The formation of the small highly constrained peptide conotoxins with their unusually high density of disulphide bridges is achieved by the folding of the conotoxin as a part of a precursor molecule. This allows for a high degree of tertiary structural organisation, which is required to produce peptides such as the alpha conotoxins of Conus Geographus where there are 3 disulphide bonds in 13 amino acid residues!
The precursor propeptides contain a high concentration of cysteine residues at the carboxy terminus that form disulphide bridges, acting as 'locking groups' during the propeptide folding.
Once the propeptide molecule has folded, the groups are locked into place, and then the carboxyl end of the peptide is cleaved (cut) to produce a small active toxin with a high density of disulphide bonds.
By this 'fold-lock-cut' method, the amino acids required to facilitate the folding of the peptide can be discarded to leave the compact conotoxin peptide that contains all of the remaining amino acids necessary for receptor interaction.
Conotoxin precursors are found in the cone shell venom in the form of microscopic granules suspended in the milky fluid. They induce little of the lethal and paralytic activity of their soluble peptide toxin counterparts, but have a similar cysteine content.The treatment of the granules with digestive enzymes results in the liberation of active toxin, and it was found that the granules also contain various enzymes, (acetylcholinesterase, proteases and phosphodiesterases) which presumably act upon the granules to activate the neuropeptide component. In this way the granules can be considered as 'packets' of inactive toxin precursors that are liberated upon demand by the action of the hydrolytic enzymes.
CG and BGL, June-95
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