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SUMMARY:External Seminar "Structural flexibility of the CyaA toxin is crit
 ical from its secretion to host cell intoxication" by Alexandre Chenal
DTSTART:20260126T100000Z
DTEND:20260126T120000Z
DTSTAMP:20260809T184700Z
UID:indico-event-261@indico.i2bc.paris-saclay.fr
DESCRIPTION:Speaker: Alexandre Chenal Biochemistry of Macromolecular Inte
 ractions unit\, Structural Biology and Chemistry Department\, Institut Pas
 teur\, Paris\, France \nTitle: Structural flexibility of the CyaA toxin i
 s critical from its secretion to host cell intoxication\nAbstract:Bordetel
 la pertussis\, the causative agent of whooping cough\, secretes an adenyla
 te cyclase toxin\, CyaA\, a 1706-residue RTX protein essential for the ear
 ly stages of colonizing the human respiratory tract. Although CyaA-mediate
 d cell intoxication is central to B. pertussis pathogenicity\, this proces
 s has remained poorly understood. Following secretion by a type I secretio
 n system\, CyaA intoxicates human target cells by directly translocating i
 ts catalytic domain (ACD) across the plasma membrane. We show that the Cya
 A translocation region (TR) exhibits an intrinsic propensity to translocat
 e across membranes and to bind endogenous calmodulin (CaM) with high affin
 ity\, thereby favoring ACD translocation. Once in the cytosol\, ACD refold
 s upon CaM binding and catalyzes the production of high levels of cAMP\, u
 ltimately leading to cell death. Our combined biophysical and integrative 
 modeling approaches reveal that the structural flexibility of CyaA is cruc
 ial for its secretion\, folding\, membrane translocation\, and subsequent 
 cell intoxication. These sequential steps rely on disorder-to-order confor
 mational transitions that are finely tuned to the environmental conditions
  CyaA encounters on its journey from the bacterium to the eukaryotic cytop
 lasm. Moreover\, high-resolution structural characterization of CyaA has l
 ong been hindered by its size\, multi-domain organization\, flexibility\, 
 and aggregation propensity. We have recently overcome these challenges and
  obtained the first structural ensembles of both non-acylated and acylated
  CyaA in solution by integrating diverse experimental data with advanced A
 I-guided modeling. Together\, these findings open new perspectives for bas
 ic research and biotechnological applications\, positioning recombinant Cy
 aA proteins as promising antigen delivery vehicles and as a potential prot
 ective antigen for the next generation of pertussis vaccines.\nInvited by 
 Marielle Valerio-Lepiniec\n\nhttps://indico.i2bc.paris-saclay.fr/event/261
 /
LOCATION:B24-N2-315 (I2BC CNRS Gif)
URL:https://indico.i2bc.paris-saclay.fr/event/261/
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