Article: article from journal or magazin.
O-mannosyl phosphorylation of alpha-dystroglycan is required for laminin binding.
Alpha-dystroglycan (alpha-DG) is a cell-surface glycoprotein that acts as a receptor for both extracellular matrix proteins containing laminin-G domains and certain arenaviruses. Receptor binding is thought to be mediated by a posttranslational modification, and defective binding with laminin underlies a subclass of congenital muscular dystrophy. Using mass spectrometry- and nuclear magnetic resonance (NMR)-based structural analyses, we identified a phosphorylated O-mannosyl glycan on the mucin-like domain of recombinant alpha-DG, which was required for laminin binding. We demonstrated that patients with muscle-eye-brain disease and Fukuyama congenital muscular dystrophy, as well as mice with myodystrophy, commonly have defects in a postphosphoryl modification of this phosphorylated O-linked mannose, and that this modification is mediated by the like-acetylglucosaminyltransferase (LARGE) protein. These findings expand our understanding of the mechanisms that underlie congenital muscular dystrophy.
Animals, Carbohydrate Conformation, Cell Line, Dystroglycans/chemistry, Dystroglycans/metabolism, Glycosylation, Humans, Laminin/metabolism, Magnetic Resonance Spectroscopy, Mannose/metabolism, Mass Spectrometry, Membrane Proteins/metabolism, Mice, Mice, Inbred C57BL, Muscle, Skeletal/metabolism, Muscular Dystrophies/metabolism, Muscular Dystrophy, Animal/metabolism, N-Acetylglucosaminyltransferases/genetics, N-Acetylglucosaminyltransferases/metabolism, Phosphorylation, Protein Binding, Recombinant Proteins/chemistry, Recombinant Proteins/metabolism
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