The next level of complexity: Crosstalk of posttranslational modifications

Abstract

Beside gene expression and translational control, which are relatively slow, PTM of proteins represents the major level of regulation, from very fast and reversible to slow or irreversible processes. PTMs affect protein structure and act as molecular switches, which regulate the interaction of proteins with DNA, cofactors, lipids, and other proteins. In the past few years, evidence for extensive crosstalk between PTMs has accumulated. The combination of different PTMs on protein surfaces can create a "PTM code," which can be recognized by specific effectors to initiate/inhibit downstream events, only inducing/retaining a signal once the complementary incoming signals are present at the same time and place. Although MS-based proteomics has substantially improved our knowledge about PTMs, currently sensitive and dedicated analytical strategies are available only for few different types of PTM. Several recent studies focused on the combinatorial analysis of PTMs, but preferentially utilized peptide-centric bottom-up strategies might be too restricted to decipher complex PTM codes. Here, we discuss the current state of PTM crosstalk research and how proteomics may contribute to understanding PTM codes, representing the next level of complexity and one of the biggest challenges for future proteomics research.

Post-translational add-ons mark the path in exosomal protein sorting

“…Compartimentalization and specificity of the different E3 ligases participate in protein localization [93,94]. In addition, competition or crosstalk with other PTMs such as SUMOylation or Neddylation alters the fate of the modified protein [100]. Also, the complexity of the ubiquitin code includes homotypic, heterotypic, mixed or branched chains that distribute protein populations among many cellular processes such as proteasome degradation or endocytic trafficking, forming a ubiquitin-based protein ZIP code that has yet to be revealed [20-25, 33, 147].…”

“…Because many PTMs can modify proteins in the same residue, competition and crosstalk between different PTMs depending on different cell factors can change protein function and localization [100]. In summary, deciphering the sophisticated ubiquitin code is necessary to unveil specific functions of every chain topology in the selective import of proteins into exosomes.…”

The intricate dance of post-translational modifications in the rhythm of life

“…To date, over 450 unique protein modifications have been identified 10 . Here, we discuss a small number of modifications known to be critical for circadian regulation.…”

What Can Proteomics Tell Us About Platelets?

“…In this context, the extensive cross talk between different PTM and the existence of a PTM code that defines the functions of proteins, protein complexes, and signaling pathways have gained more and more attention. [178][179][180] The vast amount of data that comes from quantitative proteomics studies, however, will require a thorough evaluation using systems biology approaches not only for obtaining a systematic interpretation of signaling networks and nodes but also for the simulation of experiments and conditions that cannot be realized in vivo or in vitro. [181][182][183][184][185][186] This will lead to the description of (phospho)protein clusters that are characteristic for the various levels of inhibitory and activation pathways or that represent molecular signatures for those pathways, which are known to be affected in disease.…”