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Interaction dystrophine-membrane : structure 3D de fragments de la dystrophine en présence de phospholipides

Abstract : Dystrophin is a large peripheral membrane protein that provides a supporting role for sarcolemma allowing muscle cells to withstand the mechanical stresses generated during contraction / elongation processes. Genetic mutations lead to dystrophin production in truncated form or even to a total deficit in the protein leading to severe myopathies currently incurable. Designing adapted therapies requires a huge knowledge of the biological role of dystrophin. Using a structure / function approach, our aim is to determine the molecular bases involved in the interactions of dystrophin with the membrane lipids of the sarcolemma. Using a small-angle scattering approach (SAXS and SANS) combined with molecular modeling, we show that bicelles constitute a versatile membrane mimic that is particularly adapted to analyze the structure of membrane proteins. This original methodological development was exploited to characterize the structural changes undergone by dystrophin upon lipid binding. We highlight in particular that the lipid binding induces a significant opening of the coiled-coil structure of the repeat 1 of the central domain and, in conclusion, we propose an all-atom model of the protein bound to a bicelle. These thesis works (i) constitute a significant methodological contribution for the study of membrane proteins, (ii) contribute to a better understanding of the biological role of dystrophin for therapies dedicated to patients with myopathies.
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Submitted on : Thursday, July 5, 2018 - 4:59:05 PM
Last modification on : Thursday, January 14, 2021 - 11:22:58 AM
Long-term archiving on: : Tuesday, October 2, 2018 - 3:34:40 AM


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  • HAL Id : tel-01831209, version 1


Raphael dos Santos Morais. Interaction dystrophine-membrane : structure 3D de fragments de la dystrophine en présence de phospholipides. Médecine humaine et pathologie. Université Rennes 1, 2017. Français. ⟨NNT : 2017REN1B062⟩. ⟨tel-01831209⟩



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