9C3C

Cryo-EM structure of native dystrophin-glycoprotein complex (DGC)

This is a non-PDB format compatible entry.

Summary for 9C3C

• Entry DOI: 10.2210/pdb9c3c/pdb
• EMDB information: 45165
• Descriptor: Alpha-dystroglycan, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (12 entities in total)
• Functional Keywords: beta-helix, sarcolemma, glycosylation, muscular dystrophy, membrane protein
• Biological source: Oryctolagus cuniculus (rabbit); More
• Total number of polymer chains: 9
• Total formula weight: 769844.54

Authors

Liu, S.,Su, T.,Xia, X.,Zhou, Z.H. (deposition date: 2024-05-31, release date: 2024-10-23, Last modification date: 2025-02-12)

Primary citation

Liu, S.,Su, T.,Xia, X.,Zhou, Z.H.
Native DGC structure rationalizes muscular dystrophy-causing mutations.
Nature, 637:1261-1271, 2025

PubMed Abstract: Duchenne muscular dystrophy (DMD) is a severe X-linked recessive disorder marked by progressive muscle wasting leading to premature mortality. 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). 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.

PubMed: 39663457
DOI: 10.1038/s41586-024-08324-w

Experimental method

ELECTRON MICROSCOPY (4.3 Å)