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First published online February 12, 2004
doi: 10.1242/10.1242/jcs.01055

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Tracking down lipid flippases and their biological functions

¹ Institut für Biologie, Humboldt-Universität zu Berlin, 10115 Berlin, Germany
² Department of Membrane Enzymology, Centre for Biomembranes and Lipid Enzymology, Utrecht University, 3584 CH Utrecht, The Netherlands

View larger version (37K): [in a new window]   Fig. 1. Regulation of the transbilayer lipid distribution in cellular membranes. In early secretory organelles, such as the endoplasmic reticulum (ER), membrane proteins facilitate rapid flip-flop of lipids and allow them to equilibrate between the two membrane leaflets independently of ATP. This system is unable to accumulate a given lipid in one leaflet, thereby promoting a symmetric lipid distribution across the bilayer. In contrast, flip-flop of phospholipids across the plasma membrane (PM) is constrained owing to high levels of cholesterol and sphingolipids and/or the absence of constitutive bi-directional flippases. Thus, ATP-dependent flippases can maintain an asymmetric lipid distribution by moving specific lipids towards (P-type ATPase family members) or away from the cytosolic leaflet (ABC transporters). Cellular activation triggered by cytosolic calcium can collapse the lipid asymmetry by the transient activity of an ATP-independent scramblase. PC, phosphatidylcholine; PE, phosphatidylethanolamine; PS, phosphatidylserine; SM, sphingomyelin; GL, glycolipids; Chol, cholesterol.

View larger version (31K): [in a new window]   Fig. 2. Characterization of phospholipid movement at a qualitative level in (plasma) membranes is frequently based on phospholipid probes. These analogs have a reporter group attached to a short fatty acid chain and maintain most of the properties of endogenous phospholipids, except that they are more water-soluble, which facilitates incorporation from the medium into the outer monolayer of the membrane (A). Transport of these probes is usually monitored by extracting with bovine serum albumin (BSA) the residual fraction of analogs not transported across the membrane. Depending on the head group and cell type, the lipid analog inserted into the outer plasma membrane leaflet can be internalized by spontaneous flip-flop, by protein-mediated translocation or endocytosis. In human fibroblasts, for example, disappearance of NBD-PS from the cell surface is predominantly due to fast translocation across the plasma membrane (and endosomal membranes), resulting in a labeling of various intracellular membranes (B). In contrast, NBD-SM is internalized via endocytic vesicles resulting in the appearance of intracellular fluorescent spots (C). Bar, 20 µm.

View larger version (33K): [in a new window]   Fig. 3. Role of energy-coupled lipid flippases in triggering membrane budding. (A) ATP-driven lipid translocation may be required to generate a lipid imbalance across the bilayer by increasing the proportion of total lipids in one monolayer and thereby driving budding of vesicles. noL, number of lipid molecules in the outer leaflet, niL, number of lipid molecules in the inner leaflet (e.g. at the level of the head groups, the cytoplasmic leaflet of a 60 nm diameter vesicle contains 1.5 times the number of lipid molecules of the lumenal leaflet). (B) ATP-driven lipid translocation may help to create a high local concentration of aminophospholipids in the cytosolic leaflet favorable for recruitment of peripheral proteins, such as ARF, clathrin, amphiphysin and endophilins.

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