Abstract
Post-translational modifications (PTMs) play a vital, yet often overlooked role in the living cells through modulation of protein properties, such as localization and affinity towards their interactors, thereby enabling quick adaptation to changing environmental conditions. We have previously benchmarked a computational framework for the prediction of PTMs' effects on the stability of protein-protein interactions, which has molecular dynamics simulations followed by free energy calculations at its core. In the present work, we apply this framework to publicly available data on Saccharomyces cerevisiae protein structures and PTM sites, identified in both normal and stress conditions. We predict proteome-wide effects of acetylations and phosphorylations on protein-protein interactions and find that acetylations more frequently have locally stabilizing roles in protein interactions, while the opposite is true for phosphorylations. However, the overall impact of PTMs on protein-protein interactions is more complex than a simple sum of local changes caused by the introduction of PTMs and adds to our understanding of PTM cross-talk. We further use the obtained data to calculate the conformational changes brought about by PTMs. Finally, conservation of the analyzed PTM residues in orthologues shows that some predictions for yeast proteins will be mirrored to other organisms, including human. This work, therefore, contributes to our overall understanding of the modulation of the cellular protein interaction networks in yeast and beyond.
Highlights
Since the first mentions of post-translational modifications (PTMs) in PubMed, dating to the 1940s, it has become increasingly clear that the numerous types of PTMs and their crosstalk[1] have indispensable roles in the functioning of organisms from all three domains of life
Even though acetylations more frequently have locally stabilizing effects on binding, and phosphorylations destabilizing, in this work we demonstrate that the overall effect of co-occurring PTMs on the protein-protein binding is more complex than a sum of local changes, likely as a consequence of conformational changes
Before modeling PTMs onto 3D structures of these protein complexes, acetylation and phosphorylation sites of Saccharomyces cerevisiae retrieved from the public databases were separated based on the conditions in which yeast was grown when each respective PTM has been identified
Summary
Since the first mentions of post-translational modifications (PTMs) in PubMed, dating to the 1940s, it has become increasingly clear that the numerous types of PTMs and their crosstalk[1] have indispensable roles in the functioning of organisms from all three domains of life. Additions of chemical moieties on designated amino acids are known to affect protein stability, activity and localization, as well as fine-tune the modified protein’s binding to its interacting partners.[2,3] It has been demonstrated for some types of PTMs that the interface located sites have higher conservation [4], suggesting that these PTMs might be more functionally relevant, as they can exert a direct influence on protein-protein interactions. In addition to these direct effects, PTMs are known to allosterically impact the conformation of proteins, further altering their respective functions.[5]. Acetylation has been implicated in a wide range of cellular roles, such as autophagy, cell cycle, and cytoskeleton organization, to mention just a few.[3]
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