A chimeric scorpion α-toxin displaysde novoelectrophysiological properties similar to those of α-like toxins

BotXIV and LqhαIT are two structurally related long chain scorpion α-toxins that inhibit sodium current inactivation in excitable cells. However, while LqhαIT from Leiurus quinquestriatus hebraeus is classified as a true and strong insect α-toxin, BotXIV from Buthus occitanus tunetanus is characterized by moderate biological activities. To assess the possibility that structural differences between these two molecules could reflect the localization of particular functional topographies, we compared their sequences. Three structurally deviating segments located in three distinct and exposed loops were identified. They correspond to residues 8–10, 19–22, and 38–43. To evaluate their functional role, three BotXIV/LqhαIT chimeras were designed by transferring the corresponding LqhαIT sequences into BotXIV. Structural and antigenic characterizations of the resulting recombinant chimera show that BotXIV can accommodate the imposed modifications, confirming the structural flexibility of that particular α/β fold. Interestingly, substitution of residues 8–10 yields to a new electrophysiological profile of the corresponding variant, partially comparable to that one of α-like scorpion toxins. Taken together, these results suggest that even limited structural deviations can reflect functional diversity, and also that the structure–function relationships between insect α-toxins and α-like scorpion toxins are probably more complex than expected.