Duchenne muscular dystrophy (DMD) is a severe X-linked recessive disorder marked by progressive muscle wasting leading to premature mortality^1,2. Discovery of the DMD gene encoding dystrophin both revealed the cause of DMD and helped identify a family of at least ten dystrophin-associated proteins at the muscle cell membrane, collectively forming the dystrophin–glycoprotein complex (DGC)^{3,4,5,6,7,8,9}. The DGC links the extracellular matrix to the cytoskeleton, but, despite its importance, its molecular architecture has remained elusive. Here we determined the native cryo-electron microscopy structure of rabbit DGC and conducted biochemical analyses to reveal its intricate molecular configuration. An unexpected β-helix comprising β-, γ- and δ-sarcoglycan forms an extracellular platform that interacts with α-dystroglycan, β-dystroglycan and α-sarcoglycan, allowing α-dystroglycan to contact the extracellular matrix. In the membrane, sarcospan anchors β-dystroglycan to the β-, γ- and δ-sarcoglycan trimer, while in the cytoplasm, β-dystroglycan’s juxtamembrane fragment binds dystrophin’s ZZ domain. Through these interactions, the DGC links laminin 2 to intracellular actin. Additionally, dystrophin’s WW domain, along with its EF-hand 1 domain, interacts with α-dystrobrevin. A disease-causing mutation mapping to the WW domain weakens this interaction, as confirmed by deletion of the WW domain in biochemical assays. Our findings rationalize more than 110 mutations affecting single residues associated with various muscular dystrophy subtypes and contribute to ongoing therapeutic developments, including protein restoration, upregulation of compensatory genes and gene replacement.

杜氏肌营养不良症 （DMD） 是一种严重的 X 连锁隐性遗传病，其特征是进行性肌肉萎缩，导致过早死亡^1,2。编码抗肌萎缩蛋白的 DMD 基因的发现既揭示了 DMD 的原因，也有助于在肌肉细胞膜上鉴定出至少十种抗肌萎缩蛋白相关蛋白的家族，共同形成抗肌萎缩蛋白-糖蛋白复合物 （DGC）^{3,4,5,6,7,8,9}。DGC 将细胞外基质与细胞骨架连接起来，但尽管它很重要，但其分子结构仍然难以捉摸。在这里，我们确定了兔 DGC 的天然冷冻电子显微镜结构，并进行了生化分析以揭示其复杂的分子构型。由 β-、γ 和 δ-肌聚糖组成的意外β螺旋形成一个细胞外平台，该平台与 α-肌营养不良聚糖、β-肌营养不良聚糖和 α-肌聚糖相互作用，使 α-肌营养不良聚糖能够接触细胞外基质。在膜中，肌宽将 β-肌营养不良蛋白聚糖锚定在 β-、γ 和 δ-肌聚糖三聚体上，而在细胞质中，β-肌营养不良蛋白聚糖的近膜片段结合抗肌萎缩蛋白的 ZZ 结构域。通过这些相互作用，DGC 将层粘连蛋白 2 与细胞内肌动蛋白连接起来。此外，抗肌萎缩蛋白的 WW 结构域及其 EF-hand 1 结构域与 α-dystrobrevin 相互作用。映射到 WW 结构域的致病突变削弱了这种相互作用，生化测定中 WW 结构域的缺失证实了这一点。我们的研究结果使 110 多种影响与各种肌营养不良亚型相关的单个残基的突变合理化，并有助于正在进行的治疗开发，包括蛋白质恢复、代偿基因的上调和基因替换。