On the origin of lipid asymmetry: the flip side of ion transport

Membrane lipid asymmetry influences a multitude of cellular functions, including membrane vesiculation, cell division, and lifespan. Most cells retain the bulk of aminophospholipids to the cytosolic membrane leaflet by means of ATP-fuelled flippases or translocases. Converging lines of evidence indicate that members of the P₄ subfamily of P-type ATPases catalyze aminophospholipid transport and create lipid asymmetry in late secretory and endocytic compartments. Yet P-type ATPases usually pump small cations or metal ions. Atomic structures revealed important aspects of the transport mechanism, and sequence homology indicates that this mechanism is conserved throughout the family. Consequently, understanding how P₄ ATPases acquired the ability to translocate phospholipids instead of simple ions has become a major focus of interest.