Contrasting the conformational effects of alpha-O-GaINAc and alpha-O-Man glycan protein modifications and their impact on the mucin-like region of alpha-dystroglycan

摘要

We have carried out a comparative study of the conformational impact of modifications to threonine residues of either alpha-O-Man or alpha-O-GaINAc in the context of a sequence from the mucin-like region of ot-dystroglycan. Both such modifications can coexist in this domain of the glycoprotein. Solution NMR experiments and molecular dynamics calculations were employed. Comparing the results for an unmodified peptide Ac-PPTTTTKKP-NH2 sequence from alpha-dystroglycan, and glycoconjugates with either modification on the Ts, we find that the impact of the alpha-O-Man modification on the peptide scaffold is quite limited, while that of the alpha-O-GaINAc is more profound. The results for the alpha-O-GaINAc glycoconjugate are consistent with what has been seen earlier in other systems. Further examination of the NMR-based structure and the MD results suggest a more extensive network of hydrogen bond interactions within the alpha-O-GaINAc-threonine residue than has been previously appreciated, which influences the properties of the protein backbone. The conformational effects are relevant to the mechanical properties of alpha-dystroglycan.