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Unconventional structure and mechanisms for membrane interaction and translocation of the NF-κB-targeting toxin AIP56

Author

Listed:
  • Johnny Lisboa

    (Universidade do Porto
    Universidade do Porto)

  • Cassilda Pereira

    (Universidade do Porto
    Universidade do Porto)

  • Rute D. Pinto

    (Universidade do Porto)

  • Inês S. Rodrigues

    (Universidade do Porto
    Universidade do Porto)

  • Liliana M. G. Pereira

    (Universidade do Porto)

  • Bruno Pinheiro

    (Universidade do Porto
    Universidade do Porto
    Instituto de Ciências Biomédicas Abel Salazar - Universidade do Porto)

  • Pedro Oliveira

    (Universidade do Porto)

  • Pedro José Barbosa Pereira

    (Universidade do Porto
    Universidade do Porto)

  • Jorge E. Azevedo

    (Universidade do Porto
    Universidade do Porto
    Universidade do Porto)

  • Dominique Durand

    (Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC))

  • Roland Benz

    (Constructor University)

  • Ana Vale

    (Universidade do Porto
    Universidade do Porto)

  • Nuno M. S. Santos

    (Universidade do Porto
    Universidade do Porto)

Abstract

Bacterial AB toxins are secreted key virulence factors that are internalized by target cells through receptor-mediated endocytosis, translocating their enzymatic domain to the cytosol from endosomes (short-trip) or the endoplasmic reticulum (long-trip). To accomplish this, bacterial AB toxins evolved a multidomain structure organized into either a single polypeptide chain or non-covalently associated polypeptide chains. The prototypical short-trip single-chain toxin is characterized by a receptor-binding domain that confers cellular specificity and a translocation domain responsible for pore formation whereby the catalytic domain translocates to the cytosol in an endosomal acidification-dependent way. In this work, the determination of the three-dimensional structure of AIP56 shows that, instead of a two-domain organization suggested by previous studies, AIP56 has three-domains: a non-LEE encoded effector C (NleC)-like catalytic domain associated with a small middle domain that contains the linker-peptide, followed by the receptor-binding domain. In contrast to prototypical single-chain AB toxins, AIP56 does not comprise a typical structurally complex translocation domain; instead, the elements involved in translocation are scattered across its domains. Thus, the catalytic domain contains a helical hairpin that serves as a molecular switch for triggering the conformational changes necessary for membrane insertion only upon endosomal acidification, whereas the middle and receptor-binding domains are required for pore formation.

Suggested Citation

  • Johnny Lisboa & Cassilda Pereira & Rute D. Pinto & Inês S. Rodrigues & Liliana M. G. Pereira & Bruno Pinheiro & Pedro Oliveira & Pedro José Barbosa Pereira & Jorge E. Azevedo & Dominique Durand & Rola, 2023. "Unconventional structure and mechanisms for membrane interaction and translocation of the NF-κB-targeting toxin AIP56," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43054-z
    DOI: 10.1038/s41467-023-43054-z
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