Université de Rennes1 , 35700 Rennes, France.
Biochemistry. 2013 Nov 5;52(44):7777-84. doi: 10.1021/bi400794p. Epub 2013 Oct 25.
Dystrophin is a large skeletal muscle protein located at the internal face of the plasma membrane and interacting with membrane phospholipids and a number of cytosolic proteins. Binding of neuronal nitric oxide synthase (nNOS) to dystrophin appears to be crucial for exercise-induced increases in blood supply in muscle cells. By contrast, utrophin, the developmental homologous protein of dystrophin, does not display nNOS interaction. Recent in vitro and in vivo experiments showed that the dystrophin region involved in nNOS binding is located in spectrin-like repeats R16 and R17 of its filamentous central domain. Using homology modeling and atomistic molecular dynamics simulation, we compared the structural organization and surface potentials of dystrophin, utrophin, and chimeric fragments, thus revisiting the dystrophin-nNOS binding region. Our simulation results are in good agreement with experimental data. They provide a three-dimensional representation of the repeats and give insight into the molecular organization of the regions involved in dystrophin-nNOS interaction. This study also further elucidates the physical properties crucial for this interaction, particularly the presence of a large hydrophobic patch. These results will be helpful to improving our understanding of the phenotypic features of patients bearing mutations in the nNOS-binding region of dystrophin.
肌营养不良蛋白是一种位于质膜内表面的大型骨骼肌蛋白，与膜磷脂和许多细胞质蛋白相互作用。神经元型一氧化氮合酶（nNOS）与肌营养不良蛋白的结合对于运动引起的肌肉细胞血液供应增加似乎至关重要。相比之下，肌营养不良蛋白的发育同源蛋白肌联蛋白则不显示与 nNOS 的相互作用。最近的体外和体内实验表明，与 nNOS 结合的肌营养不良蛋白区域位于其丝状中心域的 spectrin 样重复 R16 和 R17 中。使用同源建模和原子分子动力学模拟，我们比较了肌营养不良蛋白、肌联蛋白和嵌合片段的结构组织和表面电势，从而重新研究了肌营养不良蛋白-nNOS 结合区域。我们的模拟结果与实验数据非常吻合。它们提供了重复的三维表示，并深入了解了涉及肌营养不良蛋白-nNOS 相互作用的区域的分子组织。这项研究还进一步阐明了对这种相互作用至关重要的物理特性，特别是存在一个大的疏水区。这些结果将有助于提高我们对携带肌营养不良蛋白 nNOS 结合区域突变的患者表型特征的理解。
