Structural basis of laminin binding to the LARGE glycans on dystroglycan.
David C BriggsTakako Yoshida-MoriguchiTianqing ZhengDavid VenzkeMary E AndersonAndrea StrazzulliMarco MoracciLiping YuErhard HohenesterKevin P CampbellPublished in: Nature chemical biology (2016)
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.
Keyphrases
- muscular dystrophy
- skeletal muscle
- extracellular matrix
- binding protein
- high resolution
- structural basis
- duchenne muscular dystrophy
- dna binding
- insulin resistance
- machine learning
- deep learning
- mass spectrometry
- gene expression
- single cell
- dna methylation
- protein kinase
- protein protein
- electron microscopy
- tandem mass spectrometry