O-mannosyl phosphorylation of alpha-dystroglycan is required for laminin binding.

Abstract	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.
Authors	Takako Yoshida-Moriguchi, Liping Yu, Stephanie H Stalnaker, Sarah Davis, Stefan Kunz, Michael Madson, Michael B A Oldstone, Harry Schachter, Lance Wells, Kevin P Campbell
Journal	Science (New York, N.Y.) (Science) Vol. 327 Issue 5961 Pg. 88-92 (Jan 01 2010) ISSN: 1095-9203 [Electronic] United States
PMID	20044576 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	DAG1 protein, human FKTN protein, human Laminin Membrane Proteins Recombinant Proteins Dystroglycans LARGE1 protein, human Large1 protein, mouse N-Acetylglucosaminyltransferases Mannose
Topics	Animals Carbohydrate Conformation Cell Line Dystroglycans (chemistry, 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, metabolism) Phosphorylation Protein Binding Recombinant Proteins (chemistry, metabolism)

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