The insecticidal neurotoxin Aps III is an atypical knottin peptide that potently blocks insect voltage-gated sodium channels

N S Bende; E Kang; Volker Herzig; F Bosmans; G M Nicholson; M Mobli; G F King

doi:10.1016/j.bcp.2013.02.030

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The insecticidal neurotoxin Aps III is an atypical knottin peptide that potently blocks insect voltage-gated sodium channels

Journal article

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The insecticidal neurotoxin Aps III is an atypical knottin peptide that potently blocks insect voltage-gated sodium channels

N S Bende, E Kang, Volker Herzig, F Bosmans, G M Nicholson, M Mobli and G F King

Biochemical Pharmacology, Vol.85(10), pp.1542-1554

2013

DOI: https://doi.org/10.1016/j.bcp.2013.02.030

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Abstract

voltage-gated sodium channel

neurotoxin

spider-venom peptide

pore blocker

gating modifier

inhibitor cystine knot

One of the most potent insecticidal venom peptides described to date is Aps III from the venom of the trapdoor spider Apomastus schlingeri. Aps III is highly neurotoxic to lepidopteran crop pests, making it a promising candidate for bioinsecticide development. However, its disulfide-connectivity, three-dimensional structure, and mode of action have not been determined. Here we show that recombinant Aps III (rAps III) is an atypical knottin peptide; three of the disulfide bridges form a classical inhibitor cystine knot motif while the fourth disulfide acts as a molecular staple that restricts the flexibility of an unusually large β hairpin loop that often houses the pharmacophore in this class of toxins. We demonstrate that the irreversible paralysis induced in insects by rAps III results from a potent block of insect voltage-gated sodium channels. Channel block by rAps III is voltage-independent insofar as it occurs without significant alteration in the voltage-dependence of channel activation or steady-state inactivation. Thus, rAps III appears to be a pore blocker that plugs the outer vestibule of insect voltage-gated sodium channels. This mechanism of action contrasts strikingly with virtually all other sodium channel modulators isolated from spider venoms that act as gating modifiers by interacting with one or more of the four voltage-sensing domains of the channel.

Details

Title: The insecticidal neurotoxin Aps III is an atypical knottin peptide that potently blocks insect voltage-gated sodium channels
Authors: N S Bende (Author) - University of Queensland
E Kang (Author) - University of Technology, Sydney
Volker Herzig (Author) - University of Queensland
F Bosmans (Author) - Johns Hopkins University, United States
G M Nicholson (Author) - University of Technology, Sydney
M Mobli (Author) - University of Queensland
G F King (Author) - University of Queensland
Publication details: Biochemical Pharmacology, Vol.85(10), pp.1542-1554
Publisher: Lippincott Williams & Wilkins
Date published: 2013
DOI: 10.1016/j.bcp.2013.02.030
ISSN: 0006-2952
Organisation Unit: School of Science and Engineering - Legacy; University of the Sunshine Coast, Queensland; School of Science, Technology and Engineering; Centre for Bioinnovation
Language: English
Record Identifier: 99450980702621
Output Type: Journal article

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Collaboration types: Domestic collaboration; International collaboration
Web Of Science research areas: Pharmacology & Pharmacy

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