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P0C195 (CM3A_CONKI) Reviewed, UniProtKB/Swiss-Prot

Last modified February 19, 2014. Version 27. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (2) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Mu-conotoxin KIIIA
OrganismConus kinoshitai (Kinoshita's cone)
Taxonomic identifier376876 [NCBI]
Taxonomic lineageEukaryotaMetazoaLophotrochozoaMolluscaGastropodaCaenogastropodaHypsogastropodaNeogastropodaConoideaConidaeConus

Protein attributes

Sequence length18 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at transcript level

General annotation (Comments)

Function

Mu-conotoxins block voltage-gated sodium channels (Nav). This toxin potently blocks rNav1.2/SCN2A and rNav1.4/SCN4A. It also moderately blocks rNav1.1/SCN1A, rNav1.3/SCN3A, rNav1.5/SCN5A, mNav1.6/SCN8A, and rNav1.7/SCN9A. On rNav1.2/SCN2A, it produces a block that is only partially reversible. The block of SCN9A is modified when beta-subunits are coexpressed with the alpha subunit. Hence, blocks of channels containing beta-1 and beta-3 subunits are more potent (compared to channels without beta subunits), whereas blocks of channels containing beta-2 and beta-4 subunits are less potent (compared to channels without beta subunits). Ref.1 Ref.3 Ref.4 Ref.5 Ref.6 Ref.7 Ref.8

Subunit structure

Monomer. Ref.9

Subcellular location

Secreted By similarity.

Tissue specificity

Expressed by the venom duct.

Domain

The cysteine framework is III (CC-C-C-CC). Classified in the M-5 branch, since 5 residues stand between the fourth and the fifth cysteine residues.

Miscellaneous

Has no effect on hNav1.5/SCN5A and hNav1.8/SCN10A (Ref.5).

Sequence similarities

Belongs to the conotoxin M superfamily.

Ontologies

Keywords
   Cellular componentSecreted
   Molecular functionIon channel impairing toxin
Neurotoxin
Toxin
Voltage-gated sodium channel impairing toxin
   PTMAmidation
Disulfide bond
   Technical term3D-structure
Gene Ontology (GO)
   Cellular_componentextracellular region

Inferred from electronic annotation. Source: UniProtKB-SubCell

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Peptide1 – 1616Mu-conotoxin KIIIA
PRO_0000232662

Sites

Site71Key residue in the pharmacophore, alpha-helical region
Site81Key residue in the pharmacophore, alpha-helical region
Site101Key residue in the pharmacophore, alpha-helical region
Site111Key residue in the pharmacophore, alpha-helical region
Site121Key residue in the pharmacophore, alpha-helical region
Site141Key residue in the pharmacophore

Amino acid modifications

Modified residue161Cysteine amide
Disulfide bond1 ↔ 9 Ref.9
Disulfide bond2 ↔ 15 Ref.9
Disulfide bond4 ↔ 16 Ref.9

Experimental info

Mutagenesis11C → A: Structure similar to wild-type toxin, even with this disulfide bond deletion. Ref.9
Mutagenesis71K → A: Attenuates the activity against rNav1.4/SCN4A but not rNav1.2/SCN2A. Ref.3 Ref.6
Mutagenesis81W → A: Attenuates the activity against both rNav1.4/SCN4A and rNav1.2/SCN2A. Attenuates the binding affinity of rNav1.2/SCN2A, rNav1.4/SCN2A, and rNav1.7/SCN9A. Ref.3 Ref.5
Mutagenesis81W → E: 200-fold reduction of activity toward rNav1.4/SCN4A. Block of rNav1.2/SCN2A is completely reversible. Ref.3 Ref.5
Mutagenesis81W → Q: 70-fold reduction of activity toward rNav1.4/SCN4A. Block of rNav1.2/SCN2A is completely reversible. Ref.3 Ref.5
Mutagenesis81W → R: 40-fold reduction of activity toward rNav1.4/SCN4A. Block of rNav1.2/SCN2A is completely reversible. Ref.3 Ref.5
Mutagenesis91C → A: Structure similar to wild-type toxin, even with this disulfide bond deletion. Ref.9
Mutagenesis101R → A: Attenuates the activity against both rNav1.4/SCN4A and rNav1.2/SCN2A, and the binding affinity of rNav1.2/SCN2A, rNav1.4/SCN4A, and rNav1.7/SCN9A. Ref.3 Ref.6
Mutagenesis111D → A: Attenuates the activity against both rNav1.4/SCN4A and rNav1.2/SCN2A. Ref.3
Mutagenesis121H → A: Attenuates the activity against both rNav1.4/SCN4A and rNav1.2/SCN2A, and potently decreases the binding affinity of rNav1.2/SCN2A, rNav1.4/SCN4A, and rNav1.7/SCN9A. Ref.3 Ref.6
Mutagenesis141R → A: Attenuates the activity against both rNav1.4/SCN4A and rNav1.2/SCN2A, and the binding affinity of rNav1.2/SCN2A, rNav1.4/SCN4A, and rNav1.7/SCN9A. Ref.3 Ref.6

Secondary structure

... 18
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
P0C195 [UniParc].

Last modified April 18, 2006. Version 1.
Checksum: 6FA593BD458C3C39

FASTA182,104
        10 
CCNCSSKWCR DHSRCCGR 

« Hide

References

[1]"Novel conotoxins from Conus striatus and Conus kinoshitai selectively block TTX-resistant sodium channels."
Bulaj G., West P.J., Garrett J.E., Watkins M., Zhang M.-M., Norton R.S., Smith B.J., Yoshikami D., Olivera B.M.
Biochemistry 44:7259-7265(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], SYNTHESIS OF 1-16, FUNCTION.
Tissue: Venom duct.
[2]Erratum
Bulaj G., West P.J., Garrett J.E., Watkins M., Zhang M.-M., Norton R.S., Smith B.J., Yoshikami D., Olivera B.M.
Biochemistry 45:3116-3116(2006)
[3]"Structure/function characterization of mu-conotoxin KIIIA, an analgesic, nearly irreversible blocker of mammalian neuronal sodium channels."
Zhang M.-M., Green B.R., Catlin P., Fiedler B., Azam L., Chadwick A., Terlau H., McArthur J.R., French R.J., Gulyas J., Rivier J.E., Smith B.J., Norton R.S., Olivera B.M., Yoshikami D., Bulaj G.
J. Biol. Chem. 282:30699-30706(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: SYNTHESIS OF 1-16, FUNCTION, MUTAGENESIS OF LYS-7; TRP-8; ARG-10; ASP-11; HIS-12 AND ARG-14.
[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: SYNTHESIS OF 1-16, FUNCTION.
[5]"Importance of position 8 in mu-conotoxin KIIIA for voltage-gated sodium channel selectivity."
Van Der Haegen A., Peigneur S., Tytgat J.
FEBS J. 278:3408-3418(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: SYNTHESIS OF 1-16, FUNCTION, MUTAGENESIS OF TRP-8.
[6]"Interactions of key charged residues contributing to selective block of neuronal sodium channels by mu-conotoxin KIIIA."
McArthur J.R., Singh G., McMaster D., Winkfein R., Tieleman D.P., French R.J.
Mol. Pharmacol. 80:573-584(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: SYNTHESIS OF 1-16, FUNCTION, MUTAGENESIS OF LYS-7; ARG-10; HIS-12 AND ARG-14.
[7]"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.
[8]"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.
[9]"Structure of the analgesic mu-conotoxin KIIIA and effects on the structure and function of disulfide deletion."
Khoo K.K., Feng Z.-P., Smith B.J., Zhang M.-M., Yoshikami D., Olivera B.M., Bulaj G., Norton R.S.
Biochemistry 48:1210-1219(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: STRUCTURE BY NMR OF 1-16, SYNTHESIS OF 1-16, SUBUNIT, MUTAGENESIS OF CYS-1 AND CYS-9, DISULFIDE BOND.
+Additional computationally mapped references.

Web resources

Cross-references

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2LXGNMR-A1-16[»]
ModBaseSearch...
MobiDBSearch...

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Organism-specific databases

ConoServer1694. KIIIA precursor.

Family and domain databases

ProtoNetSearch...

Entry information

Entry nameCM3A_CONKI
AccessionPrimary (citable) accession number: P0C195
Entry history
Integrated into UniProtKB/Swiss-Prot: April 18, 2006
Last sequence update: April 18, 2006
Last modified: February 19, 2014
This is version 27 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programAnimal Toxin Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references