Structural basis of laminin binding to the LARGE glycans on dystroglycan
File(s)
Accepted version
Author(s)
Type
Journal Article
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 4-5 of
laminin α2 bound to a LARGE-synthesized oligosaccharide. A single glucuronic acid-
β1,3-xylose disaccharide repeat straddles a Ca2+ ion in the LG4 domain, with oxygen
atoms from both sugars replacing Ca2+-bound water molecules. The chelating binding
mode accounts for the high affinity of this protein-carbohydrate interaction. These
results reveal a novel mechanism of carbohydrate recognition and provide a structural
framework for elucidating the mechanisms underlying muscular dystrophy.
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 4-5 of
laminin α2 bound to a LARGE-synthesized oligosaccharide. A single glucuronic acid-
β1,3-xylose disaccharide repeat straddles a Ca2+ ion in the LG4 domain, with oxygen
atoms from both sugars replacing Ca2+-bound water molecules. The chelating binding
mode accounts for the high affinity of this protein-carbohydrate interaction. These
results reveal a novel mechanism of carbohydrate recognition and provide a structural
framework for elucidating the mechanisms underlying muscular dystrophy.
Date Issued
2016-08-15
Date Acceptance
2016-05-17
Citation
Nature Chemical Biology, 2016, 12, pp.810-814
ISSN
1552-4469
Publisher
Nature Publishing Group
Start Page
810
End Page
814
Journal / Book Title
Nature Chemical Biology
Volume
12
Copyright Statement
Copyright © 2016, Rights Managed by Nature Publishing Group
Sponsor
Wellcome Trust
Identifier
https://www.nature.com/articles/nchembio.2146
Grant Number
101748/Z/13/Z
Subjects
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
ALPHA-DYSTROGLYCAN
CRYSTAL-STRUCTURE
MOLECULAR-BASIS
REVEALS
DOMAIN
IDENTIFICATION
GLYCOSYLATION
DYSTROPHIN
HEPARIN
LIGAND
Binding Sites
Dystroglycans
Laminin
Models, Molecular
Molecular Structure
Dystroglycans
Laminin
Binding Sites
Molecular Structure
Models, Molecular
0304 Medicinal and Biomolecular Chemistry
0601 Biochemistry and Cell Biology
Biochemistry & Molecular Biology
Publication Status
Published
Date Publish Online
2016-08-15