Dystrophin Hot-Spot Mutants Leading to Becker Muscular Dystrophy Insert More Deeply into Membrane Models than the Native Protein.

Dystrophin (DYS) is a membrane skeleton protein whose mutations lead to lethal Duchenne muscular dystrophy or to the milder Becker muscular dystrophy (BMD). One third of BMD “in-frame” exon deletions are located in the region that codes for spectrin-like repeats R16 to R21. We focused on four prevalent mutated proteins deleted in this area (called RΔ45–47, RΔ45–48, RΔ45–49, and RΔ45–51 according to the deleted exon numbers), analyzing protein/membrane interactions. Two of the mutants, RΔ45–48 and RΔ45–51, led to mild pathologies and displayed a similar triple coiled-coil structure as the full-length DYS R16–21, whereas the two others, RΔ45–47 and RΔ45–49, induced more severe pathologies and showed “fractional” structures unrelated to the normal one. To explore lipid packing, small unilamellar liposomes (SUVs) and planar monolayers were used at various initial surface pressures. The dissociation constants determined by microscale thermophoresis (MST) were much higher for the full-length DYS R161–21 than fo...