• Le 08 mars 2019

" Structural flexibility of the CyaA toxin is crucial for its secretion, folding and host cell hijacking "

Presented by Alexandre CHENAL & Alexis VOEGELE, invité par Michel De Waard (Eq IIb)
Alexandre CHENAL est Directeur de recherche et chef de groupe, Alexis VOEGELE est son doctorant.
Unité Biochimie des Interactions Macromoléculaires
INSTITUT PASTEUR, Département Biologie Structurale et Chimie, UMR CNRS 3528 - Biologie Structurale & Agents Infectieux

Abstract

Bordetella pertussis, the causative agent of whooping cough, secretes an adenylate cyclase toxin (CyaA, an RTX protein of 1706 residues) that plays an essential role in the early stages of respiratory tract colonization. The cell intoxication process of CyaA is still poorly understood. After its secretion through a type 1 secretion system, CyaA intoxicates human cells via a direct translocation of its catalytic domain (AC) across the plasma membrane. Once in the cytosol, AC binds to calmodulin (CaM) and catalyses high amounts of cAMP, leading to cell death. Our results, based on a combination of biophysical approaches, including SAXS, HDX-MS and SR-CD, illustrate how the structural flexibility of CyaA is essential for its secretion, its folding, its translocation across membranes into target cells, and its activation by CaM. All of these steps involve disorder-to-order structural transitions that are finely tuned to the environmental conditions that CyaA successively experiences along its journey from the bacterium to the eukaryotic cell cytoplasm. These data open up new avenues for both basic science, as well as biotechnological applications of recombinant CyaA as an antigen delivery vehicle, and as a potential protective antigen in the next-generation of pertussis vaccines.


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