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Membrane-Active Properties of an Amphitropic Peptide from the CyaA Toxin Translocation Region

Abstract : The adenylate cyclase toxin CyaA is involved in the early stages of infection by Bordetella pertussis, the causative agent of whooping cough. CyaA intoxicates target cells by a direct translocation of its catalytic domain (AC) across the plasma membrane and produces supraphysiological levels of cAMP, leading to cell death. The molecular process of AC translocation remains largely unknown, however. We have previously shown that deletion of residues 375-485 of CyaA selectively abrogates AC translocation into eukaryotic cells. We further identified within this "translocation region" (TR), P454 (residues 454-484), a peptide that exhibits membrane-active properties, i.e., is able to bind and permeabilize lipid vesicles. Here, we analyze various sequences from CyaA predicted to be amphipatic and show that although several of these peptides can bind membranes and adopt a helical conformation, only the P454 peptide is able to permeabilize membranes. We further characterize the contributions of the two arginine residues of P454 to membrane partitioning and permeabilization by analyzing the peptide variants in which these residues are substituted by different amino acids (e.g., A, K, Q, and E). Our data shows that both arginine residues significantly contribute, although diversely, to the membrane-active properties of P454, i.e., interactions with both neutral and anionic lipids, helix formation in membranes, and disruption of lipid bilayer integrity. These results are discussed in the context of the translocation process of the full-length CyaA toxin.
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Alexis Voegele, Orso Subrini, Nicolas Sapay, Daniel Ladant, Alexandre Chenal. Membrane-Active Properties of an Amphitropic Peptide from the CyaA Toxin Translocation Region. Toxins, MDPI, 2017, 9 (11), pp.369. ⟨10.3390/toxins9110369⟩. ⟨pasteur-02882330⟩

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