Crosstalk between phosphorylation and O‐GlcNAcylation: friend or foe

Abstract

A wide variety of protein post-translational modifications (PTMs) decorate cellular proteins, regulating their structure, interactions and ultimately their function. The density of co-occurring PTMs on proteins can be very high, where multiple PTMs can positively or negatively influence each other's actions, termed PTM crosstalk. In this review, we highlight recent progress in the area of PTM crosstalk, whereby we focus on crosstalk between protein phosphorylation and O-GlcNAcylation. These two PTMs largely target identical (i.e., Ser and Thr) amino acids in proteins. Phosphorylation/O-GlcNAcylation crosstalk comes in many flavors, for instance by competition for the same site/residue (reciprocal crosstalk), as well as by modifications influencing each other in proximity or even distal on the protein sequence. PTM crosstalk is observed on the writers of these modifications (i.e., kinases and O-GlcNAc transferase), on the erasers (i.e., phosphatases and O-GlcNAcase), and on the readers and the substrates. We describe examples of all these different flavors of crosstalk, and additionally the methods that are emerging to better investigate in particular phosphorylation/O-GlcNAcylation crosstalk.

Functional analysis tools for post‐translational modification: a post‐translational modification database for analysis of proteins and metabolic pathways

“…While this result does indicate that these two modifications can compete with one another, this number of shared sites is quite low compared with other organisms and may reflect the currently low number of SUMOylation events with precise sequence localization in the FAT‐PTM database. We further examined the PTM site overlap between serine/threonine phosphorylation and O ‐GlcNAc modification, since site‐specific competitive modification of proteins with these PTMs is known to differentially regulate protein function (van der Laarse et al ., ). In this analysis, we identified 29 proteins and 37 serine or threonine sites that contained experimentally supported phosphorylation and O ‐GlcNAcylation modifications.…”

“…Increasing evidence also suggests that proteins are subject to multiple PTMs, and that these PTM patterns can be used to integrate multiple stimuli for a combined protein output (Beltrao et al ., ; van der Laarse et al ., ). Indeed, our current database indicates that 35.3% of the Arabidopsis proteins in the FAT‐PTM database are modified by two or more distinct PTMs.…”

Common and Strain-Specific Post-Translational Modifications of the Potyvirus Plum pox virus Coat Protein in Different Hosts

“…PTMs not only expand proteome size but also provide individual proteins with greater functional dynamism. This especially applies to phosphorylation and O-GlcNAcylation, two very frequent and closely related PTMs [31,66]. Thus, it is not unexpected that these PTMs have been found in a protein, such as potyviral CP, responsible for coordinating so many important functions [25,29,67].…”

“…The CP of another potyvirus, Plum pox virus (PPV), is also phosphorylated [28,29]. Interestingly, PPV CP is also modified by a second PTM, O-GlcNAcylation [28,30], which is known to be functionally linked to phosphorylation in many dynamic regulatory activities [31] and has been shown to play important roles in animal virus infections [32][33][34][35]. This makes PPV CP an attractive subject to study the joint contribution of these closely related PTMs in the regulation of viral infection.…”

Study of cross talk between phosphatases and OGA on a ZO-3-derived peptide

“…The mapping of O-GlcNAcylation sites in proteins using mass spectrometry revealed that in addition to the above interplay involving serine and threonine phosphorylation (Leney et al 2017;van der Laarse et al 2018), there may also be cross talk between O-GlcNAcylation and tyrosine phosphorylation (Mishra et al 2011;van der Laarse et al 2018).…”