Structure and assembly of the dystrophin glycoprotein complex

Nature. 2025 Jan;637(8048):1252-1260. doi: 10.1038/s41586-024-08310-2. Epub 2024 Dec 11.

Abstract

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 matrix1-3. 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.

MeSH terms

  • Animals
  • Binding Sites
  • Cryoelectron Microscopy
  • Dystroglycans* / chemistry
  • Dystroglycans* / metabolism
  • Dystrophin* / chemistry
  • Dystrophin* / genetics
  • Dystrophin* / metabolism
  • Dystrophin-Associated Protein Complex / chemistry
  • Dystrophin-Associated Protein Complex / metabolism
  • Glycoproteins / chemistry
  • Glycoproteins / metabolism
  • Male
  • Mice
  • Models, Molecular*
  • Muscle, Skeletal* / metabolism
  • Sarcoglycans* / chemistry
  • Sarcoglycans* / genetics
  • Sarcoglycans* / metabolism

Substances

  • Dystrophin
  • Dystroglycans
  • Sarcoglycans
  • Glycoproteins
  • Dystrophin-Associated Protein Complex