Abstract
Protein phosphorylation in eukaryotes is carried out by a large and diverse family of protein kinases, which display remarkable diversity and complexity in their modes of regulation. The complex modes of regulation have evolved as a consequence of natural selection operating on protein kinase sequences for billions of years. Here we describe how quantitative comparisons of protein kinase sequences from diverse organisms, in particular prokaryotes, have contributed to our understanding of the structural organization and evolution of allosteric regulation in the protein kinase domain. An emerging view from these studies is that regulatory diversity and complexity in the protein kinase domain evolved in a ‘modular’ fashion through elaboration of an ancient core component, which existed before the emergence of eukaryotes. The core component provided the conformational flexibility required for ATP binding and phosphoryl transfer in prokaryotic kinases, but evolved into a highly regulatable domain in eukaryotes through the addition of exaggerated structural features that facilitated tight allosteric control. Family and group-specific features are built upon the core component in eukaryotes to provide additional layers of control. We propose that ‘modularity’ and ‘conformational flexibility’ are key evolvable traits of the protein kinase domain that contributed to its extensive regulatory diversity and complexity.
Highlights
Eukaryotic protein kinases (EPKs) catalyse the transfer of the terminal phosphate group from ATP (g-phosphate) to the hydroxyl group of a serine, threonine or tyrosine residue in protein substrates
Since signalling pathways control important cellular processes such as transcription, cell cycle progression, differentiation and apoptosis, precise regulation of protein kinase activity is critical for the survival of the eukaryotic cell
Crystal structures of several EPKs solved in both active and inactive forms reveal the conformational flexibility of the catalytic core and its role in regulating protein kinase activity
Summary
Eukaryotic protein kinases (EPKs) catalyse the transfer of the terminal phosphate group from ATP (g-phosphate) to the hydroxyl group of a serine, threonine or tyrosine residue in protein substrates. Crystal structures of APH solved in nucleotide bound and unbound forms do not display the dramatic conformational changes typically observed in EPKs [23] Both EPKs and ELKs are more distantly related to several distinct classes of atypical kinases (APKs) [25] that phosphorylate certain protein and small molecule substrates. These motifs, shown, correspond to: (i) a glycine within the ATP-binding G-loop (sub-domain I), (ii) a lysine/ arginine in beta sheet 3 (sub-domain II) that binds ATP, (iii) glutamate in C-helix (sub-domain III) that coordinates with the beta sheet 3 lysine/arginine, (iv) aspartate in the catalytic loop (sub-domain VIb) that serves as a catalytic base, (v) a magnesium ion coordinating asparagine in the catalytic loop (subdomain VIb) [36], and (vi) a magnesium coordinating aspartate in the beginning of the activation segment (sub-domain VII) [41,42] These residues/motifs, which mostly occur in the N-terminal ATP-binding lobe (figure 1), appear to define the minimum structural requirements for adopting the PKL fold [25,33]. Such separation of functions (ATP binding in N-lobe and substrate binding in C-lobe) would lend the kinase domain a substantial degree of flexibility/robustness in evolving multiple substrate specificities within the same catalytic framework (figure 2b)
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