Séminaire - Alexandre Chenal

Alexandre Chenal, Biochemistry of Macromolecular Interactions Unit, Department of Structural Biology and Chemistry, Institut Pasteur, CNRS UMR3528, Paris, invité par Marie Galloux

Structural flexibility of Bordetella pertussis CyaA toxin is critical from secretion to host cell hijacking

Jeudi 30 janvier 2025, à 11h

Abstract

Bordetella pertussis, the causative agent of whooping cough, secretes an adenylate cyclase toxin (CyaA), a 1706-residue RTX protein. CyaA plays an essential role in the early stages of colonizing the human respiratory tract, yet the mechanism of cell intoxication by CyaA remains poorly understood. Following secretion by a type I secretion system, CyaA intoxicates human cells by translocating its catalytic domain (ACD) directly across the plasma membrane. Once in the cytosol, ACD binds to calmodulin (CaM) and catalyzes the production of high levels of cAMP, ultimately leading to cell death. Our results, based on a combination of biophysical approaches, illustrate that the structural flexibility of CyaA is crucial for its secretion, folding, translocation across the plasma membrane, and subsequent cell intoxication. These processes involve disorder-to-order conformational transitions that are finely tuned to the environmental conditions CyaA encounters on its journey from the bacterium to the cytoplasm of the eukaryotic cell. These results open new perspectives for both basic research and biotechnological applications, positioning recombinant CyaA proteins as a promising antigen delivery vehicle and as a potential protective antigen for the next generation of pertussis vaccines.

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