Decoding Post-Translational Modification Crosstalk With Proteomics

Abstract

Post-translational modification (PTM) of proteins allows cells to regulate protein functions, transduce signals and respond to perturbations. PTMs expand protein functionality and diversity, which leads to increased proteome complexity. PTM crosstalk describes the combinatorial action of multiple PTMs on the same or on different proteins for higher order regulation. Here we review how recent advances in proteomic technologies, mass spectrometry instrumentation, and bioinformatics spurred the proteome-wide identification of PTM crosstalk through measurements of PTM sites. We provide an overview of the basic modes of PTM crosstalk, the proteomic methods to elucidate PTM crosstalk, and approaches that can inform about the functional consequences of PTM crosstalk.

Keywords: crosstalk; mass spectrometry; post-translational modification; proteomics.

Graphical abstract

Fig. 1

The Toolbox for PTM crosstalk.A, the PTM machinery includes proteins that write, erase, and read the PTM. PTMs come in reversible and non-reversible forms, as monomers, polymers, and branched polymers. B, different modes of PTM crosstalk are separated based on intra- or inter-protein crosstalk. Proteins are illustrated in black, different PTMs as blue and red circles, the modification site is depicted as “x.”

Fig. 2

Predicted PTM crosstalk. Network plot indicating experimentally measured and predicted intra-protein crosstalk of selected PTMs in humans based on data collected and computed by PTMcode2 (29). Nodes correspond to selected PTM types and edges represent their connectivity. Edge color is indicative of crosstalk evidence (manual identification, same residue, structural prediction, or coevolution), and weight of the edge corresponds to observed/predicted pairs. The plot visualizes the immense space of potential crosstalk between PTMs in contrast to the few experimentally observed connections.

Fig. 3

Proteomic methods to study PTM crosstalk.A, different approaches to measure PTMs and their potential interactions. Proteins are illustrated as black tangled lines, peptides are shorter linear black lines, different PTMs as blue and red circles. B, technologies to directly study PTM crosstalk and functional consequences of PTM crosstalk.

Fig. 4

Web resources and databases to study PTM crosstalk. The PTMcode2, PTM-X, dbPTM, and CrosstalkDB are described. Illustration outlines type and form of input query, underlying algorithm or type of database and expected output.