Crossing the membrane—What does it take to flip a phospholipid? Structural and biochemical advances on P4-ATPase flippases

Membrane asymmetry is critical for maintenance of several different processes such as cell signaling, apoptosis, and vesicular transport in various eukaryotic systems. Flippases of the P4-ATPase family are associated with flipping phospholipids from the luminal or exoplasmic leaflet to the cytosolic leaflet. P4-ATPases belong to the P-type ATPase family, which are activated by phosphorylation and couple ATPase activity to substrate translocation. These proteins possess a transmembrane domain responsible for substrate transport, while the cytosolic machinery performs the necessary ATP hydrolysis for this process. Several high-resolution structures of human or yeast P4-ATPases have recently been resolved, but a comprehensive overview of the changes for reaction cycle in different members was crucial for future research. In this review, we have compiled available data reflecting the reaction cycle-associated changes in conformation of P4-ATPases. Together, this will provide an improved understanding of the similarities and differences between these members, which will drive further structural, functional, and computational studies to understand the mechanisms of these flippases.