flippases

Flippases are membrane proteins that catalyze the translocation of phospholipids from the outer (exoplasmic) leaflet to the inner (cytosolic) leaflet of biological membranes, helping to establish and maintain lipid asymmetry that is essential for membrane function and signaling.

In eukaryotes, the predominant flippases are the P4-ATPases, a subfamily of P-type ATPases. They use the energy of ATP hydrolysis to move aminophospholipids, particularly phosphatidylserine and phosphatidylethanolamine, inward across the bilayer. Most P4-ATPases function as complexes that require an accessory subunit of the CDC50 family for stability and activity. In humans, examples include ATP8A1 and ATP8A2 (PS/PE), ATP11A and ATP11C (PS/PE), and ATP10A/ATP10D, with tissue-specific roles in vesicle trafficking, membrane biogenesis, and signaling. Mutations or dysregulation of flippases can disrupt membrane asymmetry and are associated with a range of diseases, highlighting their biological importance.

In bacteria, flippase activity can be provided by proteins such as MprF, which synthesizes lysyl-phosphatidylglycerol and flips it to the outer leaflet, contributing to resistance to cationic antimicrobial peptides in several pathogens.

Flippases are distinguished from scramblases, which randomize lipid distribution without directional, energy-dependent transport, and from floppases, which move lipids toward the outer leaflet. See also floppase and scramblase.