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Mechanism of threonine ADP-ribosylation of F-actin by a Tc toxin

Author

Listed:
  • Alexander Belyy

    (Max Planck Institute of Molecular Physiology)

  • Florian Lindemann

    (Leibniz-Forschungsinstitut für Molekulare Pharmakologie)

  • Daniel Roderer

    (Max Planck Institute of Molecular Physiology
    Leibniz-Forschungsinstitut für Molekulare Pharmakologie)

  • Johanna Funk

    (Max Planck Institute of Molecular Physiology)

  • Benjamin Bardiaux

    (Université Paris Cité, CNRS UMR3528, Structural Bioinformatics Unit)

  • Jonas Protze

    (Leibniz-Forschungsinstitut für Molekulare Pharmakologie)

  • Peter Bieling

    (Max Planck Institute of Molecular Physiology)

  • Hartmut Oschkinat

    (Leibniz-Forschungsinstitut für Molekulare Pharmakologie)

  • Stefan Raunser

    (Max Planck Institute of Molecular Physiology)

Abstract

Tc toxins deliver toxic enzymes into host cells by a unique injection mechanism. One of these enzymes is the actin ADP-ribosyltransferase TccC3, whose activity leads to the clustering of the cellular cytoskeleton and ultimately cell death. Here, we show in atomic detail how TccC3 modifies actin. We find that the ADP-ribosyltransferase does not bind to G-actin but interacts with two consecutive actin subunits of F-actin. The binding of TccC3 to F-actin occurs via an induced-fit mechanism that facilitates access of NAD+ to the nucleotide binding pocket. The following nucleophilic substitution reaction results in the transfer of ADP-ribose to threonine-148 of F-actin. We demonstrate that this site-specific modification of F-actin prevents its interaction with depolymerization factors, such as cofilin, which impairs actin network turnover and leads to steady actin polymerization. Our findings reveal in atomic detail a mechanism of action of a bacterial toxin through specific targeting and modification of F-actin.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31836-w
    DOI: 10.1038/s41467-022-31836-w
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    References listed on IDEAS

    as
    1. Alexander Belyy & Felipe Merino & Undine Mechold & Stefan Raunser, 2021. "Mechanism of actin-dependent activation of nucleotidyl cyclase toxins from bacterial human pathogens," Nature Communications, Nature, vol. 12(1), pages 1-9, December.
    2. Jason N. Busby & Santosh Panjikar & Michael J. Landsberg & Mark R. H. Hurst & J. Shaun Lott, 2013. "The BC component of ABC toxins is an RHS-repeat-containing protein encapsulation device," Nature, Nature, vol. 501(7468), pages 547-550, September.
    3. Daniel Roderer & Felix Bröcker & Oleg Sitsel & Paulina Kaplonek & Franziska Leidreiter & Peter H. Seeberger & Stefan Raunser, 2020. "Glycan-dependent cell adhesion mechanism of Tc toxins," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    4. Johanna Funk & Felipe Merino & Matthias Schaks & Klemens Rottner & Stefan Raunser & Peter Bieling, 2021. "A barbed end interference mechanism reveals how capping protein promotes nucleation in branched actin networks," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    5. Daniel Roderer & Evelyn Schubert & Oleg Sitsel & Stefan Raunser, 2019. "Towards the application of Tc toxins as a universal protein translocation system," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    6. 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.
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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.

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