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

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, Roland Benz, Ana Vale and Nuno M. S. Santos ()
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Johnny Lisboa: Universidade do Porto
Cassilda Pereira: Universidade do Porto
Rute D. Pinto: Universidade do Porto
Inês S. Rodrigues: Universidade do Porto
Liliana M. G. Pereira: Universidade do Porto
Bruno Pinheiro: Universidade do Porto
Pedro Oliveira: Universidade do Porto
Pedro José Barbosa Pereira: Universidade do Porto
Jorge E. Azevedo: 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
Nuno M. S. Santos: Universidade do Porto

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-43054-z

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