Mammalian O-mannosylation: unsolved questions of structure/function

Abstract

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.

Regulation of Glycan Structures in Murine Embryonic Stem Cells

“…Glycoprotein and glycolipid modifications by polysialic acid or sulfation to form human natural killer-1 epitopes in neural crest cells regulate adhesion and neurite outgrowth from various neural cell types (100 -104). Distinct glycosylation of the dystrophin glycoprotein complex at the neuromuscular junction has also been shown to contribute a critical bridge between the extracellular matrix, the plasma membrane, and the cytoskeleton (105). The regulated expression of glycan structures also plays critical roles in numerous stages of organogenesis and hematopoiesis (75, 106 -109).…”

Protein O-glycosylation analysis

“…Another modifi cation, O-mannosylation, has been observed on various proteins from the brain and skeletal muscles, and defects in the involved transferases are associated with various congenital diseases (Stalnaker et al , 2011 ). Other O-glycans exhibit an innermost fucose, glucose, galactose, xylose, or N-acetylglucosamine (GlcNAc) (Haltiwanger and Lowe , 2004 ;Stalnaker et al , 2011 ;Sethi et al , 2012 ).…”

“…Other O-glycans exhibit an innermost fucose, glucose, galactose, xylose, or N-acetylglucosamine (GlcNAc) (Haltiwanger and Lowe , 2004 ;Stalnaker et al , 2011 ;Sethi et al , 2012 ). A very peculiar case of O-glycosylation is the so-called O-linked GlcNAc (O-GlcNAc).…”

The O-Mannosylation Pathway: Glycosyltransferases and Proteins Implicated in Congenital Muscular Dystrophy

“…In the early 2000s, multiple groups established that deficiencies of enzymes in this pathway result in multiple forms of congenital muscular dystrophy (CMD) 2 that have now been termed dystroglycanopathies (2)(3)(4)(5)(6). Recent work has begun to unravel the structures of the functional glycans that are altered and to identify sites of modification on ␣-dystroglycan (7)(8)(9)(10)(11)(12), the most well characterized and clearly functionally relevant O-mannosylated protein (13,14). While briefly describing the dystrophin-dystroglycan complex and the diversity of O-mannosylated structures, this minireview will primarily highlight the enzymes and proteins that are known to be defective in dystroglycanopathies.…”

“…Other recent reviews have focused on the structures, substrates, and functional implications of the O-mannosylation pathway and the phenotypes observed in the various muscular dystrophies (13,14,17,24,29,30). Here, I review the enzymes/ proteins of the pathway that have been implicated in CMD.…”