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Science 327 (5961): 88-92

Copyright © 2010 by the American Association for the Advancement of Science

O-Mannosyl Phosphorylation of Alpha-Dystroglycan Is Required for Laminin Binding

Takako Yoshida-Moriguchi,1,2,3,4 Liping Yu,5 Stephanie H. Stalnaker,6 Sarah Davis,1,2,3,4 Stefan Kunz,7 Michael Madson,8 Michael B. A. Oldstone,9 Harry Schachter,10 Lance Wells,6 Kevin P. Campbell1,2,3,4,*

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.

1 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.
2 Department of Molecular Physiology and Biophysics, 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.
3 Department of Neurology, 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.
4 Department of Internal Medicine, 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.
5 Medical Nuclear Magnetic Resonance Facility, University of Iowa Roy J. and Lucille A. Carver College of Medicine, B291 Carver Biomedical Research Building, 285 Newton Road, Iowa City, IA 52242-1101, USA.
6 Complex Carbohydrate Research Center, University of Georgia, 315 Riverbend Road, Athens, GA 30602, USA.
7 Institute of Microbiology, University Hospital Center and University of Lausanne, Lausanne, Switzerland.
8 Bio Logistics, 2416 North Shore Drive, Clear Lake, IA 50428, USA.
9 The Scripps Research Institute, Department of Immunology and Microbial Science, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
10 The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.

* To whom correspondence should be addressed. E-mail: kevin-campbell{at}uiowa.edu


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