科研之友
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摘要
Voltage-gated sodium channels (Na(v)s) are large transmembrane proteins that initiate action potential in electrically excitable cells. This central role in the nervous system has made them a primary target for a large number of neurotoxins. Scorpion alpha-neurotoxins bind to Na(v)s with high affinity and slow their inactivation, causing a prolonged action potential. Despite the similarity in their mode of action and three-dimensional structure, alpha-toxins exhibit great variations in selectivity toward insect and mammalian Navs, suggesting differences in the binding surfaces of the toxins and the channels. The scorpion a.-toxin binding site, termed neurotoxin receptor site 3, has been shown to involve the extracellular S3-S4 loop in domain 4 of the alpha-subunit of voltage-gated sodium channels (D4/S3-S4). In-this study, the binding site for peptides corresponding to the D4/S3-S4 loop of the para insect Na-v was mapped on the highly insecticidal cc-neurotoxin, Lqh alpha IT, from the scorpion Leiurus quinquestriatus hebraeus, by following changes in the toxin amide H-1 and N-15 chemical shifts upon binding. This analysis suggests that the five-residue turn (residues (Lq)K8-(Lq)C12) of Lqh alpha IT and those residues in its vicinity interact with the D4/S3-S4 loop of Nav. Residues (Lq)R18, (Lq)W38, and (Lq)A39 could also form a patch contributing to the interaction with D4/S3-S4. Moreover, a new bioactive residue, (Lq)V13, was identified as being important for Na-v binding and specifically for the interaction with the D4/S3-S4 loop. The contribution of (Lq)V13 to Nav binding was further verified by mutagenesis. Future studies involving other extracellular regions of Na(v)s are required for further characterization of the structure of the Lqh alpha IT-Na(v)s binding site.
- 出版日期2008-1-22
