CM3A_CONPU
ID CM3A_CONPU Reviewed; 73 AA.
AC P58925;
DT 26-JUL-2002, integrated into UniProtKB/Swiss-Prot.
DT 11-JUL-2006, sequence version 2.
DT 25-MAY-2022, entry version 97.
DE RecName: Full=Mu-conotoxin PIIIA {ECO:0000303|PubMed:9614224};
DE AltName: Full=Mu-conotoxin P3.7;
DE Flags: Precursor;
OS Conus purpurascens (Purple cone).
OC Eukaryota; Metazoa; Spiralia; Lophotrochozoa; Mollusca; Gastropoda;
OC Caenogastropoda; Neogastropoda; Conoidea; Conidae; Conus; Chelyconus.
OX NCBI_TaxID=41690;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
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 [2]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 47-73, SYNTHESIS OF 50-71, MUTAGENESIS OF
RP ARG-63, PROBABLE PYROGLUTAMATE FORMATION AT GLN-50, PROBABLE HYDROXYLATION
RP AT PRO-57 AND PRO-67, AND PROBABLE AMIDATION AT CYS-71.
RC TISSUE=Venom duct;
RX PubMed=9614224; DOI=10.1523/jneurosci.18-12-04473.1998;
RA Shon K.-J., Olivera B.M., Watkins M., Jacobsen R.B., Gray W.R.,
RA Floresca C.Z., Cruz L.J., Hillyard D.R., Brink A., Terlau H., Yoshikami D.;
RT "Mu-conotoxin PIIIA, a new peptide for discriminating among tetrodotoxin-
RT sensitive Na channel subtypes.";
RL J. Neurosci. 18:4473-4481(1998).
RN [3]
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 [4]
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 [5]
RP FUNCTION, AND SYNTHESIS OF 50-71.
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 [6]
RP FUNCTION, AND SYNTHESIS OF 50-71.
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 [7]
RP FUNCTION.
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).
RN [8]
RP STRUCTURE BY NMR OF 50-71, SYNTHESIS OF 50-71, FUNCTION, AND DISULFIDE
RP BONDS FOR 3 SYNTHETIC ISOMERS.
RX PubMed=22407516; DOI=10.1002/anie.201107011;
RA Tietze A.A., Tietze D., Ohlenschlager O., Leipold E., Ullrich F., Kuhl T.,
RA Mischo A., Buntkowsky G., Gorlach M., Heinemann S.H., Imhof D.;
RT "Structurally diverse mu-conotoxin PIIIA isomers block sodium channel NaV
RT 1.4.";
RL Angew. Chem. Int. Ed. 51:4058-4061(2012).
RN [9]
RP STRUCTURE BY NMR OF 50-71, SYNTHESIS OF 50-71, AND DISULFIDE BONDS.
RX PubMed=12006587; DOI=10.1074/jbc.m201611200;
RA Nielsen K.J., Watson M., Adams D.J., Hammarstroem A.K., Gage P.W.,
RA Hill J.M., Craik D.J., Thomas L., Adams D., Alewood P.F., Lewis R.J.;
RT "Solution structure of mu-conotoxin PIIIA, a preferential inhibitor of
RT persistent TTX-sensitive sodium channels.";
RL J. Biol. Chem. 277:27247-27255(2002).
CC -!- FUNCTION: Mu-conotoxins block voltage-gated sodium channels (Nav). This
CC toxin potently blocks rNav1.4/SCN4A (IC(50)=36-41 nM) (PubMed:10627583,
CC PubMed:21652775). It also moderately blocks rNav1.1/SCN1A (IC(50)=120
CC nM), rNav1.2/SCN2A (IC(50)=620 nM), rNav1.3/SCN3A (IC(50)=3.2 uM),
CC mNav1.6/SCN8A (IC(50)=100 nM) (PubMed:10627583, PubMed:21652775). This
CC inhibition is reversible. The block of Nav1.1, Nav1.2, and Nav1.6 is
CC modified when beta-subunits are coexpressed with alpha subunits. Hence,
CC blocks of channels containing the beta-1 and beta-3 subunits are more
CC potent (compared to channels without beta subunits), whereas blocks of
CC channels containing the beta-2 and beta-4 are less potent (compared to
CC channels without beta subunits). In vivo, this peptide causes flaccid
CC paralysis in both mice and fish. {ECO:0000269|PubMed:10627583,
CC ECO:0000269|PubMed:18950653, ECO:0000269|PubMed:21652775,
CC ECO:0000269|PubMed:22229737, ECO:0000269|PubMed:22407516,
CC ECO:0000269|PubMed:23146020}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250|UniProtKB:P01523}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom duct.
CC {ECO:0000305|PubMed:9614224}.
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: 3D-structure of 3 disulfide-bond connectivities isomers is
CC described (PIIIA-1 (C1-C5, C2-C6, C3-C4), PIIIA-2 (C1-C4, C2-C5, C3-C6)
CC and PIIIA-3 (C1-C2, C3-C4, C5-C6)) (PubMed:22407516). Only PIIIA-2
CC contains the cysteine connectivity described as typical for native mu-
CC conotoxins. However, PIIIA-1 is more potent than PIIIA-2, suggesting
CC another possible disulfid connectivity. For this reason, both
CC connectivities have been indicated in features.
CC {ECO:0000269|PubMed:22407516}.
CC -!- MISCELLANEOUS: Exists in two forms, due to cis-trans isomerization at
CC Hyp-57. Adopts a predominately trans conformation (Probable).
CC {ECO:0000305|PubMed:12006587}.
CC -!- MISCELLANEOUS: This toxin does not or only weakly blocks rNav1.5/SCN5A,
CC rNav1.7/SCN9A (IC(50)=3.1-6.2 uM and >100 uM), and rNav1.8/SCN10A.
CC {ECO:0000269|PubMed:10627583, ECO:0000269|PubMed:21652775}.
CC -!- SIMILARITY: Belongs to the conotoxin M superfamily. {ECO:0000305}.
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DR PDB; 1R9I; NMR; -; A=50-71.
DR PDBsum; 1R9I; -.
DR AlphaFoldDB; P58925; -.
DR BMRB; P58925; -.
DR SMR; P58925; -.
DR TCDB; 8.B.28.1.2; the mu-conotoxin (mu-conotoxin) family.
DR ConoServer; 1407; PIIIA precursor.
DR EvolutionaryTrace; P58925; -.
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 2: Evidence at transcript level;
KW 3D-structure; Amidation; Cleavage on pair of basic residues;
KW Disulfide bond; Hydroxylation; Ion channel impairing toxin; Neurotoxin;
KW Pyrrolidone carboxylic acid; Secreted; Signal; Toxin;
KW Voltage-gated sodium channel impairing toxin.
FT SIGNAL 1..19
FT /evidence="ECO:0000255"
FT PROPEP 20..49
FT /evidence="ECO:0000305|PubMed:9614224"
FT /id="PRO_0000035053"
FT PEPTIDE 50..71
FT /note="Mu-conotoxin PIIIA"
FT /evidence="ECO:0000305|PubMed:9614224"
FT /id="PRO_0000035054"
FT SITE 63
FT /note="Important for activity"
FT /evidence="ECO:0000269|PubMed:9614224"
FT MOD_RES 50
FT /note="Pyrrolidone carboxylic acid"
FT /evidence="ECO:0000305|PubMed:12006587,
FT ECO:0000305|PubMed:9614224"
FT MOD_RES 57
FT /note="4-hydroxyproline"
FT /evidence="ECO:0000305|PubMed:9614224"
FT MOD_RES 67
FT /note="4-hydroxyproline"
FT /evidence="ECO:0000305|PubMed:9614224"
FT MOD_RES 71
FT /note="Cysteine amide"
FT /evidence="ECO:0000305|PubMed:9614224"
FT DISULFID 53..70
FT /note="In PIIIA-1; alternate"
FT /evidence="ECO:0000250|UniProtKB:P01523"
FT DISULFID 53..65
FT /note="In PIIIA-2; alternate"
FT /evidence="ECO:0000269|PubMed:12006587,
FT ECO:0000312|PDB:1R9I"
FT DISULFID 54..71
FT /note="In PIIIA-1; alternate"
FT /evidence="ECO:0000250|UniProtKB:P01523"
FT DISULFID 54..70
FT /note="In PIIIA-2; alternate"
FT /evidence="ECO:0000269|PubMed:12006587,
FT ECO:0000312|PDB:1R9I"
FT DISULFID 60..71
FT /note="In PIIIA-2; alternate"
FT /evidence="ECO:0000269|PubMed:12006587"
FT DISULFID 60..65
FT /note="In PIIIA-1; alternate"
FT /evidence="ECO:0000250|UniProtKB:P01523"
FT MUTAGEN 63
FT /note="R->A: Decrease in affinity to channel."
FT /evidence="ECO:0000269|PubMed:9614224"
FT TURN 52..55
FT /evidence="ECO:0007829|PDB:1R9I"
FT HELIX 59..61
FT /evidence="ECO:0007829|PDB:1R9I"
FT TURN 63..67
FT /evidence="ECO:0007829|PDB:1R9I"
SQ SEQUENCE 73 AA; 8334 MW; 1AF52E344F6EE982 CRC64;
MSKLGVLLTI CLLLFPITAL PMDGDQPADR LAERMQDNIS SEEHPFEKRQ RLCCGFPKSC
RSRQCKPHRC CGR
