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Post-translational modifications

A shift for the O-GlcNAc paradigm

Nature Chemical Biology volume 6, pages 634–635 (2010)Cite this article

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Many nuclear and cytoplasmic proteins are post-translationally modified by both O-GlcNAc and phosphate, but determining whether a single copy of a protein bears multiple modifications remains a challenge. A new analytic approach reveals a surprising correlation between phosphorylation and the O-GlcNAc modification.

Since its discovery less than 30 years ago1, O-GlcNAc glycosylation has emerged as a ubiquitous post-translational modification2. Nearly 1,000 transcription factors, translational regulators, cytoskeletal components and other nucleocytoplasmic proteins have been found to bear this simple glycan, which consists of a single N-acetylglucosamine (GlcNAc) residue attached in a β linkage to a serine or threonine side chain. Like phosphorylation, O-GlcNAc glycosylation is a dynamic modification, and all metazoans harbor genes encoding at least one O-GlcNAc transferase (OGT) that adds O-GlcNAc and one O-GlcNAcase (OGA) that removes it. Although historically overlooked, O-GlcNAc has clear physiological significance: it has been shown that OGT is required for embryogenesis in mice3, whereas OGT overexpression leads to insulin resistance and hyperleptinemia4. Through these and other organismal studies5, O-GlcNAc glycosylation is now coming into view as an essential regulatory modification. The current challenges are to discover the protein functions that are altered by O-GlcNAc modification and reveal the molecular mechanisms by which O-GlcNAc imparts these changes. Although some studies have documented the functional significance of O-GlcNAc modification at specific sites (see, for example, ref. 6), the competing and interrelated effects of multiple post-translational modifications often complicate the interpretation of data. In this issue, Rexach et al. report a simple yet innovative mass-tagging approach for quantifying O-GlcNAc modification levels and use this technique to characterize simultaneously the O-GlcNAc glycosylation states and phosphorylation states of intact proteins7. When compared to existing methods, their technique has the distinct advantage of providing information about the coexistence of multiple modifications on a single protein.

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Figure 1: Mapping multiple post-translational modifications.

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  1. Jennifer J. Kohler is in the Division of Translational Research in the Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.,

    Jennifer J Kohler

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  1. Jennifer J Kohler
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Correspondence to Jennifer J Kohler.

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The author declares no competing financial interests.

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Kohler, J. A shift for the O-GlcNAc paradigm. Nat Chem Biol 6, 634–635 (2010). https://doi.org/10.1038/nchembio.429

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