It was first discovered in 1992 that P-glycoprotein (Pgp, ABCB1), an ATP binding cassette (ABC) transporter, can transport phospholipids such as phosphatidylcholine, -ethanolamine and -serine as well as glucosylceramide and glycosphingolipids. Subsequently, many other ABC transporters were identified to act as lipid transporters. For substrate transport by ABC transporters, typically a classic, alternating access model with an ATP-dependent conformational switch between a high and a low affinity substrate binding site is evoked. Transport of small hydrophilic substrates can easily be imagined this way, as the molecule can in principle enter and exit the transporter in the same orientation. Lipids on the other hand need to undergo a 180° degree turn as they translocate from one membrane leaflet to the other. Lipids and lipidated molecules are highly diverse, so there may be various ways how to achieve their flipping and flopping. Nonetheless, an increase in biophysical, biochemical and structural data is beginning to shed some light on specific aspects of lipid transport by ABC transporters. In addition, there is now abundant evidence that lipids affect ABC transporter conformation, dynamics as well as transport and ATPase activity in general. In this review, we will discuss different ways in which lipids and ABC transporters interact and how lipid translocation may be achieved with a focus on the techniques used to investigate these processes. This article is part of a Special Issue entitled: Lipid order/lipid defects and lipid-control of protein activity edited by Dirk Schneider.
Keywords: ATP binding cassette; drug-lipid interactions; lipid bilayer; lipid flopping; protein-lipid interactions.
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