Structural Evolution of the Protein Kinase–Like Superfamily

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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. Most proteins have distinct three-dimensional structures that determine much of their functional capability. Proteins that are related usually have similar structures, owing to their shared genetic heritage and (often) similar function. Hence, one can speak of “families” of proteins that at one time all shared a common ancestor gene, but have diverged over eons of evolution into distinct forms with similar but altered sequences. In some cases, this sequence divergence can occur to the point that the structures of the proteins actually begin to change, forming “superfamilies” of distantly related proteins. Traditionally, events in protein evolution are investigated through the construction of evolutionary trees based on similarity between protein sequences. However, at the superfamily level sequence similarity weakens to the point that building accurate trees becomes much more problematic. This work attempts to address this problem by integrating structural similarity information into the analysis. Because protein structure changes much more slowly than sequence, structural similarity provides powerful signals about the relationships between proteins. When this new form of tree is considered alongside other evolutionary information, the authors are able to provide a supportable history for much of the evolution of the important protein kinase–like superfamily.