. 266:16989-16991(1991).
RN [7]
RP FUNCTION, AND MUTAGENESIS OF ASP-53; LYS-59; ARG-64 AND GLN-69.
RX PubMed=1326324; DOI=10.1021/bi00150a016;
RA Becker S., Prusak-Sochaczewski E., Zamponi G., Beck-Sickinger A.G.,
RA Gordon R.D., French R.J.;
RT "Action of derivatives of mu-conotoxin GIIIA on sodium channels. Single
RT amino acid substitutions in the toxin separately affect association and
RT dissociation rates.";
RL Biochemistry 31:8229-8238(1992).
RN [8]
RP FUNCTION.
RX PubMed=10627583; DOI=10.1523/jneurosci.20-01-00076.2000;
RA Safo P., Rosenbaum T., Shcherbatko A., Choi D.-Y., Han E.,
RA Toledo-Aral J.J., Olivera B.M., Brehm P., Mandel G.;
RT "Distinction among neuronal subtypes of voltage-activated sodium channels
RT by mu-conotoxin PIIIA.";
RL J. Neurosci. 20:76-80(2000).
RN [9]
RP SYNTHESIS OF 52-73, 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 [10]
RP FUNCTION.
RX PubMed=18950653; DOI=10.1016/j.toxicon.2008.10.017;
RA Holford M., Zhang M.-M., Gowd K.H., Azam L., Green B.R., Watkins M.,
RA Ownby J.-P., Yoshikami D., Bulaj G., Olivera B.M.;
RT "Pruning nature: biodiversity-derived discovery of novel sodium channel
RT blocking conotoxins from Conus bullatus.";
RL Toxicon 53:90-98(2009).
RN [11]
RP FUNCTION, AND SYNTHESIS OF 52-73.
RX PubMed=21652775; DOI=10.1073/pnas.1107027108;
RA Wilson M.J., Yoshikami D., Azam L., Gajewiak J., Olivera B.M., Bulaj G.,
RA Zhang M.M.;
RT "mu-Conotoxins that differentially block sodium channels Nav1.1 through 1.8
RT identify those responsible for action potentials in sciatic nerve.";
RL Proc. Natl. Acad. Sci. U.S.A. 108:10302-10307(2011).
RN [12]
RP FUNCTION.
RX PubMed=30360356; DOI=10.3390/molecules23102715;
RA Harvey P.J., Kurniawan N.D., Finol-Urdaneta R.K., McArthur J.R.,
RA Van Lysebetten D., Dash T.S., Hill J.M., Adams D.J., Durek T., Craik D.J.;
RT "NMR Structure of mu-conotoxin GIIIC: leucine 18 induces local repacking of
RT the N-terminus resulting in reduced Nav channel potency.";
RL Molecules 23:0-0(2018).
RN [13]
RP STRUCTURE BY NMR OF 52-73, HYDROXYLATION AT PRO-57; PRO-58 AND PRO-68,
RP AMIDATION AT ALA-73, AND DISULFIDE BONDS.
RX PubMed=1991506; DOI=10.1016/0014-5793(91)80107-e;
RA Ott K.-H., Becker S., Gordon R.D., Rueterjans H.;
RT "Solution structure of mu-conotoxin GIIIA analysed by 2D-NMR and distance
RT geometry calculations.";
RL FEBS Lett. 278:160-166(1991).
RN [14]
RP STRUCTURE BY NMR OF 52-73, HYDROXYLATION AT PRO-57; PRO-58 AND PRO-68,
RP AMIDATION AT ALA-73, AND DISULFIDE BONDS.
RX PubMed=2069951; DOI=10.1021/bi00242a014;
RA Lancelin J.-M., Kohda D., Tate S., Yanagawa Y., Abe T., Satake M.,
RA Inagaki F.;
RT "Tertiary structure of conotoxin GIIIA in aqueous solution.";
RL Biochemistry 30:6908-6916(1991).
RN [15]
RP STRUCTURE BY NMR OF 52-73 (WILD-TYPE AND MUTANT ARG-64), SYNTHESIS OF
RP 52-73, DISULFIDE BONDS, AND MUTAGENESIS OF ARG-64.
RX PubMed=1335283; DOI=10.1021/bi00165a006;
RA Wakamatsu K., Kohda D., Hatanaka H., Lancelin J.M., Ishida Y., Oya M.,
RA Nakamura H., Inagaki F., Sato K.;
RT "Structure-activity relationships of mu-conotoxin GIIIA: structure
RT determination of active and inactive sodium channel blocker peptides by NMR
RT and simulated annealing calculations.";
RL Biochemistry 31:12577-12584(1992).
CC -!- FUNCTION: Mu-conotoxins block voltage-gated sodium channels (Nav). This
CC toxin potently blocks rat Nav1.4/SCN4A (IC(50)= 19-110 nM)
CC (PubMed:1654319, PubMed:1326324, PubMed:10627583, PubMed:21652775,
CC PubMed:30360356). It also moderately blocks rNav1.1/SCN1A (Kd=260 nM),
CC rNav1.2/SCN2A (IC(50)=2.7-17.8 uM), and mNav1.6/SCN8A (IC(50)=680 nM)
CC (PubMed:10627583, PubMed:21652775). The inhibition is reversible. In
CC vivo, induces paralysis to an isolated skeletal muscle preparation from
CC frog (cutaneous pectoralis) within a few minutes (PubMed:2410412).
CC {ECO:0000269|PubMed:10627583, ECO:0000269|PubMed:18950653,
CC ECO:0000269|PubMed:21652775, ECO:0000269|PubMed:2410412,
CC ECO:0000269|PubMed:30360356}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:6852238}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom duct.
CC {ECO:0000305|PubMed:6852238}.
CC -!- DOMAIN: The cysteine framework is III (CC-C-C-CC). Classified in the M-
CC 4 branch, since 4 residues stand between the fourth and the fifth
CC cysteine residues. {ECO:0000305}.
CC -!- PTM: Hydroxylated; hydroxylations improve the ability to block
CC Nav1.4/SCN4A sodium channels but does not affect folding.
CC {ECO:0000269|PubMed:1991506, ECO:0000269|PubMed:2069951}.
CC -!- MISCELLANEOUS: This toxin does not or only weakly blocks rNav1.3/SCN3A,
CC rNav1.5/SCN5A, rNav1.7/SCN9A (IC(50)=6.0 uM and >100 uM), and
CC rNav1.8/SCN10A (PubMed:10627583, PubMed:21652775).
CC {ECO:0000269|PubMed:10627583, ECO:0000269|PubMed:21652775}.
CC -!- SIMILARITY: Belongs to the conotoxin M superfamily. {ECO:0000305}.
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DR EMBL; AB910835; BAO65603.1; -; mRNA.
DR PIR; A01786; MXKN1.
DR PDB; 1TCG; NMR; -; A=52-73.
DR PDB; 1TCH; NMR; -; A=52-73.
DR PDB; 1TCJ; NMR; -; A=52-73.
DR PDB; 1TCK; NMR; -; A=52-73.
DR PDBsum; 1TCG; -.
DR PDBsum; 1TCH; -.
DR PDBsum; 1TCJ; -.
DR PDBsum; 1TCK; -.
DR AlphaFoldDB; P01523; -.
DR SMR; P01523; -.
DR TCDB; 8.B.28.1.3; the mu-conotoxin (mu-conotoxin) family.
DR PRIDE; P01523; -.
DR ConoServer; 1570; GIIIA [R13A].
DR ConoServer; 1464; GIIIA precursor.
DR EvolutionaryTrace; P01523; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0019871; F:sodium channel inhibitor activity; IEA:InterPro.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
DR InterPro; IPR004214; Conotoxin.
DR InterPro; IPR008036; Conotoxin_mu-typ.
DR Pfam; PF02950; Conotoxin; 1.
DR PROSITE; PS60013; MU_CONOTOXIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Amidation; Cleavage on pair of basic residues;
KW Direct protein sequencing; Disulfide bond; Hydroxylation;
KW Ion channel impairing toxin; Neurotoxin; Secreted; Signal; Toxin;
KW Voltage-gated sodium channel impairing toxin.
FT SIGNAL 1..20
FT /evidence="ECO:0000255"
FT PROPEP 21..51
FT /evidence="ECO:0000269|PubMed:2410412,
FT ECO:0000269|PubMed:6852238"
FT /id="PRO_0000246004"
FT PEPTIDE 52..73
FT /note="Mu-conotoxin GIIIA"
FT /evidence="ECO:0000269|PubMed:2410412,
FT ECO:0000269|PubMed:6852238"
FT /id="PRO_0000044493"
FT SITE 64
FT /note="Important for binding sodium channel"
FT MOD_RES 57
FT /note="4-hydroxyproline; partial"
FT /evidence="ECO:0000269|PubMed:1991506,
FT ECO:0000269|PubMed:2069951, ECO:0000269|PubMed:2410412"
FT MOD_RES 58
FT /note="4-hydroxyproline; partial"
FT /evidence="ECO:0000269|PubMed:1991506,
FT ECO:0000269|PubMed:2069951, ECO:0000269|PubMed:2410412"
FT MOD_RES 68
FT /note="4-hydroxyproline"
FT /evidence="ECO:0000269|PubMed:1991506,
FT ECO:0000269|PubMed:2069951, ECO:0000269|PubMed:2410412"
FT MOD_RES 73
FT /note="Alanine amide"
FT /evidence="ECO:0000269|PubMed:1991506,
FT ECO:0000269|PubMed:2069951, ECO:0000269|PubMed:2410412"
FT DISULFID 54..66
FT /evidence="ECO:0000269|PubMed:1335283,
FT ECO:0000269|PubMed:1991506, ECO:0000269|PubMed:2069951,
FT ECO:0000269|PubMed:2338142, ECO:0000312|PDB:1TCG,
FT ECO:0000312|PDB:1TCH, ECO:0000312|PDB:1TCJ,
FT ECO:0000312|PDB:1TCK"
FT DISULFID 55..71
FT /evidence="ECO:0000269|PubMed:1335283,
FT ECO:0000269|PubMed:1991506, ECO:0000269|PubMed:2069951,
FT ECO:0000269|PubMed:2338142, ECO:0000312|PDB:1TCG,
FT ECO:0000312|PDB:1TCH, ECO:0000312|PDB:1TCJ,
FT ECO:0000312|PDB:1TCK"
FT DISULFID 61..72
FT /evidence="ECO:0000269|PubMed:1335283,
FT ECO:0000269|PubMed:1991506, ECO:0000269|PubMed:2069951,
FT ECO:0000269|PubMed:2338142, ECO:0000312|PDB:1TCG,
FT ECO:0000312|PDB:1TCH, ECO:0000312|PDB:1TCJ,
FT ECO:0000312|PDB:1TCK"
FT MUTAGEN 52
FT /note="R->A: 5-fold decrease in activity on Nav channels
FT (probably Nav1.4/SCN4A) from rat diaphragm."
FT /evidence="ECO:0000269|PubMed:1654319"
FT MUTAGEN 53
FT /note="D->A: 2-fold decrease in activity on Nav channels
FT (probably Nav1.4/SCN4A) from rat diaphragm."
FT /evidence="ECO:0000269|PubMed:1654319"
FT MUTAGEN 53
FT /note="D->N: Increase in activity on Nav channel from eel
FT electric membranes, and decrease in binding to rat
FT Nav1.4/SCN4A by increasing the rate of dissociation from
FT rat Nav1.4/SCN4A channel and decreasing the rate of
FT association."
FT /evidence="ECO:0000269|PubMed:1326324"
FT MUTAGEN 59
FT /note="K->Q: Important decrease in activity on Nav channel
FT from eel electric membranes, and decrease in binding to rat
FT Nav1.4/SCN4A by increasing the rate of dissociation from
FT rat Nav1.4/SCN4A channel and potently decreasing the rate
FT of association."
FT /evidence="ECO:0000269|PubMed:1326324"
FT MUTAGEN 63
FT /note="D->A: 3.5-fold decrease in activity on Nav channels
FT (probably Nav1.4/SCN4A) from rat diaphragm."
FT /evidence="ECO:0000269|PubMed:1654319"
FT MUTAGEN 64
FT /note="R->A: 200-fold decrease in activity on Nav channels
FT (probably Nav1.4/SCN4A) from rat diaphragm."
FT /evidence="ECO:0000269|PubMed:1654319"
FT MUTAGEN 64
FT /note="R->Q: Loss of activity on Nav channel from eel
FT electric membranes, and important decrease in binding to
FT rat Nav1.4/SCN4A by increasing the rate of dissociation
FT from rat Nav1.4/SCN4A channel without modifying the rate of
FT association."
FT /evidence="ECO:0000269|PubMed:1326324"
FT MUTAGEN 69
FT /note="Q->K: Increase in activity on Nav channel from eel
FT electric membranes, and important increase in binding to
FT rat Nav1.4/SCN4A (seemingly irreversible) by potently
FT decreasing the rates of both dissociation and association
FT to rat Nav1.4/SCN4A channel."
FT /evidence="ECO:0000269|PubMed:1326324"
FT MUTAGEN 70
FT /note="R->A: 25-fold decrease in activity on Nav channels
FT (probably Nav1.4/SCN4A) from rat diaphragm."
FT /evidence="ECO:0000269|PubMed:1654319"
FT STRAND 54..58
FT /evidence="ECO:0007829|PDB:1TCG"
FT HELIX 64..66
FT /evidence="ECO:0007829|PDB:1TCG"
FT TURN 70..72
FT /evidence="ECO:0007829|PDB:1TCG"
SQ SEQUENCE 75 AA; 8586 MW; 94CC673FA5DC1283 CRC64;
MMSKLGVLLT ICLLLFPLTA LPMDGDEPAN RPVERMQDNI SSEQYPLFEK RRDCCTPPKK
CKDRQCKPQR CCAGR
