Evolution of protein kinase substrate recognition at the active site

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 socalled 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 not present in prokaryotes. Overall, our results suggest that the set of eukaryotes kinase motifs present today was acquired soon after the eukaryotic last common ancestor and that early expansions of the protein kinase fold rapidly explored the space of possible target motifs.

Unraveling the molecular basis of host cell receptor usage in SARS-CoV-2 and other human pathogenic β-CoVs

“…Furt hermore, the experience in other scenarios has shown that mutating SDPs is, in general, sufficient to transform the properties between two groups of proteins of the same family, i.e. the interchange of the residues occupying the SDPs between two families implies a change in the associated biological properties (59)(60)(61)(62)(63) . Notable examples include the production of switch-of-function mutants of small GTPases with changed selectivity, or the change of transport specificity between MIP channel proteins by few amino acid substitutions (60,62) .…”

In vivoregulation of fluorescent fusion proteins by engineered kinases

“…It has been postulated that the range of possible targets is restricted by the structure of the kinase domain itself 105 . Although in principle our paradigm should be relatively easily extrapolated for use with different kinases and in other model systems, adding a protein binder to a catalytic domain of a kinase may influence protein folding, resulting in a perturbation in the positioning of the target with respect to the catalytic site and thus preventing phosphorylation.…”

dbPSP 2.0, an updated database of protein phosphorylation sites in prokaryotes

“…After the publication of dbPSP 1.0, it has been visited more than 180,000 times and has served as a highly useful resource for studying prokaryotic phosphorylation 50,[52][53][54][55][56] . For example, Garcia-Garcia et al re-analyzed the phosphoproteomic datasets in dbPSP and found that phosphoproteins are essential for the regulation of the cell cycle and DNA-mediated processes in bacteria 52 55 .…”

“…For example, Garcia-Garcia et al re-analyzed the phosphoproteomic datasets in dbPSP and found that phosphoproteins are essential for the regulation of the cell cycle and DNA-mediated processes in bacteria 52 55 . In addition, the phosphorylation data of representative prokaryotes from dbPSP was utilized for kinase motif enrichment analysis, and the results demonstrated that most eukaryotic phosphorylation motifs could not be recovered in prokaryotes 56 .…”