CM3A_CONTU
ID CM3A_CONTU Reviewed; 22 AA.
AC P0C350;
DT 29-MAY-2007, integrated into UniProtKB/Swiss-Prot.
DT 29-MAY-2007, sequence version 1.
DT 25-MAY-2022, entry version 39.
DE RecName: Full=Mu-conotoxin TIIIA {ECO:0000303|PubMed:17142296, ECO:0000303|PubMed:21652775};
OS Conus tulipa (Fish-hunting cone snail) (Tulip cone).
OC Eukaryota; Metazoa; Spiralia; Lophotrochozoa; Mollusca; Gastropoda;
OC Caenogastropoda; Neogastropoda; Conoidea; Conidae; Conus; Gastridium.
OX NCBI_TaxID=6495;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], SYNTHESIS, AMIDATION AT CYS-22, HYDROXYLATION
RP AT PRO-8 AND PRO-18, AND MUTAGENESIS OF HIS-2; LYS-6; LYS-9; ARG-14;
RP GLU-15; ARG-17; GLN-19 AND HIS-20.
RC TISSUE=Venom duct;
RX PubMed=17142296; DOI=10.1124/mol.106.028225;
RA Lewis R.J., Schroeder C.I., Ekberg J., Nielsen K.J., Loughnan M.,
RA Thomas L., Adams D.A., Drinkwater R., Adams D.J., Alewood P.F.;
RT "Isolation and structure-activity of mu-conotoxin TIIIA, a potent inhibitor
RT of tetrodotoxin-sensitive voltage-gated sodium channels.";
RL Mol. Pharmacol. 71:676-685(2007).
RN [2]
RP FUNCTION ON SODIUM CHANNELS, SYNTHESIS, HYDROXYLATION AT PRO-8 AND PRO-18,
RP AND AMIDATION AT CYS-22.
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 [3]
RP FUNCTION, AND SYNTHESIS.
RX PubMed=22229737; DOI=10.1111/j.1476-5381.2012.01837.x;
RA Favreau P., Benoit E., Hocking H.G., Carlier L., D'Hoedt D., Leipold E.,
RA Markgraf R., Schlumberger S., Cordova M.A., Gaertner H.,
RA Paolini-Bertrand M., Hartley O., Tytgat J., Heinemann S.H., Bertrand D.,
RA Boelens R., Stocklin R., Molgo J.;
RT "A novel u-conopeptide, CnIIIC, exerts potent and preferential inhibition
RT of NaV1.2/1.4 channels and blocks neuronal nicotinic acetylcholine
RT receptors.";
RL Br. J. Pharmacol. 166:1654-1668(2012).
RN [4]
RP MUTAGENESIS OF GLU-15 AND CYS-22, AND SYNTHESIS.
RX PubMed=22733528; DOI=10.1002/bip.22032;
RA Schroeder C.I., Adams D., Thomas L., Alewood P.F., Lewis R.J.;
RT "N- and C-terminal extensions of mu-conotoxins increase potency and
RT selectivity for neuronal sodium channels.";
RL Biopolymers 98:161-165(2012).
RN [5]
RP FUNCTION ON SODIUM CHANNELS.
RX PubMed=23146020; DOI=10.1111/bph.12051;
RA Zhang M.M., Wilson M.J., Azam L., Gajewiak J., Rivier J.E., Bulaj G.,
RA Olivera B.M., Yoshikami D.;
RT "Co-expression of Na(V)beta subunits alters the kinetics of inhibition of
RT voltage-gated sodium channels by pore-blocking mu-conotoxins.";
RL Br. J. Pharmacol. 168:1597-1610(2013).
CC -!- FUNCTION: Mu-conotoxins block voltage-gated sodium channels (Nav). This
CC synthetic toxin reversibly and potently blocks rNav1.4/SCN4A (IC(50) is
CC 9 nM) and rNav1.2/SCN2A (IC(50) is 40 nM). It also moderately blocks
CC rNav1.1/SCN1A, rNav1.3/SCN3A, and rNav1.6/SCN8A. The block of SCN1A and
CC SCN2A is modified when beta-subunits are coexpressed with alpha
CC subunits. Hence, blocks of channels containing beta-1 and beta-3
CC subunits are more potent (compared to channels without beta subunits),
CC whereas blocks of channels containing beta-2 and beta-4 subunits are
CC less potent (compared to channels without beta subunits).
CC {ECO:0000269|PubMed:21652775, ECO:0000269|PubMed:22229737,
CC ECO:0000269|PubMed:23146020}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom duct.
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.
CC -!- MISCELLANEOUS: Does not block Nav1.5/SCN5A, Nav1.7/SCN9A, and
CC Nav1.8/SCN10A. {ECO:0000305|PubMed:21652775}.
CC -!- MISCELLANEOUS: No cis-trans isomerization is found. {ECO:0000250}.
CC -!- SIMILARITY: Belongs to the conotoxin M superfamily. {ECO:0000305}.
CC -!- CAUTION: Native TIIIA is not detected in crude venom. {ECO:0000305}.
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DR AlphaFoldDB; P0C350; -.
DR ConoServer; 1616; TIIIA.
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; IPR008036; Conotoxin_mu-typ.
DR Pfam; PF05374; Mu-conotoxin; 1.
PE 1: Evidence at protein level;
KW Amidation; Disulfide bond; Hydroxylation; Ion channel impairing toxin;
KW Neurotoxin; Secreted; Toxin; Voltage-gated sodium channel impairing toxin.
FT PEPTIDE 1..22
FT /note="Mu-conotoxin TIIIA"
FT /evidence="ECO:0000305|PubMed:17142296,
FT ECO:0000305|PubMed:21652775"
FT /id="PRO_0000288945"
FT SITE 14
FT /note="Important for activity"
FT MOD_RES 8
FT /note="4-hydroxyproline"
FT /evidence="ECO:0000305|PubMed:17142296,
FT ECO:0000305|PubMed:21652775"
FT MOD_RES 18
FT /note="4-hydroxyproline"
FT /evidence="ECO:0000305|PubMed:17142296,
FT ECO:0000305|PubMed:21652775"
FT MOD_RES 22
FT /note="Cysteine amide"
FT /evidence="ECO:0000305|PubMed:17142296,
FT ECO:0000305|PubMed:21652775"
FT DISULFID 4..16
FT /evidence="ECO:0000250|UniProtKB:P01523"
FT DISULFID 5..21
FT /evidence="ECO:0000250|UniProtKB:P01523"
FT DISULFID 11..22
FT /evidence="ECO:0000250|UniProtKB:P01523"
FT MUTAGEN 2
FT /note="H->A: Slight increase in toxicity at rNav1.4/SCN4A."
FT /evidence="ECO:0000269|PubMed:17142296"
FT MUTAGEN 6
FT /note="K->A,Q: Little decrease in toxicity at both
FT rNav1.4/SCN4A and rNav1.2/SCN2A."
FT /evidence="ECO:0000269|PubMed:17142296"
FT MUTAGEN 9
FT /note="K->A,Q: Little decrease in toxicity at both
FT rNav1.4/SCN4A and rNav1.2/SCN2A."
FT /evidence="ECO:0000269|PubMed:17142296"
FT MUTAGEN 14
FT /note="R->A,Y,Q: Important decrease of toxicity to both
FT rNav1.4/SCN4A and rNav1.2/SCN2A."
FT /evidence="ECO:0000269|PubMed:17142296"
FT MUTAGEN 15
FT /note="E->A: 10-fold increase in affinity for both
FT rNav1.2/SCN2A and rNav1.4/SCN4A. Different changes when
FT associated with C-terminal extension, see mutated Cys-22."
FT /evidence="ECO:0000269|PubMed:17142296,
FT ECO:0000269|PubMed:22733528"
FT MUTAGEN 17
FT /note="R->A,Q: Little decrease in toxicity at both
FT rNav1.4/SCN4A and rNav1.2/SCN2A."
FT /evidence="ECO:0000269|PubMed:17142296"
FT MUTAGEN 19
FT /note="Q->A: Slight increase in toxicity at rNav1.4/SCN4A."
FT /evidence="ECO:0000269|PubMed:17142296"
FT MUTAGEN 20
FT /note="H->A: Little decrease in toxicity to both
FT rNav1.4/SCN4A and rNav1.2/SCN2A."
FT /evidence="ECO:0000269|PubMed:17142296"
FT MUTAGEN 22
FT /note="C->CA: Slight increase in affinity to Nav1.2/SCN2A,
FT but not change to Nav1.4/SCN4A; when associated with A-15
FT ([E15A,23A]TIIIA)."
FT /evidence="ECO:0000269|PubMed:22733528"
FT MUTAGEN 22
FT /note="C->CAA: Slight increase in affinity to Nav1.2/SCN2A,
FT but not change to Nav1.4/SCN4A; when associated with A-15
FT ([E15A,23A,24A]TIIIA)."
FT /evidence="ECO:0000269|PubMed:22733528"
FT MUTAGEN 22
FT /note="C->CAD: Decrease in affinity to both Nav1.2/SCN2A
FT and Nav1.4/SCN4A; when associated with A-15
FT ([E15A,23A,24D]TIIIA)."
FT /evidence="ECO:0000269|PubMed:22733528"
FT MUTAGEN 22
FT /note="C->CAK: Important decrease in affinity to
FT Nav1.2/SCN2A, but not change to Nav1.4/SCN4A; when
FT associated with A-15 ([E15A,23A,24K]TIIIA)."
FT /evidence="ECO:0000269|PubMed:22733528"
FT MUTAGEN 22
FT /note="C->CD: Decrease in affinity to both Nav1.2/SCN2A and
FT Nav1.4/SCN4A; when associated with A-15 ([E15A,23D]TIIIA)."
FT /evidence="ECO:0000269|PubMed:22733528"
FT MUTAGEN 22
FT /note="C->CK: Decrease in affinity to Nav1.4/SCN4A, but no
FT change to Nav1.2/SCN2A; when associated with A-15
FT ([E15A,23K]TIIIA)."
FT /evidence="ECO:0000269|PubMed:22733528"
SQ SEQUENCE 22 AA; 2433 MW; DE2CFD292B88B11C CRC64;
RHGCCKGPKG CSSRECRPQH CC
