Abstract
Phosphorylation is a widespread post-translational modification that modulates the function of a large number of proteins. Here we show that a significant proportion of all the domains in the human proteome is significantly enriched or depleted in phosphorylation events. A substantial improvement in phosphosites prediction is achieved by leveraging this observation, which has not been tapped by existing methods. Phosphorylation sites are often not shared between multiple occurrences of the same domain in the proteome, even when the phosphoacceptor residue is conserved. This is partly because of different functional constraints acting on the same domain in different protein contexts. Moreover, by augmenting domain alignments with structural information, we were able to provide direct evidence that phosphosites in protein-protein interfaces need not be positionally conserved, likely because they can modulate interactions simply by sitting in the same general surface area.
Highlights
Phosphorylation, the most widespread protein post-translational modification, is an important regulator of protein function
All the phosphorylation sites were mapped on UniProt sequences, checking for the identity of a 10-residue window centered on the phosphosite
Our results show that 7% of the domain types in the proteome are significantly enriched or depleted in phosphorylation
Summary
Phosphorylation, the most widespread protein post-translational modification, is an important regulator of protein function. The “context,” in a broad sense, where these motifs occur is important as sequence alone is not enough to achieve the observed specificity of phosphorylation. Placing kinases and substrates in the context of protein interaction networks has been shown to improve the prediction of phosphorylation by specific kinases [13]. Perhaps one of the most puzzling observations when looking at the phosphoproteome as a whole, is the fact that a large proportion of phosphorylation sites is poorly conserved. Especially in the regulation of protein-protein interactions, the exact position of the phosphosites may be unimportant [18, 19]
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