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Mechanism of Tc toxin action revealed in molecular detail

Author

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  • Dominic Meusch

    (Max Planck Institute of Molecular Physiology, 44227 Dortmund, Germany)

  • Christos Gatsogiannis

    (Max Planck Institute of Molecular Physiology, 44227 Dortmund, Germany)

  • Rouslan G. Efremov

    (Max Planck Institute of Molecular Physiology, 44227 Dortmund, Germany)

  • Alexander E. Lang

    (Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Albert-Ludwigs-Universität Freiburg, 79104 Freiburg, Germany)

  • Oliver Hofnagel

    (Max Planck Institute of Molecular Physiology, 44227 Dortmund, Germany)

  • Ingrid R. Vetter

    (Max Planck Institute of Molecular Physiology, 44227 Dortmund, Germany)

  • Klaus Aktories

    (Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Albert-Ludwigs-Universität Freiburg, 79104 Freiburg, Germany
    BIOSS Centre for Biological Signalling Studies, Albert-Ludwigs-Universität Freiburg, 79104 Freiburg, Germany)

  • Stefan Raunser

    (Max Planck Institute of Molecular Physiology, 44227 Dortmund, Germany
    Institute of Chemistry and Biochemistry, Freie Universität Berlin, Thielallee 63, 14195 Berlin, Germany)

Abstract

Tripartite Tc toxin complexes of bacterial pathogens perforate the host membrane and translocate toxic enzymes into the host cell, including in humans. The underlying mechanism is complex but poorly understood. Here we report the first, to our knowledge, high-resolution structures of a TcA subunit in its prepore and pore state and of a complete 1.7 megadalton Tc complex. The structures reveal that, in addition to a translocation channel, TcA forms four receptor-binding sites and a neuraminidase-like region, which are important for its host specificity. pH-induced opening of the shell releases an entropic spring that drives the injection of the TcA channel into the membrane. Binding of TcB/TcC to TcA opens a gate formed by a six-bladed β-propeller and results in a continuous protein translocation channel, whose architecture and properties suggest a novel mode of protein unfolding and translocation. Our results allow us to understand key steps of infections involving Tc toxins at the molecular level.

Suggested Citation

  • Dominic Meusch & Christos Gatsogiannis & Rouslan G. Efremov & Alexander E. Lang & Oliver Hofnagel & Ingrid R. Vetter & Klaus Aktories & Stefan Raunser, 2014. "Mechanism of Tc toxin action revealed in molecular detail," Nature, Nature, vol. 508(7494), pages 61-65, April.
    • Handle: RePEc:nat:nature:v:508:y:2014:i:7494:d:10.1038_nature13015
    DOI: 10.1038/nature13015
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    Cited by:

    1. Alexander Belyy & Philipp Heilen & Philine Hagel & Oliver Hofnagel & Stefan Raunser, 2023. "Structure and activation mechanism of the Makes caterpillars floppy 1 toxin," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    2. Dukas Jurėnas & Leonardo Talachia Rosa & Martial Rey & Julia Chamot-Rooke & Rémi Fronzes & Eric Cascales, 2021. "Mounting, structure and autocleavage of a type VI secretion-associated Rhs polymorphic toxin," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    3. Alexander Belyy & Florian Lindemann & Daniel Roderer & Johanna Funk & Benjamin Bardiaux & Jonas Protze & Peter Bieling & Hartmut Oschkinat & Stefan Raunser, 2022. "Mechanism of threonine ADP-ribosylation of F-actin by a Tc toxin," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    4. Shiheng Liu & Xian Xia & Eric Calvo & Z. Hong Zhou, 2023. "Native structure of mosquito salivary protein uncovers domains relevant to pathogen transmission," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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