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Molecular recognition by LARGE is essential for expression of functional dystroglycan.
Reduced ligand binding activity of alpha-dystroglycan is associated with muscle and central nervous system pathogenesis in a growing number of muscular dystrophies. Posttranslational processing of alpha-dystroglycan is generally accepted to be critical for the expression of functional dystroglycan. Here we show that both the N-terminal domain and a portion of the mucin-like domain of alpha-dystroglycan are essential for high-affinity laminin-receptor function. Posttranslational modification of alpha-dystroglycan by glycosyltransferase, LARGE, occurs within the mucin-like domain, but the N-terminal domain interacts with LARGE, defining an intracellular enzyme-substrate recognition motif necessary to initiate functional glycosylation. Gene replacement in dystroglycan-deficient muscle demonstrates that the dystroglycan C-terminal domain is sufficient only for dystrophin-glycoprotein complex assembly, but to prevent muscle degeneration the expression of a functional dystroglycan through LARGE recognition and glycosylation is required. Therefore, molecular recognition of dystroglycan by LARGE is a key determinant in the biosynthetic pathway to produce mature and functional dystroglycan.
Adenoviridae/genetics, Animals, Blotting, Western, Cells, Cultured, Cytoskeletal Proteins/chemistry, Cytoskeletal Proteins/genetics, Dystroglycans, Glycosylation, Glycosyltransferases/metabolism, Membrane Glycoproteins/chemistry, Membrane Glycoproteins/genetics, Mice, Mice, Knockout, Muscle, Skeletal/metabolism, Protein Processing, Post-Translational, Protein Structure, Tertiary, Rabbits, Receptors, Laminin/metabolism, Recombinant Fusion Proteins/chemistry, Recombinant Fusion Proteins/isolation & purification, Stem Cells/cytology
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