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Molecular architecture of black widow spider neurotoxins

Author

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  • Minghao Chen

    (Westfälische Wilhelms Universität Münster
    Max Planck Institute of Molecular Physiology)

  • 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
    Max Planck Institute of Molecular Physiology)

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.

Suggested Citation

  • Minghao Chen & Daniel Blum & Lena Engelhard & Stefan Raunser & Richard Wagner & Christos Gatsogiannis, 2021. "Molecular architecture of black widow spider neurotoxins," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26562-8
    DOI: 10.1038/s41467-021-26562-8
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    References listed on IDEAS

    as
    1. Lin Tang & Tamer M. Gamal El-Din & Jian Payandeh & Gilbert Q. Martinez & Teresa M. Heard & Todd Scheuer & Ning Zheng & William A. Catterall, 2014. "Structural basis for Ca2+ selectivity of a voltage-gated calcium channel," Nature, Nature, vol. 505(7481), pages 56-61, January.
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    Cited by:

    1. B. U. Klink & A. Alavizargar & K. S. Kalyankumar & M. Chen & A. Heuer & C. Gatsogiannis, 2024. "Structural basis of α-latrotoxin transition to a cation-selective pore," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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