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Protein ubiquitination is central to the regulation of various pathways in eukaryotes. The process of ubiquitination and its cellular outcome were investigated in hundreds of proteins to date. Despite this, the evolution of this regulatory mechanism has not yet been addressed comprehensively. Here, we quantify the rates of evolutionary changes of ubiquitination and SUMOylation (Small Ubiquitin-like MOdifier) sites. We estimate the time at which they first appeared, and compare them to acetylation and phosphorylation sites and to unmodified residues. We observe that the various modification sites studied exhibit similar rates. Mammalian ubiquitination sites are weakly more conserved than unmodified lysine residues, and a higher degree of relative conservation is observed when analyzing bona fide ubiquitination sites. Various reasons can be proposed for the limited level of excess conservation of ubiquitination, including shifts in locations of the sites, the presence of alternative sites, and changes in the regulatory pathways. We observe that disappearance of sites may be compensated by the presence of a lysine residue in close proximity, which is significant when compared to evolutionary patterns of unmodified lysine residues, especially in disordered regions. This emphasizes the importance of analyzing a window in the vicinity of functional residues, as well as the capability of the ubiquitination machinery to ubiquitinate residues in a certain region. Using prokaryotic orthologs of ubiquitinated proteins, we study how ubiquitination sites were formed, and observe that while sometimes sequence additions and rearrangements are involved, in many cases the ubiquitination machinery utilizes an already existing sequence without significantly changing it. Finally, we examine the evolution of ubiquitination, which is linked with other modifications, to infer how these complex regulatory modules have evolved. Our study gives initial insights into the formation of ubiquitination sites, their degree of conservation in various species, and their co-evolution with other posttranslational modifications.
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