Mammalian O-mannosylation: unsolved questions of structure/function

Post-translational modification of polypeptides with glycans increases the diversity of the structures of proteins and imparts increased functional diversity. Here, we review the current literature on a relatively new O-glycosylation pathway, the mammalian O-mannosylation pathway. The importance of O-mannosylation is illustrated by the fact that O-mannose glycan structures play roles in a variety of processes including viral entry into cells, metastasis, cell adhesion, and neuronal development. Furthermore, mutations in the enzymes of this pathway are causal for a variety of congenital muscular dystrophies. Here we highlight the protein substrates, glycan structures, and enzymes involved in O-mannosylation as well as our gaps in understanding structure/function relationships in this biosynthetic pathway.

► O-Mannosylation regulates arenavirus entry, cancer metastasis, and cell adhesion.
► Defects in enzymes of the O-mannosylation biosynthetic pathway are causal for congenital muscular dystrophy.
► Approximately 1/3 of O-glycans in mammalian brain are O-mannose-initiated.
► O-Mannose glycans are diverse and include a phosphodiester-containing structure.
► Many of the protein substrates, functional glycan structures, and enzymes are unknown.