Identification of a locality in snake venomα-neurotoxins with a singificant compositional similarity to marine snailα-conotoxins: Implications for evolution and structure/activity

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Abstract
α-neurotoxins from elapid snake venoms andα-conotoxins from marine snails bind specifically and with high affinity to nicotinic cholinoceptors. Although both types of toxin are polypeptides, there is more than a fourfold difference in size between the two and no clear sequence homology is evident. A systematic computer search of the three-dimensional structure of erabutoxin b (anα-neurotoxin from the false sea snakeLaticauda semifasciata) was performed to identify the locality that most closely matched the amino acid compositions of the smallerα-conotoxins (from the marine snailsConus magus andConus geographus). The area of greatest similarity centered on residue position 25 of erabutoxin b, a locale that is conserved throughout the snakeα-neurotoxins and their homologues. Six Proteins unrelated to erabutoxin b were compared to theα-conotoxins to show that the extent of the erabutoxin b/α-conotoxin match was too high to be coincidental. Homologues of erabutoxin b, namelyα-cobratoxin fromNaja naja siamensis and cytotoxin VII4 fromNaja mossambica mossambica, were also analyzed. The extent of the matching with theα-conotoxins decreased in the series erabutoxin b>α-cobratoxin>cytotoxin VII4, and this also relates the order of similarity to the pharmacological properties of theα-conotoxins. Theα-conotoxin-like area of the snakeα-neurotoxins is peripheral to the site previously considered important for binding to the cholinoceptor, even though it seems to represent the focus of evolutionary convergence between the two types of neurotoxin. The area of resemblance does, however, have strong associations with the conformational behavior of the snake toxins. Hence, the outcome of this study has important consequences for the current ideas on snakeα-neurotoxin structure/activity relationships and the evolutionary origins of neurotoxicity.