Structure and assembly of the dystrophin glycoprotein complex

• 成果类型: Article
• 署名作者: Wan, Li; Ge, Xiaofei; Xu, Qikui; Huang, Gaoxingyu; Yang, Tiandi; Campbell, Kevin P.; Yan, Zhen; Wu, Jianping
• 署名单位: Westlake University; Westlake Laboratory; Westlake University; Tsinghua University; University of Iowa; Howard Hughes Medical Institute; University of Iowa; University of Iowa; University of Iowa; Harvard University; Harvard Medical School
• 刊物名称: Nature
• ISSN/ISSBN: 0028-1833
• DOI: 10.1038/s41586-024-08310-2
• 发表日期: 2025-01-30
• 关键词: girdle muscular-dystrophy; delta-sarcoglycan gene; missense mutation; beta-dystroglycan; cryo-em; terminal region; binding domain; duchenne; alpha; identification

摘要

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 matrix1, 2-3. Dysfunction of dystrophin and its associated proteins results in muscular dystrophy, a disorder characterized by progressive muscle weakness and degeneration4,5. 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, beta-, gamma- and delta-sarcoglycans co-fold to form a specialized, extracellular tower-like structure, which has a central role in complex assembly by providing binding sites for alpha-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 proposed6, 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.