KU Leuven, Centre of Microbial and Plant Genetics, Leuven, Belgium.
Leiden University, Institute of Biology Leiden, Leiden, The Netherlands.
PLoS Comput Biol. 2021 May 12;17(5):e1008988. doi: 10.1371/journal.pcbi.1008988. eCollection 2021 May.
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.
翻译后修饰（PTMs）在活细胞中发挥着至关重要但常被忽视的作用，它通过调节蛋白质特性，如定位及其与相互作用分子的亲和力，从而使细胞能够快速适应不断变化的环境条件。我们之前已经对一个计算框架进行了基准测试，该框架用于预测PTMs对蛋白质 - 蛋白质相互作用稳定性的影响，其核心是分子动力学模拟，随后进行自由能计算。在本研究中，我们将此框架应用于公开可用的酿酒酵母蛋白质结构和PTM位点数据，这些数据是在正常和应激条件下确定的。我们预测了乙酰化和磷酸化对蛋白质 - 蛋白质相互作用的全蛋白质组效应，发现乙酰化在蛋白质相互作用中更频繁地具有局部稳定作用，而磷酸化则相反。然而，PTMs对蛋白质 - 蛋白质相互作用的总体影响比PTMs引入所引起的局部变化的简单总和更为复杂，这增进了我们对PTM串扰的理解。我们进一步利用获得的数据来计算PTMs引起的构象变化。最后，直系同源物中分析的PTM残基的保守性表明，对酵母蛋白质的一些预测将适用于其他生物体，包括人类。因此，这项工作有助于我们全面理解酵母及其他生物体中细胞蛋白质相互作用网络的调节。
