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Journal Articles Scientific Reports Year : 2016

Structural models of intrinsically disordered and calcium-bound folded states of a protein adapted for secretion

Abstract

Many Gram-negative bacteria use Type I secretion systems, T1SS, to secrete virulence factors that contain calcium-binding Repeat-in-ToXin (RTX) motifs. Here, we present structural models of an RTX protein, RD, in both its intrinsically disordered calcium-free Apo-state and its folded calcium-bound Holo-state. Apo-RD behaves as a disordered polymer chain comprising several statistical elements that exhibit local rigidity with residual secondary structure. Holo-RD is a folded multi-domain protein with an anisometric shape. RTX motifs thus appear remarkably adapted to the structural and mechanistic constraints of the secretion process. In the low calcium environment of the bacterial cytosol, Apo-RD is an elongated disordered coil appropriately sized for transport through the narrow secretion machinery. The progressive folding of Holo-RD in the extracellular calcium-rich environment as it emerges form the T1SS may then favor its unidirectional export through the secretory channel. This process is relevant for hundreds of bacterial species producing virulent RTX proteins. Disorder-to-order transitions play a key role in the biological functions of many proteins that contain intrinsically disordered regions 1,2. Structural disorder predictors estimate that bacterial, viral and eukaryotic proteins contain large disordered regions, mainly involved in cell signaling, physiological and patho-physiological processes, including cancer and neurodegenerative diseases. In many instances, intrinsically disordered proteins adopt a defined three-dimensional structure after binding to ligands, and thus serve as " molecular switches " to control the biological functions of the corresponding proteins and/ or ligands. We recently characterized a novel class of intrinsically disordered polypeptides that are constituted by so-called Repeat-in-ToXin (RTX) motifs found in many important virulence factors, widely distributed among Gram-negative bacterial species 3,4. RTX motifs are calcium-binding, nona-peptide sequences, that are repeated in a tandem fashion (from 6 to more than 50) and fold in the presence of calcium into a parallel β-roll structure 5. Although RTX-containing proteins display a variety of biological functions, they all require calcium binding to carry out their functions and they are all secreted by a type 1 secretion system (T1SS) 6–8. The fact that most RTX proteins are secreted by the T1SS suggests that the RTX motifs are key structural features to favor efficient secretion through the T1SS pathway. One of the best-characterized members of the RTX family is the adenylate cyclase (CyaA) toxin from Bordetella pertussis, the causative agent of whooping cough. CyaA is able to invade eukaryotic cells where
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pasteur-01406897 , version 1 (01-12-2016)

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Darragh P. O’brien, Belen Hernandez, Dominique Durand, Véronique Hourdel, Ana-Cristina Sotomayor-Pérez, et al.. Structural models of intrinsically disordered and calcium-bound folded states of a protein adapted for secretion. Scientific Reports, 2016, 5, ⟨10.1038/srep14223⟩. ⟨pasteur-01406897⟩
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