Abstract
Methionine oxidation plays a relevant role in cell signaling. Recently, we built a database containing thousands of proteins identified as sulfoxidation targets. Using this resource, we have now developed a computational approach aimed at characterizing the oxidation of human methionyl residues. We found that proteins oxidized in both cell-free preparations (in vitro) and inside living cells (ex vivo) were enriched in methionines and intrinsically disordered regions. However, proteins oxidized ex vivo tended to be larger and less abundant than those oxidized in vitro. Another distinctive feature was their subcellular localizations. Thus, nuclear and mitochondrial proteins were preferentially oxidized ex vivo but not in vitro. The nodes corresponding with ex vivo and in vitro oxidized proteins in a network based on gene ontology terms showed an assortative mixing suggesting that ex vivo oxidized proteins shared among them molecular functions and biological processes. This was further supported by the observation that proteins from the ex vivo set were co-regulated more often than expected by chance. We also investigated the sequence environment of oxidation sites. Glutamate and aspartate were overrepresented in these environments regardless the group. In contrast, tyrosine, tryptophan and histidine were clearly avoided but only in the environments of the ex vivo sites. A hypothetical mechanism of methionine oxidation accounts for these observations presented.
Highlights
The accumulation of molecular oxygen in the primitive atmosphere opened the way for the harnessing of highly exergonic reactions based on O2 as a terminal electron acceptor, leading to an efficient aerobic metabolism able to support larger sized forms of life [1]
Methionine residues in proteins can be oxidized by reactive oxygen or nitrogen species to generate methionine sulfoxide
We developed a computational approach aimed to characterize the set of proteins and methionine sites from the human proteome that may be signaling-competent
Summary
The accumulation of molecular oxygen in the primitive atmosphere opened the way for the harnessing of highly exergonic reactions based on O2 as a terminal electron acceptor, leading to an efficient aerobic metabolism able to support larger sized forms of life [1]. Molecular oxygen is involved in a myriad of biosynthetic pathways, many of which are essential for specialized cell functions found exclusively in multicellular organisms [2]. All of these metabolic innovations did not come without a price paid in terms of oxidative stress. Cells have evolved mechanisms to sense the redox status and transduce that information to trigger adequate responses. In this context, the hypothesis that the oxidative modification of methionine residues may participate in cellular signaling has gained attention during the last years [4]
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