Dual Coordination of Post Translational Modifications in Human Protein Networks

Abstract

Post-translational modifications (PTMs) regulate protein activity, stability and interaction profiles and are critical for cellular functioning. Further regulation is gained through PTM interplay whereby modifications modulate the occurrence of other PTMs or act in combination. Integration of global acetylation, ubiquitination and tyrosine or serine/threonine phosphorylation datasets with protein interaction data identified hundreds of protein complexes that selectively accumulate each PTM, indicating coordinated targeting of specific molecular functions. A second layer of PTM coordination exists in these complexes, mediated by PTM integration (PTMi) spots. PTMi spots represent very dense modification patterns in disordered protein regions and showed an equally high mutation rate as functional protein domains in cancer, inferring equivocal importance for cellular functioning. Systematic PTMi spot identification highlighted more than 300 candidate proteins for combinatorial PTM regulation. This study reveals two global PTM coordination mechanisms and emphasizes dataset integration as requisite in proteomic PTM studies to better predict modification impact on cellular signaling.

Author Summary

Normal cellular functioning is maintained by a vast array of macro-molecular machines that control both core and specialised molecular tasks. These machines are in large part multi-subunit protein complexes that undergo regulation at multiple levels, from expression of requisite components to a vast array of post translational modifications (PTMs). PTMs such as phosphorylation, ubiquitination and acetylation currently number up to more than 100,000 in the human proteome yet how, or if, they coordinate remains poorly understood. Here we show two mechanisms of systematic modification coordination that likely combine to provide finer control of protein complex function. Firstly, individual modifications selectively target protein complexes to execute specific molecular functions. Secondly, highly modified subunits of these complexes further accumulate multiple distinct modifications and contain regions of dense modification patterns, termed PTM integration (PTMi) spots. Through multiple PTM inputs, PTMi spots represent key regions for integrating multiple signals within these complexes, allowing finer regulation of protein function. Here we highlight the large extent of coordinated PTM regulation of protein complexes, and hence cellular function. Systematic dataset integration revealed biological insight into PTM mediated cellular regulatory mechanisms and further provides a resource for future hypothesis-driven studies.