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Structures of human O-GlcNAcase and its complexes reveal a new substrate recognition mode

Nature Structural & Molecular Biology volume 24, pages 362–369 (2017)Cite this article

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Abstract

Human O-GlcNAcase (hOGA) is the unique enzyme responsible for the hydrolysis of the O-linked β-N-acetyl glucosamine (O-GlcNAc) modification, an essential protein glycosylation event that modulates the function of numerous cellular proteins in response to nutrients and stress. Here we report crystal structures of a truncated hOGA, which comprises the catalytic and stalk domains, in apo form, in complex with an inhibitor, and in complex with a glycopeptide substrate. We found that hOGA forms an unusual arm-in-arm homodimer in which the catalytic domain of one monomer is covered by the stalk domain of the sister monomer to create a substrate-binding cleft. Notably, the residues on the cleft surface afford extensive interactions with the peptide substrate in a recognition mode that is distinct from that of its bacterial homologs. These structures represent the first model of eukaryotic enzymes in the glycoside hydrolase 84 (GH84) family and provide a crucial starting point for understanding the substrate specificity of hOGA, which regulates a broad range of biological and pathological processes.

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Figure 1: Overall structure of OGA and the construct used.
Figure 2: Dimerization of OGA.
Figure 3: Structure of OGAcryst in complex with thiamet-G.
Figure 4: Structure of the OGAcryst–p53 complex.

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Acknowledgements

We thank D. Smith and L. Carlson for assistance with X-ray data collection, K. Satyshur and D. McCaslin for helpful discussions, and members of the Jiang laboratory for critical reading of the manuscript. This work was supported by start-up funds from the University of Wisconsin–Madison (J.J.).

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Authors and Affiliations

  1. Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin–Madison, Madison, Wisconsin, USA

    Baobin Li, Hao Li, Lei Lu & Jiaoyang Jiang

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Contributions

J.J. oversaw all aspects of the experiments and manuscript preparation; B.L. performed cloning, mutagenesis, protein purification, enzymatic assays, analytical ultracentrifugation sedimentation equilibrium experiments, crystallization, and structural determination; H.L. synthesized thiamet-G; L.L. assisted with molecular cloning and protein purification; and B.L. and J.J. wrote the manuscript. All coauthors participated in editing the manuscript.

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Correspondence to Jiaoyang Jiang.

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Integrated supplementary information

Supplementary Figure 1 Substrate-assisted mechanism of OGA.

OGA-catalyzed hydrolysis of O-GlcNAcylation via a substrate-assisted mechanism, adapted from a previous report (Dennis, R. J. et al., Nat. Struct. Mol. Biol. 13, 365–371, 2006). The roles of ancillary residues Lys98 and Tyr219 are inferred from the crystal structure of OGAcryst–thiamet-G from this study.

Supplementary Figure 2 Kinetic parameters of hOGA and OGAcryst proteins.

(a) Michaelis–Menten plots of hOGA and OGAcryst with varying concentrations of 4MU-NAG. Data were fitted using GraphPad Prism. Error bars represent s.d. values derived from three independent experiments. (b) Summary of the kinetic parameters of hOGA and OGAcryst. The Km and kcat were determined from three independent experiments and displayed as average ± s.d.

Supplementary Figure 3 Structural comparison of the two sister monomers of OGAcryst.

Two perpendicular views of superimposed OGAα and OGAβ reveal that the catalytic domains are folded into an identical (β/α)8-barrel, while the stalk domains display a slight variation. OGAα is colored yellow; the catalytic domain and stalk domain of OGAβ are colored magenta and cyan, respectively.

Supplementary Figure 4 The sequence and structure of the hOGA stalk domain are markedly different from those of its bacterial homologs.

(a) Sequence alignment and (b-c) structural comparison of the stalk domains of OGA proteins from human (hOGA, cyan) and representative bacterial species: Oceanicola granulosus (OgOGA, PDB: 2XSA, magenta) (Schimpl, M. et al., Biochem. J. 432, 1–7, 2010), Bacteroides thetaiotaomicron (BtGH84, PDB: 2CHO, orange) (Dennis, R. J. et al., Nat. Struct. Mol. Biol. 13, 365–371, 2006), Clostridium perfringens (CpOGA, PDB: 2CBJ, green) (Rao, F. V. et al., EMBO J. 25, 1569–1578, 2006) and Thermobaculum terrenum (TtOGA, PDB: 5DIY, grey) (Ostrowski, A., et al., J. Biol. Chem. 290, 30291–30305, 2015). In the sequence alignment, variable and similar residues are shown in black and red, respectively.

Supplementary Figure 5 Extensive polar interactions stabilize the dimerization of OGAcryst.

(a) Two different views of OGAcryst with dimerization interface. OGAα is colored gray; the catalytic domain and stalk domain of OGAβ are colored magenta and cyan, respectively. (b) Schematic representation of the hydrogen bonds detected at the dimerization interface. (c) Schematic representation of the salt bridges detected at the dimerization interface. Residues from OGAα and OGAβ participating in the polar interactions are colored in yellow and green, respectively.

Supplementary Figure 6 Relative activities and substrate-binding evaluation of hOGA variants.

(a) The activities of hOGA mutants were measured using 4MU-NAG and normalized to the wild-type enzyme. The error bars represent the s.d. values derived from three independent experiments. (b) To evaluate the contribution of hydrophobic interactions with the p53 glycopeptide (Ac-QLWVDS(O-GlcNAc)TPPPG), the Michaelis constants of hOGA and mutants were determined using 4MU-NAG as the reporter substrate following multisubstrate enzyme kinetics as shown previously (Schimpl, M. et al., Biochem. J. 432, 1–7, 2010; Schimpl, M. et al., Chem. Biol. 19, 173–178, 2012; Xie, D. et al., Protein Science 8, 2460–2464, 1999). *The Michaelis constant of wild-type hOGA was measured towards a W(-3)A mutant of p53 glycopeptide (Ac-QLAVDS(O-GlcNAc)TPPPG) using a similar assay. The Km´ values were determined from three independent experiments and displayed as average ± s.d.

Supplementary Figure 7 Binding conformation of p53 glycopeptides in the OGAcryst–p53 complex.

(a) Fo–Fc difference map of p53 glycopeptides from the OGAcryst–p53 complex (contoured at 3σ). The peptides from OGAα and OGAβ are shown in orange and green sticks, respectively. Intramolecular hydrogen bonds are displayed as dotted lines. (b) Superposition of OGAcryst–p53 complex structures collected from three independent soaking experiments (inserts: enlarged p53 glycopeptides from each monomer. The p53 glycopeptides in the right insert have been rotated for better clarity). (c-d) Close-up views of the binding conformations of p53 glycopeptides in (c) OGAα and (d) OGAβ. Residues on the inner surface of the substrate-binding cleft that are in close vicinity of the peptide are highlighted in (c) blue sticks and (d) yellow sticks, respectively. Hydrogen bonds are displayed in dashed lines. (e-f) Crystal packing potentially contributes to stabilize p53 glycopeptide in OGAβ but not in OGAα. OGAα and OGAβ are shown in magenta and yellow, respectively. The symmetric molecule is shown in grey.

Supplementary Figure 8 The p53 glycopeptide adopts distinct binding conformations in the structures of human and bacterial OGAs.

(a) Superposition of the p53 glycopeptide (stick representation) in the CpOGA–p53 complex (PDB: 2YDR) (Schimpl, M. et al., Chem. Biol. 19, 173–178, 2012) with those in the OGAcryst–p53 complex. (b) Surface representation of the CpOGA–p53 complex, highlighting the p53 glycopeptide (yellow) bound on top of the active site (PDB: 2YDR). (c) Surface representation of the p53 glycopeptide (orange) bound in the substrate-binding cleft that comprises the catalytic domain of OGAα (grey) and the stalk domain of OGAβ (cyan). (d) Surface representation of the p53 glycopeptide (green) bound in the substrate-binding cleft that comprises the stalk domain of OGAα (grey) and the catalytic domain of OGAβ (magenta). In b-d panels, stick presentation of p53 glycopeptides is displayed as semitransparent.

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Li, B., Li, H., Lu, L. et al. Structures of human O-GlcNAcase and its complexes reveal a new substrate recognition mode. Nat Struct Mol Biol 24, 362–369 (2017). https://doi.org/10.1038/nsmb.3390

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