Conformational consequences of O‐GalNAc and O‐Man protein modifications: implications for the structural role of O‐GalNAc in the mucin‐like region of alpha‐dystroglycan

The ramifications of protein glycosylation extend beyond the display of particular carbohydrate epitopes, to potentially inducing changes in the protein conformation. Both properties can impact physiological effects. In general only one form of glycosylation is found in a region of a glycoprotein, however a major exception is alpha dystroglycan (aDG). Its mucin‐like region carries glycans initiated by both O‐GalNAc and O‐Man. It is known that OGalNAc based modifications induce extended structures, which may be relevant to the shape of aDG and its role linking the cytoskeleton to the extracellular matrix. The conformational effects of O‐Man are not so clear, although these glycans are important for functional physiological properties, with aberrations in their structures related to forms of muscular dystrophy. To elucidate comparative conformational aspects of the two kinds of modifications, NMR studies have been carried out on a peptide segment from aDG, itself, and also modified with O‐Man and OGalNAc, prepared synthetically. These results are being complemented by extensive molecular dynamics simulations to further understand the consequences of the modifications on the protein flexibility. The O‐Man modification induces much less conformational restriction than that of O‐GalNAc. The results offer new insights into conformational effects of O‐glycosylation.