Abstract
The protein kinase family is large and important, but it is only one family in a larger superfamily of homologous kinases that phosphorylate a variety of substrates and play important roles in all three superkingdoms of life. We used a carefully constructed structural alignment of selected kinases as the basis for a study of the structural evolution of the protein kinase–like superfamily. The comparison of structures revealed a “universal core” domain consisting only of regions required for ATP binding and the phosphotransfer reaction. Remarkably, even within the universal core some kinase structures display notable changes, while still retaining essential activity. Hence, the protein kinase–like superfamily has undergone substantial structural and sequence revision over long evolutionary timescales. We constructed a phylogenetic tree for the superfamily using a novel approach that allowed for the combination of sequence and structure information into a unified quantitative analysis. When considered against the backdrop of species distribution and other metrics, our tree provides a compelling scenario for the development of the various kinase families from a shared common ancestor. We propose that most of the so-called “atypical kinases” are not intermittently derived from protein kinases, but rather diverged early in evolution to form a distinct phyletic group. Within the atypical kinases, the aminoglycoside and choline kinase families appear to share the closest relationship. These two families in turn appear to be the most closely related to the protein kinase family. In addition, our analysis suggests that the actin-fragmin kinase, an atypical protein kinase, is more closely related to the phosphoinositide-3 kinase family than to the protein kinase family. The two most divergent families, α-kinases and phosphatidylinositol phosphate kinases (PIPKs), appear to have distinct evolutionary histories. While the PIPKs probably have an evolutionary relationship with the rest of the kinase superfamily, the relationship appears to be very distant (and perhaps indirect). Conversely, the α-kinases appear to be an exception to the scenario of early divergence for the atypical kinases: they apparently arose relatively recently in eukaryotes. We present possible scenarios for the derivation of the α-kinases from an extant kinase fold.
Highlights
A protein superfamily has been defined as a group of proteins that share structure, sequence, and functional features that strongly suggest they are all derived from the same common ancestor protein [1]
The kinase superfamily provides an interesting example of the types of changes seen in proteins over long evolutionary timescales
It would appear that a major driving force for these large structural changes is the diversity of substrates that kinases from the superfamily must recognize and phosphorylate
Summary
A protein superfamily has been defined as a group of proteins that share structure, sequence, and functional features that strongly suggest they are all derived from the same common ancestor protein [1]. These insertions effectively replace the Activation/Pþ1 Loop of the TPKs (see character 14) Though they do not align perfectly (Figure 3), the striking similarity of these elements, and their absence in all other kinases, suggests that they are a product of relatively close common ancestry between CKs and APHs. 9: Structure underlying the catalytic region. Though many other kinase families have conserved hydrophobic residues at these positions (Figure 3) and have a clear hydrophobic pocket, this distinctive link is specific to the TPK, APH, and CK families These interactions are important because they form a direct link between the Catalytic Loop and Helix E, stabilizing the conformation of the Catalytic Loop. Regardless of the source protein, this process would have led to its distinctive structure and great sequence distance from the TPKs and other AKs (Figures 2, 4, and 6)
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