Circles within circles: crosstalk between protein Ser/Thr/Tyr-phosphorylation and Met oxidation

Abstract

BackgroundReversible posttranslational protein modifications such as phosphorylation of Ser/Thr/Tyr and Met oxidation are critical for both metabolic regulation and cellular signalling. Although these modifications are typically studied individually, herein we describe the potential for cross-talk and hierarchical regulation.ResultsThe proximity of Met to Ser/Thr/Tyr within the proteome has not previously been addressed. In order to consider the possibility of a generalized interaction, we performed a trans-kingdom sequence analysis of known phosphorylation sites in proteins from bacteria, fungi, plants, and animals. The proportion of phosphorylation sites that include a Met within a 13-residue window centered upon Ser/Thr/Tyr is significantly less than the occurrence of Met in proximity to all Ser/Thr/Tyr residues. Met residues are present at all positions (-6 to +6, inclusive) within the 13-residue window that we have considered. Detailed analysis of sequences from eight disparate plant taxa revealed that many conserved phosphorylation sites have a Met residue in the proximity. Results from GO enrichment analysis indicated that the potential for phosphorylation and Met oxidation crosstalk is most prevalent in kinases and proteins involved in signalling.ConclusionThe large proportion of known phosphorylation sites with Met in the proximity fulfils the necessary condition for cross-talk. Kinases/signalling proteins are enriched for Met around phosphorylation sites. These proteins/sites are likely candidates for cross-talk between oxidative signalling and reversible phosphorylation.

Convergent signaling pathways—interaction between methionine oxidation and serine/threonine/tyrosine O-phosphorylation

“…However, the common occurrence of Met adjacent to Ser/ Thr/Tyr residues (Rao et al 2013) and the frequent occurrence of MetSO (Ghesquière et al 2011;Liu et al 2013;Salvato et al 2014) near O-phosphorylation-sites (Song et al 2012) suggests that crosstalk between these two PTM's is widespread. (Hardin et al 2009;Miernyk et al 2009), oxidation of Met might directly inhibit O-phosphorylation of a nearby Ser/Thr/Tyr-residue by interfering with the kinase recognition/binding (Fig.…”

“…Furthermore, many enzymes have an activesite Cys residue (e.g., Waszczak et al 2014). In contrast, there is no established catalytic role for Met, and the structural role of Met can often be replaced by any other hydrophobic residues (Ile, Leu, Phe, and Val; Levine et al 1996;Rao et al 2013). Thus, reversible Met oxidation has a separate, distinct, and more specific regulatory potential.…”

“…While reversible Met oxidation is an effective mechanism to directly regulate many protein activities, interactions (or crosstalk) with other PTM has the potential for a far broader dynamic control of protein activities and cellular processes (Rao et al 2013). An obvious candidate for such a crosstalk would be O-phosphorylation, the most well-known PTMbased signaling mechanism.…”

Methionine residues around phosphorylation sites are preferentially oxidized in vivo under stress conditions

“…However, the identification of PTM crosstalk at the proteome level remains a great challenge. As a first approach, Rao and co-workers performed computational analyses of the phosphoproteome of several species, concluding that the large proportion of known phosphorylation sites with methionine in their proximity fulfils the necessary condition for crosstalk22. On the other hand, the awareness that methionine oxidation may provide a mechanism for the redox-dependent modulation of a wide range of protein functions and cellular processes has prompted proteome-wide studies of methionine oxidation, which have allowed the identification of a large number of human cellular proteins as potential targets of oxidative signals23.…”

Recent advances and challenges in plant phosphoproteomics

“…Protein phosphorylation may crosstalk with redox modifications such as methionine oxidation. A large number of conserved phosphorylation sites were found in the proximity of methionine residues in the proteomes of eight disparate plant taxa . Interestingly, protein kinases and proteins involved in signaling have the most prevalent phosphorylation and methionine oxidation sites, supporting the potential crosstalk between oxidative signaling and protein kinase signaling.…”