Cryogenic electron microscopy (cryoEM), advanced through NSF’ STROBE, a National Science Foundation Science and Technology Center, enables unparalleled resolution for complex membrane proteins like the dystrophin-glycoprotein complex (DGC). DGC is critical in Duchenne Muscular Dystrophy (DMD), affecting 1 in 3,500–5,000 male newborns. This enormous membrane protein complex, with dystrophin at its core, links the extracellular matrix to the cytoskeleton, protecting muscle membranes during contraction. Its multi-subunit complexity defies traditional methods like X-ray crystallography. STROBE’s cutting-edge cryoEM techniques allowed us to image DGC from rabbit skeletal muscle directly, collecting ~27,000 high-resolution images for near-atomic resolution 3D reconstruction, bypassing recombinant artifacts and revealing structural details unattainable by prior approaches (see figure).
Zhou lab’s cryoEM study unveiled DGC’s “keychain-like” architecture. Extracellularly, a β-helix trimer (β-, γ-, δ-sarcoglycans) anchors dystroglycan to the matrix; mutations disrupting its flexible bend cause Limb-Girdle Muscular Dystrophy. Sarcospan stabilizes the transmembrane region via a β-DG-mediated interface, a promising therapeutic target. Cytoplasmically, novel interactions between β-DG, α-/δ-SG, and dystrophin’s ZZ domain, plus a conformationally dynamic WW-α-dystrobrevin interface, drive signaling. Over 110 mutations were mapped, linking structural defects to DMD, Becker, and Limb-Girdle dystrophies, clarifying disease mechanisms.
This STROBE-supported, NSF-funded cryoEM study elucidates DGC’s mechanoprotective role, guiding therapies like gene replacement and small-molecule stabilizers for muscular dystrophies. It showcases cryoEM’s transformative potential for native membrane complexes, with implications for other diseases like cardiomyopathies, advancing precision medicine.