CO6A_CONMF
ID CO6A_CONMF Reviewed; 32 AA.
AC P0DM15;
DT 18-JUL-2018, integrated into UniProtKB/Swiss-Prot.
DT 18-JUL-2018, sequence version 1.
DT 25-MAY-2022, entry version 8.
DE RecName: Full=MuO-conotoxin MfVIA {ECO:0000303|PubMed:22609441, ECO:0000303|PubMed:27026701};
OS Conus magnificus (Magnificent cone) (Darioconus magnificus).
OC Eukaryota; Metazoa; Spiralia; Lophotrochozoa; Mollusca; Gastropoda;
OC Caenogastropoda; Neogastropoda; Conoidea; Conidae; Conus; Darioconus.
OX NCBI_TaxID=257332;
RN [1]
RP PROTEIN SEQUENCE, SYNTHESIS, MASS SPECTROMETRY, SUBCELLULAR LOCATION, AND
RP DISULFIDE BOND.
RC TISSUE=Venom;
RX PubMed=22609441; DOI=10.1016/j.bcp.2012.05.008;
RA Vetter I., Dekan Z., Knapp O., Adams D.J., Alewood P.F., Lewis R.J.;
RT "Isolation, characterization and total regioselective synthesis of the
RT novel muO-conotoxin MfVIA from Conus magnificus that targets voltage-gated
RT sodium channels.";
RL Biochem. Pharmacol. 84:540-548(2012).
RN [2]
RP STRUCTURE BY NMR, FUNCTION, MUTAGENESIS OF GLU-5; LYS-6; TRP-7; GLU-8;
RP ILE-14; LEU-15; PHE-17; VAL-18; TYR-19 AND PHE-29, AND SYNTHESIS.
RX PubMed=27026701; DOI=10.1074/jbc.m116.721662;
RA Deuis J.R., Dekan Z., Inserra M.C., Lee T.H., Aguilar M.I., Craik D.J.,
RA Lewis R.J., Alewood P.F., Mobli M., Schroeder C.I., Henriques S.T.,
RA Vetter I.;
RT "Development of a muO-conotoxin analogue with improved lipid membrane
RT interactions and potency for the analgesic sodium channel Nav1.8.";
RL J. Biol. Chem. 291:11829-11842(2016).
CC -!- FUNCTION: MuO-conotoxins are gating-modifier toxins that inhibit sodium
CC current by trapping the domain II voltage sensor in the closed position
CC to prevent opening of the sodium channel. This toxin shows high
CC activity on Nav1.4/SCN4A (IC(50)=81 nM) and Nav1.8/SCN10A (IC(50)=96-
CC 529 nM). It also shows low activity on other sodium channels
CC (Nav1.5/SCN5A, IC(50)=431-3900 nM > Nav1.1/SCN1A, IC(50)=3.3 uM;
CC Nav1.2/SCN2A, IC(50)=5.1-6.3 uM; Nav1.3/SCN3A, IC(50)=2.2 uM;
CC Nav1.6/SCN8A, IC(50)=1.2-4.6 uM; Nav1.7/SCN9A, IC(50)=2.3-5.5 uM)
CC (PubMed:22609441). On Nav1.8/SCN10A, it causes a small left shift in
CC the voltage dependence of activation and the voltage dependence of
CC inactivation (PubMed:27026701). In addition, it has been shown to
CC interact with lipid membranes (PubMed:27026701).
CC {ECO:0000269|PubMed:22609441, ECO:0000269|PubMed:27026701}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:22609441}.
CC -!- TISSUE SPECIFICITY: Expressed by the venom duct.
CC {ECO:0000305|PubMed:22609441}.
CC -!- DOMAIN: The presence of a 'disulfide through disulfide knot'
CC structurally defines this protein as a knottin.
CC {ECO:0000269|PubMed:27026701}.
CC -!- DOMAIN: The cysteine framework is VI/VII (C-C-CC-C-C). {ECO:0000305}.
CC -!- MASS SPECTROMETRY: Mass=3647.7; Method=MALDI; Note=Average mass.;
CC Evidence={ECO:0000269|PubMed:22609441};
CC -!- MISCELLANEOUS: On Nav1.8/SCN10A, the mutant (E5K,E8K)MfVIA causes a
CC small left shift in the voltage dependence of activation and the
CC voltage dependence of inactivation (PubMed:27026701). In addition, it
CC inserts more deeply into the membranes than the wild-type toxin
CC (PubMed:27026701). In vivo, the mutant (E5K,E8K)MfVIA is analgesic in a
CC formalin-induced mouse pain model (PubMed:27026701).
CC {ECO:0000269|PubMed:27026701}.
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DR PDB; 2N7F; NMR; -; A=1-32.
DR PDBsum; 2N7F; -.
DR AlphaFoldDB; P0DM15; -.
DR SMR; P0DM15; -.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0017080; F:sodium channel regulator activity; IEA:UniProtKB-KW.
DR GO; GO:0090729; F:toxin activity; IEA:UniProtKB-KW.
PE 1: Evidence at protein level;
KW 3D-structure; Direct protein sequencing; Disulfide bond;
KW Ion channel impairing toxin; Knottin; Neurotoxin; Secreted; Toxin;
KW Voltage-gated sodium channel impairing toxin.
FT CHAIN 1..32
FT /note="MuO-conotoxin MfVIA"
FT /evidence="ECO:0000269|PubMed:22609441"
FT /id="PRO_0000444691"
FT DISULFID 3..21
FT /evidence="ECO:0000269|PubMed:22609441,
FT ECO:0000269|PubMed:27026701, ECO:0000312|PDB:2N7F"
FT DISULFID 10..26
FT /evidence="ECO:0000269|PubMed:22609441,
FT ECO:0000269|PubMed:27026701, ECO:0000312|PDB:2N7F"
FT DISULFID 20..31
FT /evidence="ECO:0000269|PubMed:22609441,
FT ECO:0000269|PubMed:27026701, ECO:0000312|PDB:2N7F"
FT MUTAGEN 5..8
FT /note="EKWE->KKWK: 3-fold increase in potency to inhibit
FT human Nav1.8/SCN10A sodium channels, and important increase
FT in interaction with lipid membrane."
FT /evidence="ECO:0000269|PubMed:27026701"
FT MUTAGEN 5
FT /note="E->A: 2-fold increase in potency to inhibit human
FT Nav1.8/SCN10A sodium channels, and small decrease in
FT interaction with lipid membrane."
FT /evidence="ECO:0000269|PubMed:27026701"
FT MUTAGEN 6
FT /note="K->A: 1.5-fold decrease in potency to inhibit human
FT Nav1.8/SCN10A sodium channels."
FT /evidence="ECO:0000269|PubMed:27026701"
FT MUTAGEN 7
FT /note="W->A: 2.5-fold decrease in potency to inhibit human
FT Nav1.8/SCN10A sodium channels, and important decrease in
FT interaction with lipid membrane."
FT /evidence="ECO:0000269|PubMed:27026701"
FT MUTAGEN 8
FT /note="E->A: 2-fold increase in potency to inhibit human
FT Nav1.8/SCN10A sodium channels, and small decrease in
FT interaction with lipid membrane."
FT /evidence="ECO:0000269|PubMed:27026701"
FT MUTAGEN 14
FT /note="I->A: 5-fold decrease in potency to inhibit human
FT Nav1.8/SCN10A sodium channels, and no change in interaction
FT with lipid membrane."
FT /evidence="ECO:0000269|PubMed:27026701"
FT MUTAGEN 15
FT /note="L->A: 2.5-fold decrease in potency to inhibit human
FT Nav1.8/SCN10A sodium channels."
FT /evidence="ECO:0000269|PubMed:27026701"
FT MUTAGEN 17
FT /note="F->A: 2-fold decrease in potency to inhibit human
FT Nav1.8/SCN10A sodium channels."
FT /evidence="ECO:0000269|PubMed:27026701"
FT MUTAGEN 18
FT /note="V->A: 2-fold decrease in potency to inhibit human
FT Nav1.8/SCN10A sodium channels."
FT /evidence="ECO:0000269|PubMed:27026701"
FT MUTAGEN 19
FT /note="Y->A: 12-fold decrease in potency to inhibit human
FT Nav1.8/SCN10A sodium channels, and no change in interaction
FT with lipid membrane."
FT /evidence="ECO:0000269|PubMed:27026701"
FT MUTAGEN 19
FT /note="Y->F: 1.3-fold decrease in potency to inhibit human
FT Nav1.8/SCN10A sodium channels."
FT /evidence="ECO:0000269|PubMed:27026701"
FT MUTAGEN 19
FT /note="Y->W: 2-fold decrease in potency to inhibit human
FT Nav1.8/SCN10A sodium channels, and no change in interaction
FT with lipid membrane."
FT /evidence="ECO:0000269|PubMed:27026701"
FT MUTAGEN 29
FT /note="F->A: 6-fold decrease in potency to inhibit human
FT Nav1.8/SCN10A sodium channels, and important decrease in
FT interaction with lipid membrane."
FT /evidence="ECO:0000269|PubMed:27026701"
SQ SEQUENCE 32 AA; 3654 MW; 355B70AE0527FC2D CRC64;
RDCQEKWEYC IVPILGFVYC CPGLICGPFV CV
