Authors
Gaia Scilironi, Nicolas Carvalho, Jacinthe Frangieh, Corentin Léger, Dorothée Raoux-Barbot, J Iñaki Guijarro, Daniel Ladant, Sophie Cribier, Nicolas Rodriguez, Alexandre Chenal
Published in
Advanced science (Weinheim, Baden-Wurttemberg, Germany). Pages e77133. Aug 21, 2026. Epub Aug 21, 2026.
Abstract
The adenylate cyclase toxin (CyaA) from Bordetella pertussis intoxicates host cells by directly translocating its N-terminal catalytic domain across the plasma membrane; however, the forces driving this unique process remain poorly defined. Here, we dissect the membrane translocation mechanisms of two peptide segments derived from CyaA: P233 and P454 from the catalytic domain and the translocation region, respectively. Both P454 and P233 are calmodulin-binding segments that are sequentially involved in the translocation and activation of the catalytic domain. Using a newly developed Droplet Interface Bilayer (DIB) approach, called DIB-Pipette, which enables direct visualization of peptide transport under controlled membrane potentials, we show that P454 translocates across membranes independently of membrane potential, whereas P233 translocation requires a negative electric membrane potential. Strikingly, covalent coupling of P233 and P454 enables efficient translocation of the resulting peptide even in the absence of a membrane potential. Together, these results suggest that two distinct membrane-active segments within CyaA act cooperatively to promote translocation at the peptide level, revealing an intrinsic mechanism that may contribute to membrane potential-dependent translocation. These findings provide new mechanistic insights into the CyaA cell intoxication process and reveal a multifunctional strategy for protein delivery across membranes.
PMID:
42627250
Bibliographic data and abstract were imported from PubMed on 21 Aug 2026.
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