CM3A_CONST
ID CM3A_CONST Reviewed; 73 AA.
AC Q86DU6;
DT 16-JAN-2004, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2003, sequence version 1.
DT 25-MAY-2022, entry version 64.
DE RecName: Full=Mu-conotoxin SIIIA;
DE Flags: Precursor;
OS Conus striatus (Striated cone).
OC Eukaryota; Metazoa; Spiralia; Lophotrochozoa; Mollusca; Gastropoda;
OC Caenogastropoda; Neogastropoda; Conoidea; Conidae; Conus; Pionoconus.
OX NCBI_TaxID=6493;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], SYNTHESIS OF 52-71, AND FUNCTION.
RC TISSUE=Venom duct;
RX PubMed=16325217; DOI=10.1016/j.toxicon.2005.10.008;
RA Wang C.-Z., Zhang H., Jiang H., Lu W.-Y., Zhao Z.-Q., Chi C.-W.;
RT "A novel conotoxin from Conus striatus, mu-SIIIA, selectively blocking rat
RT tetrodotoxin-resistant sodium channels.";
RL Toxicon 47:122-132(2006).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 52-73, SYNTHESIS OF 52-71, AND FUNCTION.
RC TISSUE=Venom duct;
RX PubMed=15882064; DOI=10.1021/bi0473408;
RA Bulaj G., West P.J., Garrett J.E., Watkins M., Zhang M.-M., Norton R.S.,
RA Smith B.J., Yoshikami D., Olivera B.M.;
RT "Novel conotoxins from Conus striatus and Conus kinoshitai selectively
RT block TTX-resistant sodium channels.";
RL Biochemistry 44:7259-7265(2005).
RN [3]
RP ERRATUM OF PUBMED:15882064.
RX DOI=10.1021/bi068001c;
RA Bulaj G., West P.J., Garrett J.E., Watkins M., Zhang M.-M., Norton R.S.,
RA Smith B.J., Yoshikami D., Olivera B.M.;
RL Biochemistry 45:3116-3116(2006).
RN [4]
RP PROTEIN SEQUENCE OF 52-71, SYNTHESIS OF 52-71, FUNCTION, SUBCELLULAR
RP LOCATION, TISSUE SPECIFICITY, MASS SPECTROMETRY, PYROGLUTAMATE FORMATION AT
RP GLN-52, AMIDATION AT CYS-71, STRUCTURE BY NMR OF 52-71, AND MUTAGENESIS OF
RP GLN-52; LYS-62; TRP-63; ARG-65; ASP-66; HIS-67 AND ARG-69.
RC TISSUE=Venom;
RX PubMed=18522941; DOI=10.1074/jbc.m802852200;
RA Schroeder C.I., Ekberg J., Nielsen K.J., Adams D., Loughnan M.L.,
RA Thomas L., Adams D.J., Alewood P.F., Lewis R.J.;
RT "Neuronally mu-conotoxins from Conus striatus utilize an alpha-helical
RT motif to target mammalian sodium channels.";
RL J. Biol. Chem. 283:21621-21628(2008).
RN [5]
RP FUNCTION ON SODIUM CHANNELS.
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 [6]
RP MUTAGENESIS OF GLN-52; ASP-66 AND CYS-71, AND SYNTHESIS OF 52-71.
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 [7]
RP FUNCTION, AND SYNTHESIS OF 52-71.
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 [8]
RP STRUCTURE BY NMR OF 52-71, SYNTHESIS OF 52-71, DISULFIDE BONDS, AND
RP FUNCTION.
RX PubMed=18798648; DOI=10.1021/bi801010u;
RA Yao S., Zhang M.M., Yoshikami D., Azam L., Olivera B.M., Bulaj G.,
RA Norton R.S.;
RT "Structure, dynamics, and selectivity of the sodium channel blocker mu-
RT conotoxin SIIIA.";
RL Biochemistry 47:10940-10949(2008).
CC -!- FUNCTION: Mu-conotoxins block voltage-gated sodium channels (Nav). This
CC toxin moderately blocks rNav1.1/SCN1A, rNav1.2/SCN2A, rNav1.3/SCN3A,
CC rNav1.4/SCN4A, and mNav1.6/SCN8A. {ECO:0000269|PubMed:15882064,
CC ECO:0000269|PubMed:16325217, ECO:0000269|PubMed:18522941,
CC ECO:0000269|PubMed:18798648, ECO:0000269|PubMed:21652775,
CC ECO:0000269|PubMed:22229737}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:18522941}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom duct.
CC {ECO:0000269|PubMed:18522941}.
CC -!- DOMAIN: The cysteine framework is III (CC-C-C-CC). Classified in the M-
CC 5 branch, since 5 residues stand between the fourth and the fifth
CC cysteine residues.
CC -!- MASS SPECTROMETRY: Mass=2206.8; Method=Electrospray;
CC Evidence={ECO:0000269|PubMed:18522941};
CC -!- MISCELLANEOUS: Does not inhibit Nav1.5/SCN5A (PubMed:18522941),
CC Nav1.7/SCN9A (PubMed:18522941) and Nav1.8/SCN10A (PubMed:18522941,
CC PubMed:21652776). {ECO:0000305|PubMed:18522941}.
CC -!- SIMILARITY: Belongs to the conotoxin M superfamily. {ECO:0000305}.
CC -!- CAUTION: All results of mutagenesis experiments are compared with the
CC mutant DEL-52. {ECO:0000305}.
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DR EMBL; AY207469; AAO48588.1; -; mRNA.
DR AlphaFoldDB; Q86DU6; -.
DR BMRB; Q86DU6; -.
DR TCDB; 8.B.28.1.1; the mu-conotoxin (mu-conotoxin) family.
DR ConoServer; 825; SIIIA precursor.
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 Amidation; Cleavage on pair of basic residues; Direct protein sequencing;
KW Disulfide bond; Ion channel impairing toxin; Neurotoxin;
KW Pyrrolidone carboxylic acid; Secreted; Signal; Toxin;
KW Voltage-gated sodium channel impairing toxin.
FT SIGNAL 1..20
FT /evidence="ECO:0000255"
FT PROPEP 21..49
FT /evidence="ECO:0000250"
FT /id="PRO_0000035057"
FT PEPTIDE 52..71
FT /note="Mu-conotoxin SIIIA"
FT /id="PRO_0000035058"
FT REGION 20..40
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 52
FT /note="Pyrrolidone carboxylic acid"
FT /evidence="ECO:0000269|PubMed:18522941"
FT MOD_RES 71
FT /note="Cysteine amide"
FT /evidence="ECO:0000269|PubMed:18522941"
FT DISULFID 54..64
FT /evidence="ECO:0000269|PubMed:18798648"
FT DISULFID 55..70
FT /evidence="ECO:0000269|PubMed:18798648"
FT DISULFID 59..71
FT /evidence="ECO:0000269|PubMed:18798648"
FT MUTAGEN 52
FT /note="Q->R: Increase of affinity for both Nav1.2/SCN2A and
FT Nav1.4/SCN4A."
FT /evidence="ECO:0000269|PubMed:18522941,
FT ECO:0000269|PubMed:22733528"
FT MUTAGEN 52
FT /note="Missing: Increase of affinity at Nav1.2/SCN2A and
FT decrease of affinity at Nav1.4/SCN4A."
FT /evidence="ECO:0000269|PubMed:18522941,
FT ECO:0000269|PubMed:22733528"
FT MUTAGEN 62
FT /note="K->A: 6-fold decrease of affinity to both
FT Nav1.2/SCN2A and Nav1.4/SCN4A; when associated with DEL-
FT 52."
FT /evidence="ECO:0000269|PubMed:18522941"
FT MUTAGEN 62
FT /note="K->R: 10-fold increase of affinity at Nav1.2/SCN2A
FT without affecting Nav1.4/SCN4A affinity; when associated
FT with DEL-52 and A-66."
FT /evidence="ECO:0000269|PubMed:18522941"
FT MUTAGEN 63
FT /note="W->A: 22- and 87-fold decrease of affinity to
FT Nav1.2/SCN2A and Nav1.4/SCN4A, respectively; when
FT associated with DEL-52."
FT /evidence="ECO:0000269|PubMed:18522941"
FT MUTAGEN 65
FT /note="R->A: Decrease of affinity to both Nav1.2/SCN2A and
FT Nav1.4/SCN4A; when associated with DEL-52."
FT /evidence="ECO:0000269|PubMed:18522941"
FT MUTAGEN 66
FT /note="D->A: 10-fold increase of affinity at Nav1.2/SCN2A
FT without affecting Nav1.4/SCN4A affinity; when associated
FT with DEL-52. 30-fold decrease of affinity to Nav1.4/SCN4A
FT without affecting Nav1.2/SCN2A affinity; when associated
FT with DEL-52 and R-67. 100,000- and 400-fold decrease in
FT affinity to Nav1.2/SCN2A and Nav1.4/SCN4A, respectively;
FT when associated with DEL-52 and D-67. Different changes
FT when associated with C-terminal extension, see mutated Cys-
FT 71."
FT /evidence="ECO:0000269|PubMed:18522941,
FT ECO:0000269|PubMed:22733528"
FT MUTAGEN 66
FT /note="D->K: Decrease of affinity to both Nav1.2/SCN2A and
FT Nav1.4/SCN4A; when associated with DEL-52."
FT /evidence="ECO:0000269|PubMed:18522941,
FT ECO:0000269|PubMed:22733528"
FT MUTAGEN 67
FT /note="H->A: Most important decrease of affinity to both
FT Nav1.2/SCN2A and Nav1.4/SCN4A; when associated with DEL-
FT 52."
FT /evidence="ECO:0000269|PubMed:18522941"
FT MUTAGEN 67
FT /note="H->D: 100,000- and 400-fold decrease in affinity to
FT Nav1.2/SCN2A and Nav1.4/SCN4A, respectively; when
FT associated with DEL-52 and A-66."
FT /evidence="ECO:0000269|PubMed:18522941"
FT MUTAGEN 67
FT /note="H->R: 30-fold decrease of affinity at Nav1.4/SCN4A
FT without affecting Nav1.2/SCN2A affinity; when associated
FT with DEL-52 and A-66."
FT /evidence="ECO:0000269|PubMed:18522941"
FT MUTAGEN 69
FT /note="R->A: 30- and 500-fold decrease of affinity to
FT Nav1.2/SCN2A and Nav1.4/SCN4A, respectively; when
FT associated with DEL-52."
FT /evidence="ECO:0000269|PubMed:18522941"
FT MUTAGEN 71
FT /note="C->CA: Increase in affinity for Nav1.2/SCN2A, no
FT change in affinity for Nav1.4/SCN4A; when associated with
FT DEL-52 and A-66."
FT /evidence="ECO:0000269|PubMed:22733528"
FT MUTAGEN 71
FT /note="C->CAA: Increase in affinity for Nav1.2/SCN2A,
FT little decrease in affinity for Nav1.4/SCN4A; when
FT associated with DEL-52 and A-66."
FT /evidence="ECO:0000269|PubMed:22733528"
FT MUTAGEN 71
FT /note="C->CAD: Important decrease in affinity for both
FT Nav1.2/SCN2A and Nav1.4/SCN4A; when associated with DEL-52
FT and A-66."
FT /evidence="ECO:0000269|PubMed:22733528"
FT MUTAGEN 71
FT /note="C->CAK: Little decrease in affinity for
FT Nav1.4/SCN4A, no change in affinity for Nav1.2/SCN2A; when
FT associated with DEL-52 and A-66."
FT /evidence="ECO:0000269|PubMed:22733528"
FT MUTAGEN 71
FT /note="C->CD: The second most selective for Nav1.2/SCN2A
FT over Nav1.4/SCVN4A; when associated with DEL-52 and A-66."
FT /evidence="ECO:0000269|PubMed:22733528"
FT MUTAGEN 71
FT /note="C->CK: The most selective for Nav1.2/SCN2A over
FT Nav1.4/SCVN4A; when associated with DEL-52 and A-66."
FT /evidence="ECO:0000269|PubMed:22733528"
SQ SEQUENCE 73 AA; 8105 MW; 5AE22E12A64B9B57 CRC64;
MMSKLGVLLT VCPLLFPLTA LPPDGDQPAD RPAERMQDDI SSDEHPLFDK RQNCCNGGCS
SKWCRDHARC CGR
