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TitleCalmodulin fishing with a structurally disordered bait triggers CyaA catalysis.
Journal, issue, pagesPLoS Biol, Vol. 15, Issue 12, Page e2004486, Year 2017
Publish dateDec 29, 2017
AuthorsDarragh P O'Brien / Dominique Durand / Alexis Voegele / Véronique Hourdel / Marilyne Davi / Julia Chamot-Rooke / Patrice Vachette / Sébastien Brier / Daniel Ladant / Alexandre Chenal /
PubMed AbstractOnce 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 ...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.
External linksPLoS Biol / PubMed:29287065 / PubMed Central
MethodsSAS (X-ray synchrotron)
Structure data

SASDCK9:
Catalytic domain (AC) of B. Pertussis Adenylate Cyclase Toxin (CyaA)
Method: SAXS/SANS

SASDCL9:
Catalytic domain (AC) of B. Pertussis Adenylate Cyclase Toxin (CyaA) in complex with calmodulin
Method: SAXS/SANS

Source
  • Bordetella pertussis (strain tohama i / atcc baa-589 / nctc 13251) (bacteria)
  • Homo sapiens (human)

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