PROSITE documentation PDOC60004

Conotoxin families signatures




Description

Cone snail toxins, conotoxins, are small peptides with disulfide connectivity, that target ion-channels or G-protein coupled receptors. Based on the number and pattern of disulfide bonds and biological activities, conotoxins can be classified into several families [1]. Omega, delta and kappa families of conotoxins have a knottin or inhibitor cystine knot scaffold. The knottin scaffold is a very special disulfide through disulfide knot, in which the III-VI disulfide bond crosses the macrocycle formed by two other disulfide bonds (I-IV and II-V) and the interconnecting backbone segments, where I-VI indicates the six cysteine residues starting from the N-terminus [2,E1].

Conotoxins represent a unique arsenal of neuropharmacologically active peptides that have been evolutionarily tailored to afford unprecedented and exquisite selectivity for a wide variety of ion-channel subtypes. The toxins derived from cone snails are currently being investigated for the treatment of chronic pain, epilepsy, cardiovascular diseases, psychiatric and movement disorders, spasticity, cancer, stroke as well as an anesthetic agent. Several potential analgesic and anti-inflammatory peptides from conotoxin families have been identified and patented [3,4]:

  • Conus magus omega-conotoxin MVIIa (Ziconotide) is used for the treatment of chronic pain.
  • Conus catus omega-conotoxin CVID is tested for treating severe morphine- resistant pain stress.
  • Conus geographus omega-conotoxin GVIA may exert antagonistic effects against β-endorphin induced anti-nociception.

The disulfide bonding network as well as specific amino acids in inter-cysteine loops provide specificity of conotoxins [5]. The cysteine arrangement [C-C-CC-C-C] is the same for omega and delta families, which belong to the O-superfamily. The omega conotoxins are calcium channel blockers, whereas delta conotoxins delay the inactivation of sodium channels [1]. The M-superfamily Mu conotoxins have two types of cysteine arrangement [CC-C-C-CC] and [CC-C-C-C-C], but knottin scaffold is not observed. Mu conotoxins target the voltage-gated sodium channels [1] and are useful probes for investigating voltage-dependent sodium channels of excitable tissues [6]. α conotoxins belong to the A-superfamily and have two types of cysteine arrangement [CC-C-C] and [CCC-C-C-C] [7]. α conotoxins are competitive nicotinic acetylcholine receptor antagonists. The I-superfamily of conotoxins is characterized by a pattern of eight cysteine residues that form four disulfide bridges. The arrangement of cysteine residues is similar to the Janus-faced atracotoxin peptides characterized from spider venoms (see <PDOC60020>) [8,9].

Three signature patterns were developed for omega, delta and mu conotoxin families. The patterns each include six conserved cysteines thought to be important for the maintenance of the tertiary structure of the conotoxins. We have defined a pattern for the common part of the cysteine arrangement [CC-C-C] in all members of α conotoxin family. The pattern includes four conserved cysteines thought to be important for the maintenance of the tertiary structure of α conotoxins. The pattern for the I-superfamily conotoxin covers the eight conserved cysteines.

Expert(s) to contact by email:

Ramakumar S.

Last update:

October 2006 / Pattern for the I-superfamily revised.

Technical section

PROSITE methods (with tools and information) covered by this documentation:

ALPHA_CONOTOXIN, PS60014; Alpha-conotoxin family signature  (PATTERN)

DELTA_CONOTOXIN, PS60005; Delta-conotoxin family signature  (PATTERN)

I_CONOTOXIN, PS60019; I-superfamily conotoxin signature  (PATTERN)

MU_CONOTOXIN, PS60013; Mu-conotoxin family signature  (PATTERN)

OMEGA_CONOTOXIN, PS60004; Omega-conotoxin family signature  (PATTERN)


References

1AuthorsMcIntosh J.M., Jones R.M.
TitleCone venom--from accidental stings to deliberate injection.
SourceToxicon 39:1447-1451(2001).
PubMed ID11478951

2AuthorsGelly J.-C., Gracy J., Kaas Q., Le-Nguyen D., Heitz A., Chiche L.
TitleThe KNOTTIN website and database: a new information system dedicated to the knottin scaffold.
SourceNucleic Acids Res. 32:D156-D159(2004).
PubMed ID14681383
DOI10.1093/nar/gkh015

3AuthorsJones R.M., Bulaj G.
TitleConotoxins - new vistas for peptide therapeutics.
SourceCurr. Pharm. Des. 6:1249-1285(2000).
PubMed ID10903392

4AuthorsRajendra W., Armugam A., Jeyaseelan K.
TitleToxins in anti-nociception and anti-inflammation.
SourceToxicon 44:1-17(2004).
PubMed ID15225557
DOI10.1016/j.toxicon.2004.04.014

5AuthorsBalaji R.A., Ohtake A., Sato K., Gopalakrishnakone P., Kini R.M., Seow K.T., Bay B.-H.
TitleLambda-conotoxins, a new family of conotoxins with unique disulfide pattern and protein folding. Isolation and characterization from the venom of Conus marmoreus.
SourceJ. Biol. Chem. 275:39516-39522(2000).
PubMed ID10988292
DOI10.1074/jbc.M006354200

6AuthorsCruz L.J., Gray W.R., Olivera B.M., Zeikus R.D., Kerr L., Yoshikami D., Moczydlowski E.
TitleConus geographus toxins that discriminate between neuronal and muscle sodium channels.
SourceJ. Biol. Chem. 260:9280-9288(1985).
PubMed ID2410412

7AuthorsRamilo C.A., Zafaralla G.C., Nadasdi L., Hammerland L.G., Yoshikami D., Gray W.R., Kristipati R., Ramachandran J., Miljanich G., Olivera B.M.
TitleNovel alpha- and omega-conotoxins from Conus striatus venom.
SourceBiochemistry 31:9919-9926(1992).
PubMed ID1390774

8AuthorsJimenez E.C., Shetty R.P., Lirazan M., Rivier J., Walker C., Abogadie F.C., Yoshikami D., Cruz L.J., Olivera B.M.
TitleNovel excitatory Conus peptides define a new conotoxin superfamily.
SourceJ. Neurochem. 85:610-621(2003).
PubMed ID12694387

9AuthorsKauferstein S., Huys I., Kuch U., Melaun C., Tytgat J., Mebs D.
TitleNovel conopeptides of the I-superfamily occur in several clades of cone snails.
SourceToxicon 44:539-548(2004).
PubMed ID15450929
DOI10.1016/j.toxicon.2004.07.006

E1Sourcehttp://knottin.cbs.cnrs.fr



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