Systematic Characterization and Prediction of Post-Translational Modification Cross-Talk *

Abstract

Post-translational modification (PTM) 1 plays an important role in regulating the functions of proteins. PTMs of multiple residues on one protein may work together to determine a functional outcome, which is known as PTM crosstalk. Identification of PTM cross-talks is an emerging theme in proteomics and has elicited great interest, but their properties remain to be systematically characterized. To this end, we collected 193 PTM cross-talk pairs in 77 human proteins from the literature and then tested location preference and co-evolution at the residue and modification levels. We found that cross-talk events preferentially occurred among nearby PTM sites, especially in disordered protein regions, and cross-talk pairs tended to co-evolve. Given the properties of PTM cross-talk pairs, a naïve Bayes classifier integrating different features was built to predict cross-talks for pairwise combination of PTM sites. By using a 10-fold cross-validation, the integrated prediction model showed an area under the receiver operating characteristic (ROC) curve of 0.833, superior to using any individual feature alone. The prediction performance was also demonstrated to be robust to the biases in the collected PTM cross-talk pairs. The integrated approach has the potential for large-scale prioritization of PTM cross-talk candidates for functional validation and was implemented as a web server available at

Structural-functional diversity of p53 proteoforms

“…Взаимозависимость обнаружена для ацетилирования и метилирования сайтов в С-концевой области p53 [75,76]. Разработаны программы для предсказания взаимовлияния ПТМ в различных белках, в том числе в белке р53 [77]. Авторы данных расчётов определили, что взаимовлияние предпочтительно происходит между ПТМ ближайших сайтов, особенно в неструктурированных областях белков.…”

Recent advances in phosphoproteomics and application to neurological diseases

“…192 Another group utilized PTM sequence and structural proximity along with co-evolution among vertebrates to build a naïve Bayesian model for prediction of PTM crosstalk. 193 Finally, it is possible to use text mining to find PTM-dependent protein-protein interactions with enzymes that modify the same protein at another site; 194 this last approach does not definitively indicate PTM crosstalk but provides sites for further study.…”

Towards understanding the crosstalk between protein post‐translational modifications: Homo‐ and heterotypic PTM pair distances on protein surfaces are not random

“…Phosphorylation sites were shown to cluster along protein sequences with other PTM types such as acetylation, ubiquitination, and sumoylation . Considering PTM pairs that not only co‐occur but also have a potential mutual relationship determining a specific functional outcome, a closer than expected sequence and spatial proximity was reported . Positive crosstalk, where one PTM triggers the addition of another PTM, was detected between sequentially close acetylation sites, whereas distant ones feature negative crosstalk, which is defined by a competitive behavior of PTMs .…”

“…39 Although several studies investigating the interactions of PTMs have been performed already, most of them consider particular PTM type pairs 13,35-37 or provide insights into particular proteins and their PTMs only. 32,33 Most computational studies investigated the proximity of PTM sites focusing on sequence information, 26,35,36,38,39 which, as a proxy for spatial closeness, is limited to short sequence separations. While the comparison of actual PTM distributions in proteins to independent references was implemented to a certain degree and even 3D-structural calculations were performed, 21,38 factors such as the redundancy of proteins in the individual datasets, the solvent-accessibility of the respective PTM sites, and the introduction of independent random references have not been yet considered explicitly.…”