Protein O-Linked Mannose ?-1,4-N-Acetylglucosaminyl-transferase 2 (POMGNT2) Is a Gatekeeper Enzyme for Functional Glycosylation of ?-Dystroglycan.

ABSTRACT: Disruption of the O-mannosylation pathway involved in functional glycosylation of ?-dystroglycan gives rise to congenital muscular dystrophies. Protein O-linked mannose ?-1,4-N-acetylglucosaminyltransferase 2 (POMGNT2) catalyzes the first step toward the functional matriglycan structure on ?-dystroglycan that is responsible for binding extracellular matrix proteins and certain arenaviruses. Alternatively, protein O-linked mannose ?-1,2-N-acetylglucosaminyltransferase 1 (POMGNT1) catalyzes the first step toward other various glycan structures present on ?-dystroglycan of unknown function. Here, we demonstrate that POMGNT1 is promiscuous for O-mannosylated peptides, whereas POMGNT2 displays significant primary amino acid selectivity near the site of O-mannosylation. We define a POMGNT2 acceptor motif, conserved among 59 vertebrate species, in ?-dystroglycan that when engineered into a POMGNT1-only site is sufficient to convert the O-mannosylated peptide to a substrate for POMGNT2. Additionally, an acceptor glycopeptide is a less efficient substrate for POMGNT2 when two of the conserved amino acids are replaced. These findings begin to define the selectivity of POMGNT2 and suggest that this enzyme functions as a gatekeeper enzyme to prevent the vast majority of O-mannosylated sites on proteins from becoming modified with glycan structures functional for binding laminin globular domain-containing proteins.

SUBMITTER: Halmo SM 

PROVIDER: S-EPMC5313085 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature