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. 2020 Mar 20;15(3):602-617.
doi: 10.1021/acschembio.9b01015. Epub 2020 Mar 10.

The O-GlcNAc Modification on Kinases

Paul A Schwein  1 , Christina M Woo  1
Affiliations

The O-GlcNAc Modification on Kinases

Paul A Schwein et al. ACS Chem Biol. .

Abstract

O-Linked N-acetyl glucosamine (O-GlcNAc) is a protein modification found on thousands of nuclear, cytosolic, and mitochondrial proteins. Many O-GlcNAc sites occur in proximity to protein sites that are likewise modified by phosphorylation. While several studies have uncovered crosstalk between these two signaling modifications on individual proteins and pathways, an understanding of the role of O-GlcNAc in regulating kinases, the enzymes that install the phosphate modification, is still emerging. Here we review recent methods to profile the O-GlcNAc modification on a global scale that have revealed more than 100 kinases are modified by O-GlcNAc and highlight existing studies about regulation of these kinases by O-GlcNAc. Continuing efforts to profile the O-GlcNAc proteome and understand the role of O-GlcNAc on kinases will reveal new mechanisms of regulation and potential avenues for manipulation of the signaling mechanisms at the intersection of O-GlcNAc and phosphorylation.

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Figures

Figure 1.
Figure 1.
The essential O-GlcNAc modification of proteins. A. Structure of O-GlcNAc (highlighted in red) and phosphate appended to a serine or threonine amino acid. B. O-GlcNAc is installed by OGT and removed by OGA to over 3,000 known nuclear and cytoplasmic proteins.
Figure 2.
Figure 2.
Modes of crosstalk between O-GlcNAc and phosphorylation. A. Post-translational modification of a protein with O-GlcNAc or phosphorylation may be competitive, where one modification precludes the other, or cooperative, where multiple modifications propagate specific regulatory outcomes. B. Modification of a kinase with O-GlcNAc can alter downstream substrate selection and signaling through phosphorylation.
Figure 3.
Figure 3.
Structure of OGT. A. Linear representation of full length OGT(13.5), mOGT(9), and sOGT(2.5). B. Model of the TPR domain (purple) and catalytic domain of OGT (yellow). Point mutations at H508 and K852 reduce catalytic activity (highlighted in red).
Figure 4.
Figure 4.
Structure of OGA isoforms. A. Linear representation of OGA isoforms I and II. Isoform I is full length OGA. Isoform II lacks the HAT-like domain. B. Crystal structure of the human OGA homodimer analogous to OGA(II) from the side view (PDB: 5UN9). The catalytic domain is grey and the stalk domain blue.
Figure 5.
Figure 5.
Workflow for Isotope Targeted Glycoproteomics (IsoTaG). Live cells are labeled with an azidosugar (e.g., Ac4GalNAz) as a reporter for the O-GlcNAc modification. Enrichment, digestion, and acid cleavage of the tag recovers the modified glycopeptide for characterization by MS.
Figure 6.
Figure 6.
Human kinome with known O-GlcNAc modified kinases circled in red. Illustration reproduced courtesy of Cell Signaling Technology, Inc. (www.cellsignal.com).
See this image and copyright information in PMC

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