Biology:Conotoxin

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Short description: Group of neurotoxins
Alpha conotoxin precursor
Alpha-Conotoxin from Conus pennaceus 1AKG.png
α-Conotoxin PnIB from C. pennaceus, disulfide bonds shown in yellow. From the University of Michigan's Orientations of Proteins in Membranes database, PDB: 1AKG​.
Identifiers
SymbolToxin_8
PfamPF07365
InterProIPR009958
PROSITEPDOC60004
SCOP21mii / SCOPe / SUPFAM
OPM superfamily148
OPM protein1akg
Omega conotoxin
Ziconotide 1DW5.png
Schematic diagram of the three-dimensional structure of ω-conotoxin MVIIA (ziconotide). Disulfide bonds are shown in gold. From PDB: 1DW5​.
Identifiers
SymbolConotoxin
PfamPF02950
InterProIPR004214
SCOP22cco / SCOPe / SUPFAM
OPM superfamily112
OPM protein1fyg

A conotoxin is one of a group of neurotoxic peptides isolated from the venom of the marine cone snail, genus Conus.

Conotoxins, which are peptides consisting of 10 to 30 amino acid residues, typically have one or more disulfide bonds. Conotoxins have a variety of mechanisms of actions, most of which have not been determined. However, it appears that many of these peptides modulate the activity of ion channels.[1] Over the last few decades conotoxins have been the subject of pharmacological interest.[2]

The LD50 of conotoxin ranges from 5-25 μg/kg.[3][4][5]

Hypervariability

Conotoxins are hypervariable even within the same species. They do not act within a body where they are produced (endogenously) but act on other organisms.[6] Therefore, conotoxin genes experience less selection against mutations (like gene duplication and nonsynonymous substitution), and mutations remain in the genome longer, allowing more time for potentially beneficial novel functions to arise.[7] Variability in conotoxin components reduces the likelihood that prey organisms will develop resistance; thus cone snails are under constant selective pressure to maintain polymorphism in these genes because failing to evolve and adapt will lead to extinction (Red Queen hypothesis).[8]

Disulfide connectivities

Types of conotoxins also differ in the number and pattern of disulfide bonds.[9] The disulfide bonding network, as well as specific amino acids in inter-cysteine loops, provide the specificity of conotoxins.[10]

Types and biological activities

The number of conotoxins whose activities have been determined so far is five, and they are called the α(alpha)-, δ(delta)-, κ(kappa)-, μ(mu)-, and ω(omega)- types. Each of the five types of conotoxins attacks a different target:

  • α-conotoxin inhibits nicotinic acetylcholine receptors at nerves and muscles.[11]
  • δ-conotoxin inhibits fast inactivation of voltage-dependent sodium channels.[12]
  • κ-conotoxin inhibits potassium channels.[13]
  • μ-conotoxin inhibits voltage-dependent sodium channels in muscles.[14]
  • ω-conotoxin inhibits N-type voltage-dependent calcium channels.[15] Because N-type voltage-dependent calcium channels are related to algesia (sensitivity to pain) in the nervous system, ω-conotoxin has an analgesic effect: the effect of ω-conotoxin M VII A is 100 to 1000 times that of morphine.[16] Therefore, a synthetic version of ω-conotoxin M VII A has found application as an analgesic drug ziconotide (Prialt).[17]

Alpha

Alpha conotoxins have two types of cysteine arrangements,[18] and are competitive nicotinic acetylcholine receptor antagonists.

Delta, kappa, and omega

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. The cysteine arrangements are the same for omega, delta and kappa families, even though omega conotoxins are calcium channel blockers, whereas delta conotoxins delay the inactivation of sodium channels, and kappa conotoxins are potassium channel blockers.[9]

Mu

Mu-conotoxin
PDB 1r9i EBI.jpg
nmr solution structure of piiia toxin, nmr, 20 structures
Identifiers
SymbolMu-conotoxin
PfamPF05374
Pfam clanCL0083
InterProIPR008036
SCOP21gib / SCOPe / SUPFAM
OPM superfamily112
OPM protein1ag7

Mu-conotoxins have two types of cysteine arrangements, but the knottin scaffold is not observed.[19] Mu-conotoxins target the muscle-specific voltage-gated sodium channels,[9] and are useful probes for investigating voltage-dependent sodium channels of excitable tissues.[19][20] Mu-conotoxins target the voltage-gated sodium channels, preferentially those of skeletal muscle,[21] and are useful probes for investigating voltage-dependent sodium channels of excitable tissues.[22]

Different subtypes of voltage-gated sodium channels are found in different tissues in mammals, e.g., in muscle and brain, and studies have been carried out to determine the sensitivity and specificity of the mu-conotoxins for the different isoforms.[23]

See also

References

This article incorporates text from the public domain Pfam and InterPro:
  1. ↑ "Conus venoms: a rich source of novel ion channel-targeted peptides". Physiol. Rev. 84 (1): 41–68. 2004. doi:10.1152/physrev.00020.2003. PMID 14715910. 
  2. ↑ "Diversity of the neurotoxic Conus peptides: a model for concerted pharmacological discovery.". Molecular Interventions 7 (5): 251–60. 2007. doi:10.1124/mi.7.5.7. PMID 17932414. https://pubmed.ncbi.nlm.nih.gov/17932414. 
  3. ↑ "Archived copy". http://www.aristatek.com/Newsletter/MAY08/TechSpeak.pdf. 
  4. ↑ "Biological Agent Reference Sheet - Conotoxin". Emory University. https://www.ehso.emory.edu/content-guidelines/BARS_Conotoxin.pdf. 
  5. ↑ Baker, A.L.. "toxin ld50 list". http://cfb.unh.edu/phycokey/Choices/Toxins/Toxin%20ld50s/toxin%20ld50%20list.htm. 
  6. ↑ "Adaptive radiation of venomous marine snail lineages and the accelerated evolution of venom peptide genes". Ann. N. Y. Acad. Sci. 1267 (1): 61–70. September 2012. doi:10.1111/j.1749-6632.2012.06603.x. PMID 22954218. Bibcode: 2012NYASA1267...61O. 
  7. ↑ "Venom evolution through gene duplications". Gene 496 (1): 1–7. March 2012. doi:10.1016/j.gene.2012.01.009. PMID 22285376. 
  8. ↑ "Red Queen: from populations to taxa and communities". Trends Ecol. Evol. 26 (7): 349–58. July 2011. doi:10.1016/j.tree.2011.03.016. PMID 21511358. 
  9. ↑ 9.0 9.1 9.2 "Cone venom--from accidental stings to deliberate injection". Toxicon 39 (10): 1447–1451. 2001. doi:10.1016/S0041-0101(01)00145-3. PMID 11478951. 
  10. ↑ "lambda-conotoxins, a new family of conotoxins with unique disulfide pattern and protein folding. Isolation and characterization from the venom of Conus marmoreus". J. Biol. Chem. 275 (50): 39516–39522. 2000. doi:10.1074/jbc.M006354200. PMID 10988292. 
  11. ↑ "Alpha-conotoxins as tools for the elucidation of structure and function of neuronal nicotinic acetylcholine receptor subtypes". Eur. J. Biochem. 271 (12): 2305–2319. 2004. doi:10.1111/j.1432-1033.2004.04145.x. PMID 15182346. 
  12. ↑ "Molecular interaction of delta-conotoxins with voltage-gated sodium channels". FEBS Lett. 579 (18): 3881–3884. 2005. doi:10.1016/j.febslet.2005.05.077. PMID 15990094. 
  13. ↑ "kappa-Conotoxin PVIIA is a peptide inhibiting the shaker K+ channel". J. Biol. Chem. 273 (1): 33–38. 1998. doi:10.1074/jbc.273.1.33. PMID 9417043. 
  14. ↑ "Using the deadly mu-conotoxins as probes of voltage-gated sodium channels". Toxicon 44 (2): 117–122. 2004. doi:10.1016/j.toxicon.2004.03.028. PMID 15246758. 
  15. ↑ "Structure-activity relationships of omega-conotoxins at N-type voltage-sensitive calcium channels" (abstract). J. Mol. Recognit. 13 (2): 55–70. 2000. doi:10.1002/(SICI)1099-1352(200003/04)13:2<55::AID-JMR488>3.0.CO;2-O. PMID 10822250. http://www3.interscience.wiley.com/cgi-bin/abstract/72502378/ABSTRACT. 
  16. ↑ "Pharmacotherapeutic potential of omega-conotoxin MVIIA (SNX-111), an N-type neuronal calcium channel blocker found in the venom of Conus magus". Toxicon 36 (11): 1651–1658. 1998. doi:10.1016/S0041-0101(98)00158-5. PMID 9792182. 
  17. ↑ Prommer E (2006). "Ziconotide: a new option for refractory pain". Drugs Today 42 (6): 369–78. doi:10.1358/dot.2006.42.6.973534. PMID 16845440. 
  18. ↑ "Novel alpha- and omega-conotoxins from Conus striatus venom". Biochemistry 31 (41): 11864–11873. 1992. doi:10.1021/bi00156a009. PMID 1390774. 
  19. ↑ 19.0 19.1 "Solution structure of mu-conotoxin PIIIA, a preferential inhibitor of persistent tetrodotoxin-sensitive sodium channels". J. Biol. Chem. 277 (30): 27247–55. July 2002. doi:10.1074/jbc.M201611200. PMID 12006587. https://researchonline.jcu.edu.au/266/1/thomas_1.pdf. 
  20. ↑ "Conus geographus toxins that discriminate between neuronal and muscle sodium channels". J. Biol. Chem. 260 (16): 9280–8. 1985. doi:10.1016/S0021-9258(17)39364-X. PMID 2410412. 
  21. ↑ "Cone venom--from accidental stings to deliberate injection". Toxicon 39 (10): 1447–51. October 2001. doi:10.1016/S0041-0101(01)00145-3. PMID 11478951. 
  22. ↑ "Conus geographus toxins that discriminate between neuronal and muscle sodium channels". J. Biol. Chem. 260 (16): 9280–8. August 1985. doi:10.1016/S0021-9258(17)39364-X. PMID 2410412. 
  23. ↑ Floresca CZ (2003). "A comparison of the mu-conotoxins by [3Hsaxitoxin binding assays in neuronal and skeletal muscle sodium channel."]. Toxicol Appl Pharmacol 190 (2): 95–101. doi:10.1016/s0041-008x(03)00153-4. PMID 12878039. https://pubmed.ncbi.nlm.nih.gov/12878039. 

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