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Systematic Proteomic Analysis of Protein Methylation in Prokaryotes and Eukaryotes Revealed Distinct Substrate Specificity

The studies of protein methylation mainly focus on lysine and arginine residues due to their diverse roles in essential cellular processes from gene expression to signal transduction. Nevertheless, atypical protein methylation occurring on amino acid residues, such as glutamine and glutamic acid, is largely neglected until recently. In addition, the systematic analysis for the distribution of methylation on different amino acids in various species is still lacking, which hinders our understanding of its functional roles. In this study, we deeply explored the methylated sites in three species Escherichia coli, Saccharomyces cerevisiae, and HeLa cells by employing MS‐based proteomic approach coupled with heavy methyl SILAC method. We identify a total of 234 methylated sites on 187 proteins with high localization confidence, including 94 unreported methylated sites on nine different amino acid residues. KEGG and gene ontology analysis show the pathways enriched with methylated proteins are mainly involved in central metabolism for E. coli and S. cerevisiae, but related to spliceosome for HeLa cells. The analysis of methylation preference on different amino acids is conducted in three species. Protein N‐terminal methylation is dominant in E. coli while methylated lysines and arginines are widely identified in S. cerevisiae and HeLa cells, respectively. To study whether some atypical protein methylation has biological relevance in the pathological process in mammalian cells, we focus on histone methylation in diet‐induced obese (DIO) mouse. Two glutamate methylation sites showed statistical significance in DIO mice compared with chow‐fed mice, suggesting their potential roles in diabetes and obesity. Together, these findings expanded the methylome database from microbes to mammals, which will benefit our further appreciation for the protein methylation as well as its possible functions on disease.