Elucidating crosstalk mechanisms between phosphorylation and O-GlcNAcylation

作者：Leney Aneika C; El Atmioui Dris; Wu Wei; Ovaa Huib; Heck Albert J R^*

来源：Proceedings of the National Academy of Sciences, 2017, 114(35): E7255-E7261.

DOI：10.1073/pnas.1620529114

• O-GlcNAcylation
• phosphorylation
• crosstalk
• signaling
• regulation

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.

• 出版日期2017-8-29