Abstract
BackgroundProtein phosphorylation is the best studied post-translational modification strongly influencing protein function. Phosphorylated amino acids not only differ in physico-chemical properties from non-phosphorylated counterparts, but also exhibit different evolutionary patterns, tending to mutate to and originate from negatively charged amino acids (NCAs). The distribution of phosphosites along protein sequences is non-uniform, as phosphosites tend to cluster, forming so-called phospho-islands.MethodsHere, we have developed a hidden Markov model-based procedure for the identification of phospho-islands and studied the properties of the obtained phosphorylation clusters. To check robustness of evolutionary analysis, we consider different models for the reconstructions of ancestral phosphorylation states.ResultsClustered phosphosites differ from individual phosphosites in several functional and evolutionary aspects including underrepresentation of phosphotyrosines, higher conservation, more frequent mutations to NCAs. The spectrum of tissues, frequencies of specific phosphorylation contexts, and mutational patterns observed near clustered sites also are different.
Highlights
Protein post-translational modifications (PTMs) are important for a living cell (Schweiger & Linial, 2010; Kurmangaliyev, Goland & Gelfand, 2011; Studer et al, 2016; Huang et al, 2017)
Conserved phosphosites As protein phosphorylation in a vast majority of organisms has not been studied or has been studied rather poorly (Huang et al, 2017), the evolutionary analyses of phosphosites typically rely on the assumption of absolute conservation of the phosphorylation label assigned to STY amino acids on a considered tree (Kurmangaliyev, Goland & Gelfand, 2011; Miao et al, 2018)
We have demonstrated that clustered phosphosites differ from non-clustered ones in a number of aspects: (i) overrepresentation of phosphothreonines and underrepresentation of phosphotyrosines in phospho-islands (Fig. 2F); (ii) stronger conservation of clustered phosphoserines and phosphothreonines (Fig. 2G); (iii) larger proportion of sites phosphorylated in many tissues (Fig. 4C); (iv) significantly larger probability of mutations to glutamate for clustered relative to the individual phosphoserines; (v) larger fraction of sites with specific motifs in phospho-islands (Fig. 4A); (vi) mutational patterns in the proximity of phosphosites consistent with the context-retention hypothesis (Fig. 5)
Summary
Protein post-translational modifications (PTMs) are important for a living cell (Schweiger & Linial, 2010; Kurmangaliyev, Goland & Gelfand, 2011; Studer et al, 2016; Huang et al, 2017). By changing physico-chemical properties of proteins, PTMs affect their function, often introducing novel biological features (Pearlman, Serber & Ferrell, 2011). Protein phosphorylation is likely both the most common and the best studied PTM (Ptacek & Snyder, 2006; Schweiger & Linial, 2010; Huang et al, 2017). Phosphorylated amino acids differ in physico-chemical properties from non-phosphorylated counterparts, and exhibit different evolutionary patterns, tending to mutate to and originate from negatively charged amino acids (NCAs). Methods: Here, we have developed a hidden Markov model-based procedure for the identification of phospho-islands and studied the properties of the obtained phosphorylation clusters. The spectrum of tissues, frequencies of specific phosphorylation contexts, and mutational patterns observed near clustered sites are different
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