Abstract
P4-ATPases comprise a family of P-type ATPases that actively transport or flip phospholipids across cell membranes. This generates and maintains membrane lipid asymmetry, a property essential for a wide variety of cellular processes such as vesicle budding and trafficking, cell signaling, blood coagulation, apoptosis, bile and cholesterol homeostasis, and neuronal cell survival. Some P4-ATPases transport phosphatidylserine and phosphatidylethanolamine across the plasma membrane or intracellular membranes whereas other P4-ATPases are specific for phosphatidylcholine. The importance of P4-ATPases is highlighted by the finding that genetic defects in two P4-ATPases ATP8A2 and ATP8B1 are associated with severe human disorders. Recent studies have provided insight into how P4-ATPases translocate phospholipids across membranes. P4-ATPases form a phosphorylated intermediate at the aspartate of the P-type ATPase signature sequence, and dephosphorylation is activated by the lipid substrate being flipped from the exoplasmic to the cytoplasmic leaflet similar to the activation of dephosphorylation of Na+/K+-ATPase by exoplasmic K+. How the phospholipid is translocated can be understood in terms of a peripheral hydrophobic gate pathway between transmembrane helices M1, M3, M4, and M6. This pathway, which partially overlaps with the suggested pathway for migration of Ca2+ in the opposite direction in the Ca2+-ATPase, is wider than the latter, thereby accommodating the phospholipid head group. The head group is propelled along against its concentration gradient with the hydrocarbon chains projecting out into the lipid phase by movement of an isoleucine located at the position corresponding to an ion binding glutamate in the Ca2+- and Na+/K+-ATPases. Hence, the P4-ATPase mechanism is quite similar to the mechanism of these ion pumps, where the glutamate translocates the ions by moving like a pump rod. The accessory subunit CDC50 may be located in close association with the exoplasmic entrance of the suggested pathway, and possibly promotes the binding of the lipid substrate. This review focuses on properties of mammalian and yeast P4-ATPases for which most mechanistic insight is available. However, the structure, function and enigmas associated with mammalian and yeast P4-ATPases most likely extend to P4-ATPases of plants and other organisms.
Highlights
Non-random distribution of lipids across the lipid bilayer is a characteristic feature of most eukaryotic cell membranes
Membrane lipid asymmetry plays a crucial role in numerous cellular processes that take place at the plasma membrane and intracellular membranes including cell and organelle shape determination and dynamics, vesicle budding and trafficking, membrane protein regulation, membrane stability and impermeability, cell signaling, neurite extension, blood coagulation, apoptosis, fertilization, and bile and cholesterol homeostasis, among others
Because flippase activity is retained following purification and reconstitution of ATP8A2 together with its accessory CDC50A subunit in lipid vesicles (Coleman et al, 2009, 2012; Coleman and Molday, 2011), there is no doubt that these are the only protein components required for the movement of the lipid and its coupling with ATP hydrolysis, providing a sound basis for using sitedirected mutagenesis to search for residues interacting with the lipid substrate during the flipping
Summary
Non-random distribution of lipids across the lipid bilayer is a characteristic feature of most eukaryotic cell membranes. Heterologous expression studies point to the crucial role of CDC50 in protein folding and formation of a functionally active P4-ATPase complex (Paulusma et al, 2008; Bryde et al, 2010; Van Der Velden et al, 2010b; Coleman and Molday, 2011).
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