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Synergy of Peptide and Sugar in O-GlcNAcase Substrate Recognition

DOI: 10.1016/j.chembiol.2012.01.011 DOI Help
PMID: 22365600 PMID Help

Authors: Marianne Schimpl (Division of Cell Signalling & Immunology, College of Life Sciences, University of Dundee, U.K.) , Vladimir s. Borodkin (Division of Cell Signalling & Immunology, College of Life Sciences, University of Dundee, U.K.) , Lindsey j. Gray (Division of Cell Signalling & Immunology, College of Life Sciences, University of Dundee, U.K.) , Daan m.f. Van aalten (Division of Cell Signalling & Immunology, College of Life Sciences, University of Dundee, U.K.)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chemistry & Biology , VOL 19 (2) , PAGES 173 - 178

State: Published (Approved)
Published: February 2012
Diamond Proposal Number(s): 1223

Open Access Open Access

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.

Journal Keywords: Binding; Carbohydrates; Crystallography; X-Ray; Enzyme; Glycosylation; Humans; Hydrogen; Hydrophobic; Kinetics; N-Acetylglucosaminyltransferases; Peptides; Protein; Tertiary; Proteome; Substrate Specificity

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography

Other Facilities: ESRF