Abstract
Aurora kinases (AKs) are serine/threonine kinases that are essential for cell division. Humans have three AK genes: AKA, AKB, and AKC. AKA is required for centrosome assembly, centrosome separation, and bipolar spindle assembly, and its mutation leads to abnormal spindle morphology. AKB is required for the spindle checkpoint and proper cytokinesis, and mutations cause chromosome misalignment and cytokinesis failure. AKC is expressed in germ cells, and has a role in meiosis analogous to that of AKB in mitosis. Mutation of any of the three isoforms can lead to cancer. AK proteins possess divergent N- and C-termini and a conserved central catalytic domain. We examined the evolution of the AK gene family using an identity matrix and by building a phylogenetic tree. The data suggest that AKA is the vertebrate ancestral gene, and that AKB and AKC resulted from gene duplication in placental mammals. In a nonsynonymous/synonymous rate substitution analysis, we found that AKB experienced the strongest, and AKC the weakest, purifying selection. Both the N- and C-termini and regions within the kinase domain experienced differential selection among the AK isoforms. These differentially selected sequences may be important for species specificity and isoform specificity, and are therefore potential therapeutic targets.
Highlights
Aurora kinases (AKs) are serine/threonine kinases that are essential for the orderly progression of mitotic and/or meiotic events in eukaryotic cells
Genes were chosen to ensure a broad representation of species rather than complete AK gene content from each species
Our data suggest that AKA is the ancestral gene in vertebrates, and that the duplication of AKBC in placental mammals led to the presence of three AK genes
Summary
Aurora kinases (AKs) are serine/threonine kinases that are essential for the orderly progression of mitotic and/or meiotic events in eukaryotic cells. The identity between human AKA and Saccharomyces cerevisiae Ipl1p is 41%, whereas their kinase domains share 49% identity [1]. AKs consist of a central protein kinase domain bordered by short N- and C-terminal domains [3]. Protein kinase domains range in size from 250–300 amino acids and form a two-lobed structure (N- and C-terminal lobes). They contain twelve conserved subdomains that are separated by less highly conserved regions that serve as sites for insertions [4]. AKs possess an activation loop in the C-terminal lobe containing a threonine residue whose phosphorylation activates its kinase activity [6]
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