Molecular architecture of black widow spider neurotoxins

Minghao Chen, Daniel Blum, Lena Engelhard, Stefan Raunser, Richard Wagner and Christos Gatsogiannis ()
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Minghao Chen: Westfälische Wilhelms Universität Münster
Daniel Blum: Jacobs University Bremen
Lena Engelhard: Max Planck Institute of Molecular Physiology
Stefan Raunser: Max Planck Institute of Molecular Physiology
Richard Wagner: Jacobs University Bremen
Christos Gatsogiannis: Westfälische Wilhelms Universität Münster

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Latrotoxins (LaTXs) are presynaptic pore-forming neurotoxins found in the venom of Latrodectus spiders. The venom contains a toxic cocktail of seven LaTXs, with one of them targeting vertebrates (α-latrotoxin (α-LTX)), five specialized on insects (α, β, γ, δ, ε- latroinsectotoxins (LITs), and one on crustaceans (α-latrocrustatoxin (α-LCT)). LaTXs bind to specific receptors on the surface of neuronal cells, inducing the release of neurotransmitters either by directly stimulating exocytosis or by forming Ca2+-conductive tetrameric pores in the membrane. Despite extensive studies in the past decades, a high-resolution structure of a LaTX is not yet available and the precise mechanism of LaTX action remains unclear. Here, we report cryoEM structures of the α-LCT monomer and the δ-LIT dimer. The structures reveal that LaTXs are organized in four domains. A C-terminal domain of ankyrin-like repeats shields a central membrane insertion domain of six parallel α-helices. Both domains are flexibly linked via an N-terminal α-helical domain and a small β-sheet domain. A comparison between the structures suggests that oligomerization involves major conformational changes in LaTXs with longer C-terminal domains. Based on our data we propose a cyclic mechanism of oligomerization, taking place prior membrane insertion. Both recombinant α-LCT and δ-LIT form channels in artificial membrane bilayers, that are stabilized by Ca2+ ions and allow calcium flux at negative membrane potentials. Our comparative analysis between α-LCT and δ-LIT provides first crucial insights towards understanding the molecular mechanism of the LaTX family.

Date: 2021
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DOI: 10.1038/s41467-021-26562-8

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