Abstract
Protein kinases catalyse the phosphorylation of target proteins, controlling most cellular processes. The specificity of serine/threonine kinases is partly determined by interactions with a few residues near the phospho-acceptor residue, forming the so-called kinase-substrate motif. Kinases have been extensively duplicated throughout evolution, but little is known about when in time new target motifs have arisen. Here, we show that sequence variation occurring early in the evolution of kinases is dominated by changes in specificity-determining residues. We then analysed kinase specificity models, based on known target sites, observing that specificity has remained mostly unchanged for recent kinase duplications. Finally, analysis of phosphorylation data from a taxonomically broad set of 48 eukaryotic species indicates that most phosphorylation motifs are broadly distributed in eukaryotes but are not present in prokaryotes. Overall, our results suggest that the set of eukaryotes kinase motifs present today was acquired around the time of the eukaryotic last common ancestor and that early expansions of the protein kinase fold rapidly explored the space of possible target motifs.
Highlights
Protein kinases are essential for signal transduction and have been found in every eukaryotic species so far examined
We have explored the evolution of protein kinase specificity at the active site, using a combination of kinase sequence data, phosphorylation data, and kinase specificity models
Using the sequence of protein kinases across several species, we have shown that the evolution of new kinase families is dominated by sequence changes that are likely to impact upon kinase function, including kinase peptide specificity
Summary
Protein kinases are essential for signal transduction and have been found in every eukaryotic species so far examined. They are required for almost all cellular processes [1], and mutations in protein kinases are often associated with diseases such as cancer and diabetes [2,3,4]. Multiple factors define the specificity of the kinase [5]. The kinase and substrate must be coexpressed and colocalised, for example, and their interaction may be mediated by adaptor or scaffold proteins [6,7]. Selectivity is often defined by the structural interface between the kinase active site and the residues flanking the target serine, threonine, or tyrosine—the so-called peptide specificity of the kinase
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