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1476-468763780482025JanNatureNatureStructure and assembly of the dystrophin glycoprotein complex.125212601252-126010.1038/s41586-024-08310-2The dystrophin glycoprotein complex (DGC) has a crucial role in maintaining cell membrane stability and integrity by connecting the intracellular cytoskeleton with the surrounding extracellular matrix1-3. 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, 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 proposed6-8. 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.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.WanLiLKey Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China.Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China.Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, China.GeXiaofeiX0009-0005-9626-7061State Key Laboratory of Membrane Biology, Beijing Frontier Research Center for Biological Structure, School of Life Sciences, Tsinghua University, Beijing, China.XuQikuiQKey Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China.Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China.Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, China.HuangGaoxingyuGKey Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China.Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China.Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, China.YangTiandiTHoward Hughes Medical Institute, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA.Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA.Department of Molecular Physiology and Biophysics, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA.Department of Neurology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA.Department of Immunology, Harvard Medical School, Boston, MA, USA.CampbellKevin PKP0000-0003-2066-5889Howard Hughes Medical Institute, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA.Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA.Department of Molecular Physiology and Biophysics, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA.Department of Neurology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA.YanZhenZ0000-0002-1999-8451Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China. yanzhen@westlake.edu.cn.Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China. yanzhen@westlake.edu.cn.Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, China. yanzhen@westlake.edu.cn.WuJianpingJ0000-0001-9869-7691Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China. wujianping@westlake.edu.cn.Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China. wujianping@westlake.edu.cn.Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, China. wujianping@westlake.edu.cn.engP50 NS053672NSNINDS NIH HHSUnited StatesJournal ArticleResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov't20241211
EnglandNature04104620028-0836146888-27-9Dystroglycans0Dystrophin0SarcoglycansIMAnimalsMiceBinding SitesCryoelectron MicroscopyDystroglycanschemistrymetabolismultrastructureDystrophinchemistrymetabolismultrastructureModels, MolecularMuscle, SkeletalchemistrymetabolismProtein BindingSarcoglycanschemistrymetabolismultrastructureCompeting interests: The authors declare no competing interests.2024613202410302025130019202412120242024121123302026515ppublish39663450NIHMS2116392PMC1317878710.1038/s41586-024-08310-210.1038/s41586-024-08310-2Campbell KP & Kahl SD Association of dystrophin and an integral membrane glycoprotein. Nature 338, 259–262 (1989).2493582Ibraghimov-Beskrovnaya O et al. Primary structure of dystrophin-associated glycoproteins linking dystrophin to the extracellular matrix. Nature 355, 696–702 (1992).1741056Ervasti JM & Campbell KP A role for the dystrophin-glycoprotein complex as a transmembrane linker between laminin and actin. J. 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