Membrane lipids diffuse rapidly in the plane of the membrane but their ability to flip spontaneously across a membrane bilayer is hampered by a significant energy barrier. Thus spontaneous flip-flop of polar lipids across membranes is very slow, even though it must occur rapidly to support diverse aspects of cellular life. Here we discuss the mechanisms by which rapid flip-flop occurs, and what role lipid flipping plays in membrane homeostasis and cell growth. We focus on conceptual aspects, highlighting mechanistic insights from biochemical and in silico experiments, and the recent, ground-breaking identification of a number of lipid scramblases.

Phospholipid flipping across cellular membranes contributes to vesicle biogenesis in eukaryotes and involves flippases (P4-ATPases). However, the minimal composition of the flippase machinery remains to be determined. We demonstrate that cellular targeting and lipid specificity of P4-ATPases require the α-subunit but are independent of the β-subunit.