Substrate trajectory through phospholipid-transporting P4-ATPases

A difference in the lipid composition between the two leaflets of the same membrane is a relatively simple instance of lipid compositional heterogeneity. The large activation energy barrier for transbilayer movement for some (but not all) membrane lipids creates a regime governed by active transport processes. An early step in eukaryote evolution was the development of a capacity for generating transbilayer compositional heterogeneity far from equilibrium by directly tapping energy from the ATP pool. The mechanism of the P-type ATPases that create lipid asymmetry is well understood in terms of ATP hydrolysis, but the trajectory taken by the phospholipid substrate through the enzyme is a matter of current active research. There are currently three different models for this trajectory, all with support by mutation/activity measurements and analogies with known atomic structures.