Hundreds of such modifications have been reported in the literature and some of these appear to be playing dominant roles, at least in terms of occurrence. Among the major sources of posttranslational regulation and cellular complexity are posttranslational modifications (PTMs Jensen, 2006), which are additions of peptides, chemical groups or other complex molecules to proteins that modify their activity, stability, degradation, localization, and ability to interact ( Sprang et al., 1988 Madeo et al., 1998 Vazquez et al., 2000 Khmelinskii et al., 2009). We now contemplate the idea that a large fraction of biological diversity originates in mechanisms that regulate protein expression and functions posttranscriptionally and posttranslationally. The rate of discovery of new protein forms is increasing with the growing sensitivity of biochemical, analytical and bioinformatics tools ( Smith et al., 2013). We describe how the evolution of clusters of phosphorylation sites can be studied under the framework of complex traits evolution and stabilizing selection. Here we discuss these two types of regulation and examine how they affect the rate and patterns of protein phosphorylation evolution. In this case, a group of phosphorylation sites in a given protein region contributes collectively to the modification of the protein, irrespective of the precise position of individual sites, through an aggregate property. The second mode is more akin to a rheostat than a switch. The first mode corresponds to the canonical and qualitative view whereby single phosphorylation sites act as molecular switches that either turn on or off specific protein functions through direct or allosteric effects. Two broad modes of action have been described for protein phosphorylation. While the mode of action and the function of most phosphorylation sites remain unknown, functional studies have shown that phosphorylation affects protein stability, localization and ability to interact. Phosphorylation of serines, threonines, and tyrosines are the most common modifications identified to date in eukaryotic proteomes. Most proteins are regulated by posttranslational modifications and changes in these modifications contribute to evolutionary changes as well as to human diseases. 6Center for Analysis of Genome Evolution and Function, University of Toronto, Toronto, ON, Canada.5Department of Ecology and Evolutionary Biology, University of Toronto, Toronto, ON, Canada.4Department of Cell and Systems Biology, University of Toronto, Toronto, ON, Canada.3Network for Research on Protein Function, Structure, and Engineering (PROTEO), Univeristé Laval, Québec, QC, Canada.2Institut de Biologie Intégrative et des Systèmes (IBIS), Université Laval, Québec, QC, Canada.1Département de Biologie, Université Laval, Québec, QC, Canada.Landry 1,2,3*, Luca Freschi 1,2,3, Taraneh Zarin 4 and Alan M.
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