Elucidating crosstalk mechanisms between phosphorylation and O-GlcNAcylation

Aneika C. Leney, Dris El Atmioui, Wei Wu, Huib Ovaa, Albert J.R. Heck*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

61 Citations (Scopus)


Proteins can be modified by multiple posttranslational modifications (PTMs), creating a PTM code that controls the function of proteins in space and time. Unraveling this complex PTM code is one of the great challenges in molecular biology. Here, using mass spectrometry-based assays, we focus on the most common PTMs - phosphorylation and O-GlcNAcylation - and investigate how they affect each other. We demonstrate two generic crosstalk mechanisms. First, we define a frequently occurring, very specific and stringent phosphorylation/ O-GlcNAcylation interplay motif, (pSp/T)P(V/A/T)(gS/gT), whereby phosphorylation strongly inhibits O-GlcNAcylation. Strikingly, this stringent motif is substantially enriched in the human (phospho)proteome, allowing us to predict hundreds of putative O-GlcNAc transferase (OGT) substrates. A set of these we investigate further and show them to be decent substrates of OGT, exhibiting a negative feedback loop when phosphorylated at the P-3 site. Second, we demonstrate that reciprocal crosstalk does not occur at PX(S/T)P sites, i.e., at sites phosphorylated by proline-directed kinases, which represent 40% of all sites in the vertebrate phosphoproteomes.

Original languageEnglish
Pages (from-to)E7255-E7261
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number35
Publication statusPublished - 29 Aug 2017


  • Crosstalk
  • O-GlcNAcylation
  • Phosphorylation
  • Regulation
  • Signaling

ASJC Scopus subject areas

  • General


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