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

ABSTRACT: 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 ?-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 ?3 linked GlcNAc known, we biochemically interrogated this human enzyme. Here we report this enzyme is not a ?-1,3-N-acetylglucosaminyltransferase with catalytic activity towards ?-galactose but rather a ?-1,4-glucuronyltransferase, designated B4GAT1, towards both ?- and ?-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 ?-dystroglycan that is lacking in secondary dystroglycanopathies.

SUBMITTER: Praissman JL 

PROVIDER: S-EPMC4227051 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature