Abstract
Proteomics techniques can identify thousands of phosphorylation sites in a single experiment, the majority of which are new and lack precise information about function or molecular mechanism. Here we present a fast method to predict potential phosphorylation switches by mapping phosphorylation sites to protein-protein interactions of known structure and analysing the properties of the protein interface. We predict 1024 sites that could potentially enable or disable particular interactions. We tested a selection of these switches and showed that phosphomimetic mutations indeed affect interactions. We estimate that there are likely thousands of phosphorylation mediated switches yet to be uncovered, even among existing phosphorylation datasets. The results suggest that phosphorylation sites on globular, as distinct from disordered, parts of the proteome frequently function as switches, which might be one of the ancient roles for kinase phosphorylation.
Highlights
Most biological processes occur by molecules connecting to other molecules, and the precise details of these connections can often be seen in their three-dimensional structures or inferred from those of similar molecules
Protein phosphorylation is important for many cellular processes, including signalling (e.g. [1]), transcription (e.g. [2]) and metabolism (e.g. [3])
To search for new potential switches we used a processed dataset of 223,971 phosphosites in 19,483 proteins from five organisms, defining the 1.6 million to date unphosphorylated Serine, Threonine and Tyrosine residues in the same proteins as background (Fig 1A)
Summary
Protein phosphorylation is important for many cellular processes, including signalling (e.g. [1]), transcription (e.g. [2]) and metabolism (e.g. [3]). Protein phosphorylation is important for many cellular processes, including signalling Many phosphorylation sites act as switches to regulate inter-protein interactions [17]) meaning that the molecular consequences of phosphorylation are not understood for most sites. Functional phosphosites have been proposed to have evolved from negatively charged amino acids, by making charge-mediated protein interactions tunable by kinases [21]. Functional coupling and/or co-evolution of sites has been suggested to be an important determinant of protein function [20,22], with codes of posttranslational modifications refining protein function, for example in transcription factors [23,24]. While many important proteins are known to be modified at multiple sites, the functional implications of these codes are understood for only a handful
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