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Calmodulin fishing with a structurally disordered bait triggers CyaA catalysis

Abstract : Once translocated into the cytosol of target cells, the catalytic domain (AC) of the adenylate cyclase toxin (CyaA), a major virulence factor of Bordetella pertussis, is potently activated by binding calmodulin (CaM) to produce supraphysiological levels of cAMP, inducing cell death. Using a combination of small-angle X-ray scattering (SAXS), hydrogen/deuterium exchange mass spectrometry (HDX-MS), and synchrotron radiation circular dichroism (SR-CD), we show that, in the absence of CaM, AC exhibits significant structural disorder, and a 75-residue-long stretch within AC undergoes a disorder-to-order transition upon CaM binding. Beyond this local folding, CaM binding induces long-range allosteric effects that stabilize the distant catalytic site, whilst preserving catalytic loop flexibility. We propose that the high enzymatic activity of AC is due to a tight balance between the CaM-induced decrease of structural flexibility around the catalytic site and the preservation of catalytic loop flexibility, allowing for fast substrate binding and product release. The CaM-induced dampening of AC conformational disorder is likely relevant to other CaM-activated enzymes.
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https://hal.archives-ouvertes.fr/hal-02294928
Contributor : Marie-Claude Serre <>
Submitted on : Wednesday, April 28, 2021 - 6:16:34 PM
Last modification on : Thursday, May 6, 2021 - 10:51:43 AM

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Darragh P. O'Brien, Dominique Durand, Alexis Voegele, Véronique Hourdel, Marilyne Davi, et al.. Calmodulin fishing with a structurally disordered bait triggers CyaA catalysis. PLoS Biology, Public Library of Science, 2017, 15 (12), pp.e2004486. ⟨10.1371/journal.pbio.2004486⟩. ⟨hal-02294928⟩

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