Evolution and a revised nomenclature of P4 ATPases, a eukaryotic family of lipid flippases

In all eukaryotic cells, P4 ATPases, also named phospholipid flippases, generate phospholipid asymmetry across biological membranes. This process is essential for cell survival, as it is required for vesicle budding and fusion in the secretory pathway. Several P4 ATPase isoforms can be identified in all sequenced eukaryotic genomes, but their evolution and interrelationships are poorly described. In this study, we conducted a thorough phylogenetic analysis of P4 ATPases in all major eukaryotic super-groups and found that they can be divided into three distinct families, P4A, P4B and P4C ATPases, all of which have an ancient origin. While P4B ATPases have been lost in plants, P4A ATPases are present in all eukaryotic super-groups. P4C ATPases form an intermediate group between the other two but appear to share a common origin with P4A ATPases. Sequence motifs unique to P4 ATPases are situated in the basal ATP hydrolyzing machinery. In addition, no clear signature motifs within P4 ATPase subgroups were found that could be related to lipid specificity, likely pointing to an elaborate transport mechanism in which different amino acid residue combinations in these pumps can result in recognition of the same substrate.