AbstractVarious post-translational modifications (PTMs) fine-tune the functions of almost all eukaryotic proteins, and co-regulation of different types of PTMs has been shown within and between a number of proteins. Aiming at a more global view of the interplay between PTM types, we collected modifications for 13 frequent PTM types in 8 eukaryotes, compared their speed of evolution and developed a method for measuring PTM co-evolution within proteins based on the co-occurrence of sites across eukaryotes. As many sites are still to be discovered, this is a considerable underestimate, yet, assuming that most co-evolving PTMs are functionally associated, we found that PTM types are vastly interconnected, forming a global network that comprise in human alone 50 000 residues in about 6000 proteins. We predict substantial PTM type interplay in secreted and membrane-associated proteins and in the context of particular protein domains and short-linear motifs. The global network of co-evolving PTM types implies a complex and intertwined post-translational regulation landscape that is likely to regulate multiple functional states of many if not all eukaryotic proteins.SynopsisThis study is the first large-scale comparative analysis of multiple types of post-translational modifications in different eukaryotic species. The resulting network of co-evolving and functionally associated modifications reveals the global landscape of post-translational regulation.In all, 115 149 non-redundant post-translational modifications (PTMs) of 13 different types were collected from 8 eukaryotes.Comparison of evolution speed reveals that carboxylation is the most conserved while SUMOylation is the fastest evolving PTM type.Co-evolution of PTM pairs that co-occur within proteins reveals a vastly interconnected global network of functionally associated PTM types in eukaryotes.Central to the network of functionally associated PTM types appear phosphorylation, acetylation, ubiquitination and O-linked glycosylation that control both temporal events and processes that govern protein localization.
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