Abstract
Protein kinases have evolved in eukaryotes to be highly dynamic molecular switches that regulate a plethora of biological processes. Two motifs, a dynamic activation segment and a GHI helical subdomain, distinguish the eukaryotic protein kinases (EPKs) from the more primitive eukaryotic-like kinases. The EPKs are themselves highly regulated, typically by phosphorylation, and this allows them to be rapidly turned on and off. The EPKs have a novel hydrophobic architecture that is typically regulated by the dynamic assembly of two hydrophobic spines that is usually mediated by the phosphorylation of an activation loop phosphate. Cyclic AMP-dependent protein kinase (protein kinase A (PKA)) is used as a prototype to exemplify these features of the PKA superfamily. Specificity in PKA signalling is achieved in large part by packaging the enzyme as inactive tetrameric holoenzymes with regulatory subunits that then are localized to macromolecular complexes in close proximity to dedicated substrates by targeting scaffold proteins. In this way, the cell creates discrete foci that most likely represent the physiological environment for cyclic AMP-mediated signalling.
Highlights
The concept of protein phosphorylation as a mechanism for regulation began with the pioneering studies of Krebs and Fischer in the middle of the last century [1,2]
How did these unique proteins evolve, and how are they different from the metabolic enzymes that we have studied in such depth? We discuss here the essential features that define the eukaryotic protein kinases (EPKs) and distinguish them from the earlier and simpler eukaryotic-like kinases (ELKs)
From such genome-wide screens, we discover that EPKs evolved from much simpler ELKs that are abundant in prokaryotes [27]
Summary
The concept of protein phosphorylation as a mechanism for regulation began with the pioneering studies of Krebs and Fischer in the middle of the last century [1,2]. Each PKA R-subunit contains two contiguous cyclic nucleotide-binding (CNB) domains, and these CNB domains are widespread in the prokaryotic world [12] They appear to be an ancient motif that has co-evolved with cAMP as a mechanism for translating the stress-induced cAMP second messenger into a biological response. The closest homologue to PKA is cyclic GMP (cGMP)-dependent protein kinase (protein kinase G (PKG)), but in this case the kinase domain is fused to the CNB domains [13,14] Both cAMP and cGMP domains are first found functionally linked to an EPK early in the evolution of eukaryotes. To achieve such an integrated understanding of signalling requires many disciplines that include computational strategies to link the proteins into well-defined pathways
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