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

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.

B3GNT1; B4GAT1; O-mannosylation; alpha-dystroglycan; biochemistry; congenital muscular dystrophy; glycosylation; human; human biology; medicine.