The dystrophin glycoprotein complex (DGC) has a crucial role in maintaining cell membrane stability and integrity by connecting the intracellular cytoskeleton with the surrounding extracellular matrix^1,2,3. Dysfunction of dystrophin and its associated proteins results in muscular dystrophy, a disorder characterized by progressive muscle weakness and degeneration^4,5. Despite the important roles of the DGC in physiology and pathology, its structural details remain largely unknown, hindering a comprehensive understanding of its assembly and function. Here we isolated the native DGC from mouse skeletal muscle and obtained its high-resolution structure. Our findings unveil a markedly divergent structure from the previous model of DGC assembly. Specifically, on the extracellular side, β-, γ- and δ-sarcoglycans co-fold to form a specialized, extracellular tower-like structure, which has a central role in complex assembly by providing binding sites for α-sarcoglycan and dystroglycan. In the transmembrane region, sarcoglycans and sarcospan flank and stabilize the single transmembrane helix of dystroglycan, rather than forming a subcomplex as previously proposed^6,7,8. On the intracellular side, sarcoglycans and dystroglycan engage in assembly with the dystrophin–dystrobrevin subcomplex through extensive interaction with the ZZ domain of dystrophin. Collectively, these findings enhance our understanding of the structural linkage across the cell membrane and provide a foundation for the molecular interpretation of many muscular dystrophy-related mutations.

抗肌萎缩蛋白糖蛋白复合物 （DGC） 通过将细胞内细胞骨架与周围的细胞外基质连接起来，在维持细胞膜稳定性和完整性方面起着至关重要的作用^1,2,3。抗肌萎缩蛋白及其相关蛋白功能障碍导致肌营养不良症，这是一种以进行性肌无力和退化为特征的疾病^4,5。尽管 DGC 在生理学和病理学中发挥着重要作用，但其结构细节在很大程度上仍然未知，阻碍了对其组装和功能的全面理解。在这里，我们从小鼠骨骼肌中分离出天然 DGC 并获得其高分辨率结构。我们的研究结果揭示了与之前的 DGC 组装模型明显不同的结构。具体来说，在细胞外侧，β-、γ-和 δ-肌聚糖共折叠形成一种特殊的细胞外塔状结构，该结构通过为 α-肌聚糖和肌营养不良聚糖提供结合位点，在复合物组装中发挥核心作用。在跨膜区域，肌聚糖和肌桥侧翼并稳定肌营养不良蛋白聚糖的单个跨膜螺旋，而不是像以前提出的那样形成亚复合物^6,7,8。在细胞内侧，肌聚糖和肌营养不良蛋白聚糖通过与抗肌萎缩蛋白的 ZZ 结构域的广泛相互作用，与抗肌萎缩蛋白-肌营养不良蛋白亚复合物组装。总的来说，这些发现增强了我们对跨细胞膜结构连接的理解，并为许多肌营养不良相关突变的分子解释提供了基础。