Résumé :
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Duchenne muscular dystrophy (DMD) is caused by the genetic deficit of dystrophin, a large cytoskeleton protein of skeletal muscle included in the DGC sarcolemmalcomplex. Dystrophin complete deficit in DMD leads to cell degeneration induced by frequent sarcolemma ruptures. Dystrophin is a huge protein of 427 kDa where 85% ofthe protein is a large central domain constituted by 24 repeats sharing high structural homology with spectrin-like repeats and interacting with partners such as n-nitrousoxide synthase, F-actin, microtubules and lipids. However, in absence of any high resolution structural data of the repeats, the molecular basis of the dystrophin functionand interactions is not deciphered and numerous questions still remained. In this context, we propose a computational study of all the dystrophin repeats of the centralrod domain based on the homology modeling with spectrin repeats and the analysis of their surface properties. Four representative tandem repeats were then furtherstudied by molecular dynamics simulation. The repeats appeared as coiled-coils and their surface properties are highly diverse and specific in terms of electrostaticsand hydrophobicity making each of them unique. Molecular dynamics simulations revealed specific flexibility or bending properties of several inter-repeat linkers whichmay constitute small novel "junctions" between sub-domains. We finally evidenced an ordered succession of repeats and suggested a novel view of the central roddomain. It is sub-divided in seven structural sub-domains, each of them potentially playing a specific role. This new view of dystrophin central rod domain may supportthe Becker muscular dystrophy heterogeneity of severity where truncated dystrophins are expressed. Similarly, gene therapy may benefit from our work for the designtof he truncated dystrophin molecules to be expressed in DMD patients either by gene replacement or exon skipping. Our models also constitute a rationale molecularplat-form for initiating docking studies with atomic structures of the known partners such as nNOS, F-actin as well as with lipids and to guide site-directed mutagenesisto more precisely and experimentally define the surface involved in the interactions.
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