title: Dual chaperone role of the C-terminal propeptide in folding and oligomerization of the pore-forming toxin aerolysin.
abstract: Throughout evolution, one of the most ancient forms of aggression between cells or organisms has been the production of proteins or peptides affecting the permeability of the target cell membrane. This class of virulence factors includes the largest family of bacterial toxins, the pore-forming toxins (PFTs). PFTs are bistable structures that can exist in a soluble and a transmembrane state. It is unclear what drives biosynthetic folding towards the soluble state, a requirement that is essential to protect the PFT-producing cell. Here we have investigated the folding of aerolysin, produced by the human pathogen Aeromonas hydrophila, and more specifically the role of the C-terminal propeptide (CTP). By combining the predictive power of computational techniques with experimental validation using both structural and functional approaches, we show that the CTP prevents aggregation during biosynthetic folding. We identified specific residues that mediate binding of the CTP to the toxin. We show that the CTP is crucial for the control of the aerolysin activity, since it protects individual subunits from aggregation within the bacterium and later controls assembly of the quaternary pore-forming complex at the surface of the target host cell. The CTP is the first example of a C-terminal chain-linked chaperone with dual function.
authors.affiliation: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Ioan
authors.initials: I
authors.lastname: Iacovache
authors.forename: Matteo T
authors.initials: MT
authors.lastname: Degiacomi
authors.forename: Lucile
authors.initials: L
authors.lastname: Pernot
authors.forename: Sylvia
authors.initials: S
authors.lastname: Ho
authors.forename: Marc
authors.initials: M
authors.lastname: Schiltz
authors.forename: Matteo
authors.initials: M
authors.lastname: Dal Peraro
authors.forename: F Gisou
authors.initials: FG
authors.lastname: van der Goot
mesh_terms: D016980:Aeromonas hydrophila / Q000235:genetics / Q000378:metabolism*; D001427:Bacterial Toxins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D052899:Pore Forming Cytotoxic Proteins / Q000235:genetics / Q000378:metabolism*; D017510:Protein Folding; D055503:Protein Multimerization / Q000502:physiology*; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary
chemical_list: D001427:Bacterial Toxins; D018832:Molecular Chaperones; D052899:Pore Forming Cytotoxic Proteins; D011498:Protein Precursors; C032676:aerolysin