Structure and function of delta-atracotoxins: lethal neurotoxins targeting the voltage-gated sodium channel.
Delta-atracotoxins (delta-ACTX), isolated from the venom of Australian funnel-web spiders, are responsible for the potentially lethal envenomation syndrome seen following funnel-web spider envenomation. They are 42-residue polypeptides with four disulfides and an "inhibitor cystine-knot" motif with structural but not sequence homology to a variety of other spider and marine snail toxins. Delta-atracotoxins induce spontaneous repetitive firing and prolongation of action potentials resulting in neurotransmitter release from somatic and autonomic nerve endings. This results from a slowing of voltage-gated sodium channel inactivation and a hyperpolarizing shift of the voltage-dependence of activation. This action is due to voltage-dependent binding to neurotoxin receptor site-3 in a similar, but not identical, fashion to scorpion alpha-toxins and sea anemone toxins. Unlike other site-3 neurotoxins, however, delta-ACTX bind with high affinity to both cockroach and mammalian sodium channels but low affinity to locust sodium channels. At present the pharmacophore of delta-ACTX is unknown but is believed to involve a number of basic residues distributed in a topologically similar manner to scorpion alpha-toxins and sea anemone toxins despite distinctly different protein scaffolds. As such, delta-ACTX provide us with specific tools with which to study sodium channel structure and function and determinants for phyla- and tissue-specific actions of neurotoxins interacting with site-3.
Nicholson
Graham M
GM
Neurotoxin Research Group, Department of Heath Sciences, University of Technology, Sydney, PO Box 123, Broadway, NSW 2007, Australia. graham.nicholson@uts.edu.au
Little
Michelle J
MJ
Birinyi-Strachan
Liesl C
LC
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001315:Australia; D004594:Electrophysiology; D008969:Molecular Sequence Data; D009498:Neurotoxins / Q000378:metabolism*; D010455:Peptides; D011487:Protein Conformation; D016415:Sequence Alignment; D015222:Sodium Channels / Q000378:metabolism*; D013111:Spider Venoms / Q000737:chemistry* / Q000378:metabolism*; D013112:Spiders / Q000737:chemistry* / Q000145:classification; D013329:Structure-Activity Relationship; D013569:Synapses / Q000378:metabolism*
D009498:Neurotoxins; D010455:Peptides; D015222:Sodium Channels; D013111:Spider Venoms