title: Structural basis of laminin binding to the LARGE glycans on dystroglycan.
abstract: Dystroglycan is a highly glycosylated extracellular matrix receptor with essential functions in skeletal muscle and the nervous system. Reduced matrix binding by α-dystroglycan (α-DG) due to perturbed glycosylation is a pathological feature of several forms of muscular dystrophy. Like-acetylglucosaminyltransferase (LARGE) synthesizes the matrix-binding heteropolysaccharide [-glucuronic acid-β1,3-xylose-α1,3-]n. Using a dual exoglycosidase digestion, we confirm that this polysaccharide is present on native α-DG from skeletal muscle. The atomic details of matrix binding were revealed by a high-resolution crystal structure of laminin-G-like (LG) domains 4 and 5 (LG4 and LG5) of laminin-α2 bound to a LARGE-synthesized oligosaccharide. A single glucuronic acid-β1,3-xylose disaccharide repeat straddles a Ca(2+) ion in the LG4 domain, with oxygen atoms from both sugars replacing Ca(2+)-bound water molecules. The chelating binding mode accounts for the high affinity of this protein-carbohydrate interaction. These results reveal a previously uncharacterized mechanism of carbohydrate recognition and provide a structural framework for elucidating the mechanisms underlying muscular dystrophy.
authors.affiliation: Department of Life Sciences, Imperial College London, London, UK.
authors.forename: David C
authors.initials: DC
authors.lastname: Briggs
authors.affiliation: Howard Hughes Medical Institute, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USA.|Department of Molecular Physiology and Biophysics, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USA.|Department of Neurology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USA.|Department of Internal Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USA.
authors.forename: Takako
authors.initials: T
authors.lastname: Yoshida-Moriguchi
authors.affiliation: Howard Hughes Medical Institute, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USA.|Department of Molecular Physiology and Biophysics, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USA.|Department of Neurology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USA.|Department of Internal Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USA.
authors.forename: Tianqing
authors.initials: T
authors.lastname: Zheng
authors.affiliation: Howard Hughes Medical Institute, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USA.|Department of Molecular Physiology and Biophysics, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USA.|Department of Neurology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USA.|Department of Internal Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USA.
authors.forename: David
authors.initials: D
authors.lastname: Venzke
authors.affiliation: Howard Hughes Medical Institute, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USA.|Department of Molecular Physiology and Biophysics, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USA.|Department of Neurology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USA.|Department of Internal Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Anderson
authors.affiliation: Institute of Biosciences and Bioresources-National Research Council of Italy, Naples, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Strazzulli
authors.affiliation: Institute of Biosciences and Bioresources-National Research Council of Italy, Naples, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Moracci
authors.affiliation: Medical Nuclear Magnetic Resonance Facility, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USA.
authors.forename: Liping
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Life Sciences, Imperial College London, London, UK.
authors.forename: Erhard
authors.initials: E
authors.lastname: Hohenester
authors.affiliation: Howard Hughes Medical Institute, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USA.|Department of Molecular Physiology and Biophysics, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USA.|Department of Neurology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USA.|Department of Internal Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USA.
authors.forename: Kevin P
authors.identifier: 0000-0003-2066-5889
authors.initials: KP
authors.lastname: Campbell
mesh_terms: D001665:Binding Sites; D049030:Dystroglycans / Q000737:chemistry*; D007797:Laminin / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure
chemical_list: D007797:Laminin; D049030:Dystroglycans