Synergy of peptide and sugar in O-GlcNAcase substrate recognition.
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Schimpl M, Borodkin VS, Gray LJ, van Aalten DM
Synergy of peptide and sugar in O-GlcNAcase substrate recognition.
Chem Biol. 2012 Feb 24;19(2):173-8. doi: 10.1016/j.chembiol.2012.01.011.
- PubMed ID
- 22365600 [ View in PubMed]
- Abstract
Protein O-GlcNAcylation is an essential reversible posttranslational modification in higher eukaryotes. O-GlcNAc addition and removal is catalyzed by O-GlcNAc transferase and O-GlcNAcase, respectively. We report the molecular details of the interaction of a bacterial O-GlcNAcase homolog with three different synthetic glycopeptides derived from characterized O-GlcNAc sites in the human proteome. Strikingly, the peptides bind a conserved O-GlcNAcase substrate binding groove with similar orientation and conformation. In addition to extensive contacts with the sugar, O-GlcNAcase recognizes the peptide backbone through hydrophobic interactions and intramolecular hydrogen bonds, while avoiding interactions with the glycopeptide side chains. These findings elucidate the molecular basis of O-GlcNAcase substrate specificity, explaining how a single enzyme achieves cycling of the complete O-GlcNAc proteome. In addition, this work will aid development of O-GlcNAcase inhibitors that target the peptide binding site.