Fine mapping of hydrophobic contacts reassesses the organisation of the first three dystrophin coiled-coil repeats

Abstract : Coiled-coil domain is a structural motif found in proteins crucial for achievement of central biological processes, such as cellular cohesion or neuro-transmission. The coiled-coil fold consists of alpha-helices bundle that can be repeated to form larger filament. Hydrophobic residues, distributed following a regular seven-residues pattern, named heptad pattern, are commonly admitted to be essential for the formation and the stability of canonical coiled-coil repeats. Here we investigated the first three coiled-coil repeats (R1-3) of the central domain of dystrophin, a scaffolding protein in muscle cells whose deficiency leads to Duchenne and Becker Muscular Dystrophies. By an atomic description of the hydrophobic interactions, we highlighted (i) that coiled-coil filament conformational changes are associated to specific patterns of inter-helices hydrophobic contacts, (ii) that inter-repeat hydrophobic interactions determine the behaviour of linker regions including filament kinks, and (iii) that a non-strict conservation of the heptad patterns is leading to a relative plasticity of the dystrophin coiled-coil repeats. These structural features and modulations of the coiled-coil fold could better explain the mechanical properties of the central domain of dystrophin. This contribution to the understanding of the structure-function relationship of dystrophin, and especially of the R1-3 fragment frequently used in the design of protein for gene therapies, should help in the improvement of the strategies for the cure of muscular dystrophies. This article is protected by copyright. All rights reserved.
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Dominique Mias-Lucquin, Angélique Chéron, Elisabeth Le Rumeur, Jean-François Hubert, Olivier Delalande. Fine mapping of hydrophobic contacts reassesses the organisation of the first three dystrophin coiled-coil repeats. Protein Science, Wiley, 2018, 28 (3), pp.561-570. ⟨10.1002/pro.3557⟩. ⟨hal-01975699⟩

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