Native DGC structure rationalizes muscular dystrophy-causing mutations

• 成果类型: Article
• 署名作者: Liu, Shiheng; Su, Tiantian; Xia, Xian; Zhou, Z. Hong
• 署名单位: University of California System; University of California Los Angeles; University of California System; University of California Los Angeles
• 刊物名称: Nature
• ISSN/ISSBN: 0028-1642
• DOI: 10.1038/s41586-024-08324-w
• 发表日期: 2025-01-30
• 关键词: glycoprotein-complex; sarcoglycan complex; crystal-structure; beta-sarcoglycan; skeletal-muscle; molecular-organization; alpha-dystrobrevin; ww domain; sarcospan; protein

摘要

Duchenne muscular dystrophy (DMD) is a severe X-linked recessive disorder marked by progressive muscle wasting leading to premature mortality1,2. 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 beta-helix comprising beta-, gamma- and delta-sarcoglycan forms an extracellular platform that interacts with alpha-dystroglycan, beta-dystroglycan and alpha-sarcoglycan, allowing alpha-dystroglycan to contact the extracellular matrix. In the membrane, sarcospan anchors beta-dystroglycan to the beta-, gamma- and delta-sarcoglycan trimer, while in the cytoplasm, beta-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 alpha-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.