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 ?-dystroglycan (?-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-?1,3-xylose-?1,3-]n. Using a dual exoglycosidase digestion, we confirm that this polysaccharide is present on native ?-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-?2 bound to a LARGE-synthesized oligosaccharide. A single glucuronic acid-?1,3-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.

SUBMITTER: Briggs DC 

PROVIDER: S-EPMC5030134 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature