Dystrophin is a large intracellular protein that prevents sarcolemmal ruptures by providing a mechanical link between the intracellular actin cytoskeleton and the transmembrane dystroglycan complex. Dystrophin deficiency leads to the severe muscle wasting disease Duchenne Muscular Dystrophy and the milder allelic variant, Becker Muscular Dystrophy (DMD and BMD). Previous work has shown that concomitant interaction of the actin binding domain 2 (ABD2) comprising spectrin like repeats 11 to 15 (R11-15) of the central domain of dystrophin, with both actin and membrane lipids, can greatly increase membrane stiffness. Based on a combination of SAXS and SANS measurements, mass spectrometry analysis of cross-linked complexes and interactive low-resolution simulations, we explored in vitro the molecular properties of dystrophin that allow the formation of ABD2-F-actin and ABD2-membrane model complexes. In dystrophin we identified two subdomains interacting with F-actin, one located in R11 and a neighbouring region in R12 and another one in R15, while a single lipid binding domain was identified at the C-terminal end of R12. Relative orientations of the dystrophin central domain with F-actin and a membrane model were obtained from docking simulation under experimental constraints. SAXS-based models were then built for an extended central subdomain from R4 to R19, including ABD2. Overall results are compatible with a potential F-actin/dystrophin/membrane lipids ternary complex. Our description of this selected part of the dystrophin associated complex bridging muscle cell membrane and cytoskeleton opens the way to a better understanding of how cell muscle scaffolding is maintained through this essential protein.

中文翻译：

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肌营养不良蛋白的中央结构域如何作用以将F-肌动蛋白桥接至肌膜脂质。

肌营养不良蛋白是一种大的细胞内蛋白，可通过在细胞内肌动蛋白细胞骨架与跨膜营养不良复合物之间提供机械连接来防止肌膜破裂。肌营养不良蛋白缺乏症会导致严重的肌肉萎缩性疾病杜兴氏肌营养不良症和较轻的等位基因变体贝克尔肌营养不良症（DMD和BMD）。先前的工作表明，肌动蛋白结合结构域2（ABD2）包含肌营养不良蛋白中央结构域的重复序列11至15（R11-15）的血影蛋白，与肌动蛋白和膜脂同时发生相互作用，可以大大提高膜的硬度。基于SAXS和SANS测量的结合，交联复合物的质谱分析和交互式低分辨率模拟，我们在体外探索了肌营养不良蛋白的分子特性，从而可以形成ABD2-F-肌动蛋白和ABD2膜模型复合物。在肌营养不良蛋白中，我们鉴定了两个与F-肌动蛋白相互作用的亚结构域，一个位于R11和R12的邻近区域，另一个位于R15，而在R12的C末端鉴定了一个脂质结合域。在实验的约束下，通过对接模拟获得了肌营养不良蛋白中央结构域与F-肌动蛋白和膜模型的相对取向。然后为从R4到R19的扩展中央子域（包括ABD2）构建了基于SAXS的模型。总体结果与潜在的F-肌动蛋白/肌营养不良蛋白/膜脂质三元复合物相容。