The conformation of cardiotoxins and neurotoxins from snake venoms

Abstract

The conformations of a number of snake venom cardiotoxins and short (60–62 residues) neurotoxins were compared with the aid of circular dichroism spectra, sequences and theoretical predictions. The near-ultraviolet CD spectra of cardiotoxins exhibited positive Cotton effects arising mainly from the side chain of an invariant tyrosine located at position 23 of their sequences. By contrast, neurotoxins without exception had negative near-ultraviolet CD extrema, even though they contain a tyrosine in an identical position. The reversal in CD sign was attributed to the unique presence of tryptophan-28 known to be involved in neurotoxicity and which presumably possesses the necessary negative ellipticity to dominate neurotoxin near-ultraviolet spectra. A prominent positive Cotton effect invariably observed near 230 nm in neurotoxin spectra was likewise assigned to this tryptophan. Despite these characteristic differences, the deep-ultraviolet CD spectra concerned with the conformation of the polypeptide backbone of the toxins were quite similar. All had a single negative extremum near 215 nm, which is indicative of β-conformation and the absence of helix. The comparative CD results and sequence-based theoretical predictions of structure indicated that the diverse biological effects of cardiotoxins and neurotoxins are not due to gross main chain conformational differences. Changes in local side chain structure within a larger common three-dimensional framework are postulated to be sufficient to confer different binding specificities on cardiotoxins and neurotoxins, resulting in their action on different target membranes.