B4GAT1 is the priming enzyme for the LARGE-dependent functional glycosylation of α-dystroglycan

• Main Authors: Jeremy L Praissman, David H Live, Shuo Wang, Annapoorani Ramiah, Zoeisha S Chinoy, Geert-Jan Boons, Kelley W Moremen, Lance Wells
• Format: Article
• Language: English
• Published: eLife Sciences Publications Ltd 2014-10-01
• Series: eLife
• Subjects: congenital muscular dystrophy; O-mannosylation; glycosylation; alpha-dystroglycan; B4GAT1; B3GNT1
• Online Access: https://elifesciences.org/articles/03943

Recent studies demonstrated that mutations in B3GNT1, an enzyme proposed to be involved in poly-N-acetyllactosamine synthesis, were causal for congenital muscular dystrophy with hypoglycosylation of α-dystroglycan (secondary dystroglycanopathies). Since defects in the O-mannosylation protein glycosylation pathway are primarily responsible for dystroglycanopathies and with no established O-mannose initiated structures containing a β3 linked GlcNAc known, we biochemically interrogated this human enzyme. Here we report this enzyme is not a β-1,3-N-acetylglucosaminyltransferase with catalytic activity towards β-galactose but rather a β-1,4-glucuronyltransferase, designated B4GAT1, towards both α- and β-anomers of xylose. The dual-activity LARGE enzyme is capable of extending products of B4GAT1 and we provide experimental evidence that B4GAT1 is the priming enzyme for LARGE. Our results further define the functional O-mannosylated glycan structure and indicate that B4GAT1 is involved in the initiation of the LARGE-dependent repeating disaccharide that is necessary for extracellular matrix protein binding to O-mannosylated α-dystroglycan that is lacking in secondary dystroglycanopathies.