Abstract
BackgroundThe sulfoxidation of methionine residues within the phosphorylation motif of protein kinase substrates, may provide a mechanism to couple oxidative signals to changes in protein phosphorylation. Herein, we hypothesize that if the residues within a pair of phosphorylatable-sulfoxidable sites are functionally linked, then they might have been coevolving. To test this hypothesis a number of site pairs previously detected on human stress-related proteins has been subjected to analysis using eukaryote ortholog sequences and a phylogenetic approach.ResultsOverall, the results support the conclusion that in the eIF2α protein, serine phosphorylation at position 218 and methionine oxidation at position 222, belong to the same functional network. First, the observed data were much better fitted by Markovian models that assumed coevolution of both sites, with respect to their counterparts assuming independent evolution (p-value = 0.003). Second, this conclusion was robust with respect to the methods used to reconstruct the phylogenetic relationship between the 233 eukaryotic species analyzed. Third, the co-distribution of phosphorylatable and sulfoxidable residues at these positions showed multiple origins throughout the evolution of eukaryotes, which further supports the view of an adaptive value for this co-occurrence. Fourth, the possibility that the coevolution of these two sites might be due to structure-driven compensatory mutations was evaluated. The results suggested that factors other than those merely structural were behind the observed coevolution. Finally, the relationship detected between other modifiable site pairs from ataxin-2 (S814-M815), ataxin-2-like (S211-M215) and Pumilio homolog 1 (S124-M125), reinforce the view of a role for phosphorylation-sulfoxidation crosstalk.ConclusionsFor the four stress-related proteins analyzed herein, their respective pairs of PTM sites (phosphorylatable serine and sulfoxidable methionine) were found to be evolving in a correlated fashion, which suggests a relevant role for methionine sulfoxidation and serine phosphorylation crosstalk in the control of protein translation under stress conditions.
Highlights
The sulfoxidation of methionine residues within the phosphorylation motif of protein kinase substrates, may provide a mechanism to couple oxidative signals to changes in protein phosphorylation
We started by finding the maximum likelihood estimates (MLE) of the four parameters of the model of independent evolution that best fitted to our data
The trees obtained using methods based on genetic distances, maximum parsimony and maximum likelihood were slightly different between them, in all the cases we concluded that the model of coevolution between both post-translational modification (PTM) sites fit the observed data significantly better than the model of independent evolution, regardless of the method used to reconstruct the phylogeny
Summary
The sulfoxidation of methionine residues within the phosphorylation motif of protein kinase substrates, may provide a mechanism to couple oxidative signals to changes in protein phosphorylation. The importance of this mechanism of translation attenuation may have been overestimated as convincingly argued by Knutsen and coworkers [3] These authors found that when the fission yeast Schizosaccharomyces pombe was exposed to hydrogen peroxide, protein synthesis was drastically reduced and eIF2α was phosphorylated on Ser-52 (homologous to Ser-51 in mammalian cells). Results obtained using other model organisms such as the budding yeast Saccharomyces cerevisiae and mammalian cells, point to the existence of a hitherto unrecognized mechanism contributing to the regulation of translation after stress, independent of the phosphorylation at Ser-51 on eIF2α [3,4,5]
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