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Disorder-to-Order Transition in the CyaA Toxin RTX Domain: Implications for Toxin Secretion

Abstract : The past decade has seen a fundamental reappraisal of the protein structure-to-function paradigm because it became evident that a significant fraction of polypeptides are lacking ordered structures under physiological conditions. Ligand-induced disorder-to-order transition plays a key role in the biological functions of many proteins that contain intrinsically disordered regions. This trait is exhibited by RTX (Repeat in ToXin) motifs found in more than 250 virulence factors secreted by Gram-negative pathogenic bacteria. We have investigated several RTX-containing polypeptides of different lengths, all derived from the Bordetella pertussis adenylate cyclase toxin, CyaA. Using a combination of experimental approaches, we showed that the RTX proteins exhibit the hallmarks of intrinsically disordered proteins in the absence of calcium. This intrinsic disorder mainly results from internal electrostatic repulsions between negatively charged residues of the RTX motifs. Calcium binding triggers a strong reduction of the mean net charge, dehydration and compaction, folding and stabilization of secondary and tertiary structures of the RTX proteins. We propose that the intrinsically disordered character of the RTX proteins may facilitate the uptake and secretion of virulence factors through the bacterial secretion machinery. These results support the hypothesis that the folding reaction is achieved upon protein secretion and, in the case of proteins containing RTX motifs, could be finely regulated by the calcium gradient across bacterial cell wall. OPEN ACCESS Toxins 2015, 7 2 Keywords: adenylate cyclase CyaA toxin; intrinsically disordered proteins (IDP); natively unfolded proteins; repeat in toxin (RTX); calcium-binding proteins; calcium-induced protein folding
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Ana-Cristina Sotomayor-Pé, Daniel Ladant, Alexandre Chenal. Disorder-to-Order Transition in the CyaA Toxin RTX Domain: Implications for Toxin Secretion. Toxins, MDPI, 2014, 7 (1), pp.1-20. ⟨10.3390/toxins7010001⟩. ⟨pasteur-01132650⟩

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