Journal
CHEMBIOCHEM
Volume 14, Issue 18, Pages 2392-2402Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.201300417
Keywords
alpha-dystroglycan; carbohydrates; dystroglycanopathies; glycopeptides; muscular dystrophy; protein O-mannosylation
Funding
- National Institutes of Health Grants [R21AR056055, P41GM103390, P41GM103490, R01GM090269]
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Dystroglycanopathies form a subgroup of muscular dystrophies that arise from defects in enzymes that are implicated in the recently elucidated O-mannosylation pathway, thereby resulting in underglycosylation of -dystroglycan. The emerging identification of additional brain proteins modified by O-mannosylation provides a broader context for interpreting the range of neurological consequences associated with dystroglycanopathies. This form of glycosylation is associated with protein mucin-like domains that present numerous serine and threonine residues as possible sites for modification. Furthermore, the O-Man glycans coexist in this region with O-GalNAc glycans (conventionally associated with such protein sequences), thus resulting in a complex glycoconjugate landscape. Sorting out the relationships between the various molecular defects in glycosylation and the modes of disease presentation, as well as the regulatory interplay among the O-Man glycans and the effects on other modes of glycosylation in the same domain, is challenging. Here we provide a perspective on chemical biology approaches employing synthetic and analytical methods to address these questions.
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