Synthesis, solution structure and phyla-selectivity of a spider δ-toxin that slows inactivation of specific voltage-gated sodium channel subtypes

Publisher:
Amer Soc Biochemistry Molecular Biology Inc
Publication Type:
Journal article
Citation:
Billen Bert et al. 2009, 'Synthesis, solution structure and phyla-selectivity of a spider δ-toxin that slows inactivation of specific voltage-gated sodium channel subtypes', Amer Soc Biochemistry Molecular Biology Inc, vol. 284, no. 36, pp. 24568-24582.
Issue Date:
2009
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Magi 4, now renamed delta-hexatoxin-Mg1a, is a 43-residue neurotoxic peptide from the venom of the hexathelid Japanese funnel-web spider (Macrothele gigas) with homology to delta-hexatoxins from Australian funnel-web spiders. It binds with high affinity to receptor site 3 on insect voltage-gated sodium (Na-V) channels but, unlike delta-hexatoxins, does not compete for the related site 3 in rat brain despite being previously shown to be lethal by intracranial injection. To elucidate differences in Na-V channel selectivity, we have undertaken the first characterization of a peptide toxin on a broad range of mammalian and insect Na-V channel subtypes showing that delta-hexatoxin-Mg1a selectively slows channel inactivation of mammalian Na(V)1.1, Na(V)1.3, and Na(V)1.6 but more importantly shows higher affinity for insect Na(V)1 (para) channels. Consequently, delta-hexatoxin-Mg1a induces tonic repetitive firing of nerve impulses in insect neurons accompanied by plateau potentials. In addition, we have chemically synthesized and folded delta-hexatoxin-Mg1a, ascertained the bonding pattern of the four disulfides, and determined its three-dimensional solution structure using NMR spectroscopy. Despite modest sequence homology, we show that key residues important for the activity of scorpion alpha-toxins and delta-hexatoxins are distributed in a topologically similar manner in delta-hexatoxin-Mg1a. However, subtle differences in the toxin surfaces are important for the novel selectivity of delta-hexatoxin-Mg1a for certain mammalian and insect Na-V channel subtypes. As such, delta-hexatoxin-Mg1a provides us with a specific tool with which to study channel structure and function and determinants for phylum-and tissue-specific activity.
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