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Protein

Mu-conotoxin PIIIA

Gene
N/A
Organism
Conus purpurascens (Purple cone)
Status
Reviewed-Annotation score: Annotation score: 4 out of 5-Experimental evidence at transcript leveli

Functioni

Mu-conotoxins block voltage-gated sodium channels (Nav). This toxin potently blocks rNav1.4/SCN4A. It also moderately blocks rNav1.1/SCN1A, rNav1.2/SCN2A, rNav1.3/SCN3A, mNav1.6/SCN8A, and h/rNav1.7/SCN9A. This inhibition is reversible. The block of SCN1A, SCN2A, and SCN8A is modified when beta-subunits are coexpressed with alpha subunits. Hence, blocks of channels containing the beta-1 and beta-3 subunits are more potent (compared to channels without beta subunits), whereas blocks of channels containing the beta-2 and beta-4 are less potent (compared to channels without beta subunits). This peptide causes flaccid paralysis in both mice and fish.5 Publications

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sitei63 – 631Important for activity

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Ion channel impairing toxin, Neurotoxin, Toxin, Voltage-gated sodium channel impairing toxin

Names & Taxonomyi

Protein namesi
Recommended name:
Mu-conotoxin PIIIA
Alternative name(s):
Mu-conotoxin P3.7
OrganismiConus purpurascens (Purple cone)
Taxonomic identifieri41690 [NCBI]
Taxonomic lineageiEukaryotaMetazoaLophotrochozoaMolluscaGastropodaCaenogastropodaHypsogastropodaNeogastropodaConoideaConidaeConus

Organism-specific databases

ConoServeri1407. PIIIA precursor.

Subcellular locationi

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Secreted

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi63 – 631R → A: Decrease in affinity to channel. 1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 1919Sequence analysisAdd
BLAST
Propeptidei20 – 4930PRO_0000035053Add
BLAST
Peptidei50 – 7122Mu-conotoxin PIIIAPRO_0000035054Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei50 – 501Pyrrolidone carboxylic acid
Disulfide bondi53 ↔ 70In PIIIA-1; alternateBy similarity
Disulfide bondi53 ↔ 65In PIIIA-2; alternateCurated
Disulfide bondi54 ↔ 71In PIIIA-1; alternateBy similarity
Disulfide bondi54 ↔ 70In PIIIA-2; alternateCurated
Modified residuei57 – 5714-hydroxyproline1 Publication
Disulfide bondi60 ↔ 71In PIIIA-2; alternateCurated
Disulfide bondi60 ↔ 65In PIIIA-1; alternateBy similarity
Modified residuei67 – 6714-hydroxyproline1 Publication
Modified residuei71 – 711Cysteine amide1 Publication

Post-translational modificationi

3D-structure of 3 disulfide-bond connectivities isomers is described (PIIIA-1 (C1-C5, C2-C6, C3-C4), PIIIA-2 (C1-C4, C2-C5, C3-C6) and PIIIA-3 (C1-C2, C3-C4, C5-C6)) (PubMed:22407516). Only PIIIA-2 contains the cysteine connectivity described as typical for native mu-conotoxins. However, PIIIA-1 is more potent than PIIIA-2, suggesting another possible disulfid connectivity. For this reason, both connectivities have been indicated in features.1 Publication

Keywords - PTMi

Amidation, Cleavage on pair of basic residues, Disulfide bond, Hydroxylation, Pyrrolidone carboxylic acid

Expressioni

Tissue specificityi

Expressed by the venom duct.

Structurei

Secondary structure

1
73
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Turni52 – 554Combined sources
Helixi59 – 613Combined sources
Turni63 – 675Combined sources

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
1R9INMR-A50-71[»]
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP58925.

Family & Domainsi

Domaini

The cysteine framework is III (CC-C-C-CC). Classified in the M-4 branch, since 4 residues stand between the fourth and the fifth cysteine residues.

Sequence similaritiesi

Belongs to the conotoxin M superfamily.Curated

Keywords - Domaini

Signal

Family and domain databases

InterProiIPR004214. Conotoxin.
IPR008036. Conotoxin_mu-typ.
[Graphical view]
PfamiPF02950. Conotoxin. 1 hit.
[Graphical view]
PROSITEiPS60013. MU_CONOTOXIN. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

P58925-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MSKLGVLLTI CLLLFPITAL PMDGDQPADR LAERMQDNIS SEEHPFEKRQ
60 70
RLCCGFPKSC RSRQCKPHRC CGR
Length:73
Mass (Da):8,334
Last modified:July 11, 2006 - v2
Checksum:i1AF52E344F6EE982
GO

Cross-referencesi

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
1R9INMR-A50-71[»]
ModBaseiSearch...
MobiDBiSearch...

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Organism-specific databases

ConoServeri1407. PIIIA precursor.

Miscellaneous databases

EvolutionaryTraceiP58925.

Family and domain databases

InterProiIPR004214. Conotoxin.
IPR008036. Conotoxin_mu-typ.
[Graphical view]
PfamiPF02950. Conotoxin. 1 hit.
[Graphical view]
PROSITEiPS60013. MU_CONOTOXIN. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

  1. "Definition of the M-conotoxin superfamily: characterization of novel peptides from molluscivorous Conus venoms."
    Corpuz G.P., Jacobsen R.B., Jimenez E.C., Watkins M., Walker C., Colledge C., Garrett J.E., McDougal O., Li W., Gray W.R., Hillyard D.R., Rivier J., McIntosh J.M., Cruz L.J., Olivera B.M.
    Biochemistry 44:8176-8186(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
    Tissue: Venom duct.
  2. "Mu-conotoxin PIIIA, a new peptide for discriminating among tetrodotoxin-sensitive Na channel subtypes."
    Shon K.-J., Olivera B.M., Watkins M., Jacobsen R.B., Gray W.R., Floresca C.Z., Cruz L.J., Hillyard D.R., Brink A., Terlau H., Yoshikami D.
    J. Neurosci. 18:4473-4481(1998) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 47-73, SYNTHESIS OF 50-71, HYDROXYLATION AT PRO-57 AND PRO-67, AMIDATION AT CYS-71, MUTAGENESIS OF ARG-63.
    Tissue: Venom duct.
  3. "Distinction among neuronal subtypes of voltage-activated sodium channels by mu-conotoxin PIIIA."
    Safo P., Rosenbaum T., Shcherbatko A., Choi D.-Y., Han E., Toledo-Aral J.J., Olivera B.M., Brehm P., Mandel G.
    J. Neurosci. 20:76-80(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: BINDING TO NEURONAL SODIUM CHANNELS.
  4. "Pruning nature: biodiversity-derived discovery of novel sodium channel blocking conotoxins from Conus bullatus."
    Holford M., Zhang M.-M., Gowd K.H., Azam L., Green B.R., Watkins M., Ownby J.-P., Yoshikami D., Bulaj G., Olivera B.M.
    Toxicon 53:90-98(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  5. "A novel u-conopeptide, CnIIIC, exerts potent and preferential inhibition of NaV1.2/1.4 channels and blocks neuronal nicotinic acetylcholine receptors."
    Favreau P., Benoit E., Hocking H.G., Carlier L., D'Hoedt D., Leipold E., Markgraf R., Schlumberger S., Cordova M.A., Gaertner H., Paolini-Bertrand M., Hartley O., Tytgat J., Heinemann S.H., Bertrand D., Boelens R., Stocklin R., Molgo J.
    Br. J. Pharmacol. 166:1654-1668(2012) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, SYNTHESIS.
  6. "mu-Conotoxins that differentially block sodium channels Nav1.1 through 1.8 identify those responsible for action potentials in sciatic nerve."
    Wilson M.J., Yoshikami D., Azam L., Gajewiak J., Olivera B.M., Bulaj G., Zhang M.M.
    Proc. Natl. Acad. Sci. U.S.A. 108:10302-10307(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION ON SODIUM CHANNELS, SYNTHESIS OF 50-71.
  7. "Co-expression of Na(V)beta subunits alters the kinetics of inhibition of voltage-gated sodium channels by pore-blocking mu-conotoxins."
    Zhang M.M., Wilson M.J., Azam L., Gajewiak J., Rivier J.E., Bulaj G., Olivera B.M., Yoshikami D.
    Br. J. Pharmacol. 168:1597-1610(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION ON SODIUM CHANNELS.
  8. Cited for: STRUCTURE BY NMR OF 50-71, SYNTHESIS OF 50-71, FUNCTION, DISULFIDE BONDS FOR 3 SYNTHETIC ISOMERS.
  9. "Solution structure of mu-conotoxin PIIIA, a preferential inhibitor of persistent TTX-sensitive sodium channels."
    Nielsen K.J., Watson M., Adams D.J., Hammarstroem A.K., Gage P.W., Hill J.M., Craik D.J., Thomas L., Adams D., Alewood P.F., Lewis R.J.
    J. Biol. Chem. 277:27247-27255(2002) [PubMed] [Europe PMC] [Abstract]
    Cited for: STRUCTURE BY NMR OF 50-71, SYNTHESIS OF 50-71, DISULFIDE BONDS.

Entry informationi

Entry nameiCM3A_CONPU
AccessioniPrimary (citable) accession number: P58925
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 26, 2002
Last sequence update: July 11, 2006
Last modified: September 16, 2015
This is version 82 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programAnimal Toxin Annotation Program

Miscellaneousi

Miscellaneous

Exists in two forms, due to cis-trans isomerization at Hyp-11. Adopts a predominately trans conformation (Probable).Curated
Does not block rNav1.5/SCN5A, rNav1.7/SCN9A, and rNav1.8/SCN10A.1 Publication

Keywords - Technical termi

3D-structure

Documents

  1. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  2. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.