title: 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.affiliation: Howard Hughes Medical Institute, University of Iowa Roy J. and Lucille A. Carver College of Medicine, 4283 Carver Biomedical Research Building, 285 Newton Road, Iowa City, IA 52242-1101, USA.
authors.forename: Takako
authors.initials: T
authors.lastname: Yoshida-Moriguchi
authors.forename: Liping
authors.initials: L
authors.lastname: Yu
authors.forename: Stephanie H
authors.initials: SH
authors.lastname: Stalnaker
authors.forename: Sarah
authors.initials: S
authors.lastname: Davis
authors.forename: Stefan
authors.initials: S
authors.lastname: Kunz
authors.forename: Michael
authors.initials: M
authors.lastname: Madson
authors.forename: Michael B A
authors.initials: MB
authors.lastname: Oldstone
authors.forename: Harry
authors.initials: H
authors.lastname: Schachter
authors.forename: Lance
authors.initials: L
authors.lastname: Wells
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Campbell
mesh_terms: D000818:Animals; D002236:Carbohydrate Conformation; D002460:Cell Line; D049030:Dystroglycans / Q000737:chemistry / Q000378:metabolism*; D006031:Glycosylation; D006801:Humans; D007797:Laminin / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008358:Mannose / Q000378:metabolism*; D013058:Mass Spectrometry; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism; D009136:Muscular Dystrophies / Q000378:metabolism; D009137:Muscular Dystrophy, Animal / Q000378:metabolism; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: C483081:DAG1 protein, human; C113587:FKTN protein, human; D007797:Laminin; D008565:Membrane Proteins; D011994:Recombinant Proteins; D049030:Dystroglycans; C117674:LARGE1 protein, human; C502747:Large1 protein, mouse; D017351:N-Acetylglucosaminyltransferases; D008358:Mannose