The methylproteome and the intracellular methylation network

Abstract

Since its discovery more than 50 years ago, post-translational modification (PTM) of proteins via methylation has grown in prominence, its involvement having been recognised in a number of central processes in the cell. Of these, the best characterised is its role in the epigenetic code. However, there is increasing evidence that its role extends far beyond this and we propose that it is a key regulator in interactome dynamics. In this review, we focus on the role of methylation in regulating protein-protein interactions and illustrate, by providing a broad-scale summary of our current knowledge of methylation and its impact on systems biology, how this can ultimately affect interactome dynamics. We describe the variety of analytical techniques available for the study of the methylproteome, comment on their advantages and limitations, and consider how these tools can help elucidate how methylation regulates the dynamics of the interactome. The insights gained from methyltransferase-substrate networks will be summarised and the ability of protein methylation to facilitate or block protein-protein interactions as well as their interplay with other post-translational modifications, in particular phosphorylation, is highlighted. Finally, the importance of methylation in pathology-associated protein interaction networks will be discussed using examples involving human diseases and the p53 protein.

The ribosome: A hot spot for the identification of new types of protein methyltransferases

“…can be targets for ubiquitin-E3 linked degradation (21), can facilitate or block protein-protein interactions or enzyme-substrate interactions (6,22), and can modulate interactions with RNA (7,23,24). An important recent discovery is that the three hydrogen atoms on methyl groups bound to positively charged nitrogen or sulfur atoms may themselves be able to serve as hydrogen bond donors, greatly expanding the possibilities for interactions (25,26; Figure 1).…”

“…However, it is now clear that methyl groups can stand beside phosphate groups and ubiquitin as major players in controlling the physiological functions of proteins. We are beginning to understand how the much greater diversity of protein methylation reactions can give rise to a greater diversity of function (1,(4)(5)(6)(7)(8). We are also learning the importance of crosstalk between protein and DNA methylation reactions (9) and among protein methylation, phosphorylation, acetylation, and ubiquitination reactions (10)(11)(12).…”

A Y2H-seq approach defines the human protein methyltransferase interactome

“…From comparison with other abundant modifications, it has become clear that protein methylation of arginine (R) and lysine (K) residues is an important, ubiquitous post-translational modification in eukaryotic cells 6,7 .…”

“…We applied Y2H-seq for interactome mapping of a largely unexplored set of human proteins: those involved in protein methylation and demethylation 6 . From comparison with other abundant modifications, it has become clear that protein methylation of arginine (R) and lysine (K) residues is an important, ubiquitous post-translational modification in eukaryotic cells 6,7 .…”

Protein Arginine Allylation and Subsequent Fluorophore Targeting

“…Although many analytical techniques have been developed, difficulties still exist to achieveasystemslevel understanding of the methylproteome, especially methylated proteins in low abundance. [2] To advance this area, SAM analogues bearing reactive functionalities have recently been explored to specifically label the methylation sites by using natural [3] or engineered MTases. [4] Once these reactive functionalities have been incorporated, furtherderivationcan introduce chemicale ntitiest os tudy methylation with readily available analytical and biochemical tools (Scheme 1B).…”