Journal article
Structural basis of laminin binding to the LARGE glycans on dystroglycan
Nature chemical biology, Vol.12(10), pp.810-814
10/2016
DOI: 10.1038/nchembio.2146
PMCID: PMC5030134
PMID: 27526028
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.
Details
- Title: Subtitle
- Structural basis of laminin binding to the LARGE glycans on dystroglycan
- Creators
- David C Briggs - Department of Life Sciences, Imperial College London, London, UKTakako Yoshida-Moriguchi - Department of Internal Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USATianqing Zheng - Department of Internal Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USADavid Venzke - Department of Internal Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USAMary E Anderson - Department of Internal Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USAAndrea Strazzulli - Institute of Biosciences and Bioresources-National Research Council of Italy, Naples, ItalyMarco Moracci - Institute of Biosciences and Bioresources-National Research Council of Italy, Naples, ItalyLiping Yu - Medical Nuclear Magnetic Resonance Facility, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USAErhard Hohenester - Department of Life Sciences, Imperial College London, London, UKKevin P Campbell - Department of Internal Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa, USA
- Resource Type
- Journal article
- Publication Details
- Nature chemical biology, Vol.12(10), pp.810-814
- DOI
- 10.1038/nchembio.2146
- PMID
- 27526028
- PMCID
- PMC5030134
- NLM abbreviation
- Nat Chem Biol
- ISSN
- 1552-4450
- eISSN
- 1552-4469
- Publisher
- United States
- Grant note
- Howard Hughes Medical Institute U54 NS053672 / NINDS NIH HHS 101748 / Wellcome Trust
- Language
- English
- Date published
- 10/2016
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Biochemistry and Molecular Biology; Medicine Administration
- Record Identifier
- 9984020618102771
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