Eukaryotic Protein Kinases and Choline Kinases Share a Common Ancestor Related to Ancient Glutaminyl-tRNA Synthetase

The ubiquitous occurrence of reversible protein phosphorylation by eukaryotic protein kinases (ePKs) in molecular intelligence systems supports a crucial role for this family of enzymes in the successful emergence of nucleated cells in the third superkingdom of life on Earth. Choline kinases (ChKs) also appear be important in the early evolution of eukaryotes, because of their function in the biosynthesis of phosphatidylcholine, which is unique to eukaryotic membranes and the predominant phospholipid. However, the genomic origins of ePKs and ChKs are unclear. The high degeneracy of protein sequences and the broad expansion of protein kinase families in eukaryotic organisms have made this fundamental question difficult to answer. To explore the ancestry of eukaryotic protein kinases, we defined a consensus amino acid sequence for the entire catalytic domain of human typical protein-serine/threonine kinases (STKs) and used it for genome-wide BLAST searches from multiple well-studied species. Top non-ePK hits from each individual organism were compared. Top candidates that appeared in more than one species were manually checked for particular conservation at key residues for phosphotransferase activity. Our results have revealed high similarities in primary sequences of protein kinases with two of the three class-I aminoacyl-tRNA synthetases. In particular, the glutaminyl-tRNA synthetase (GlnRS), showed conservation with most of the well characterized kinase catalytic subdomains. Our results also showed significant primary sequence similarity of ChK with ePKs, although previous studies have revealed similarities in the tertiary structure of ChK with ePKs. From the pairwise alignment of STK, ChK and GlnRS consensus sequences, GlnRS and STK shared the highest identity of 24%, among which 18 of the 30 key phosphotransferase residues were identical. ChK consensus sequence also showed 20% identity with GlnRS consensus sequence. The hypothesis that ePKs and ChKs share a common ancestor related to GlnRS was supported by further sequence analysis and tertiary structural comparisons. We propose that ePKs and ChKs share a common ancestor that is most closely related to GlnRS. EPKs and ChK are not found in bacteria. An ancient GlnRS gave rise to these two important signal transduction proteins. The emergence of ChK in eukaryotes offered the possibility for novel phospholipids for construction of larger and more complex internal and external membranes in cells. In parallel, ePKs may have facilitated communication and coordination among different cellular compartments and organelles to allow the viability of larger cells. Our findings indicate that duplications and mutations of the GlnRS gene to create ePKs and ChKs may have been a key factor in the successful establishment of ancient eukaryotic cells. This lineage of early eukaryotes then evolved and expanded to generate the rich diversity of organisms that comprise the eukaryotic kingdom of life today.