Review
Lipid dependence of ABC transporter localization and function

https://doi.org/10.1016/j.chemphyslip.2009.07.004Get rights and content

Abstract

Lipid rafts have been implicated in many cellular functions, including protein and lipid transport and signal transduction. ATP-binding cassette (ABC) transporters have also been localized in these membrane domains. In this review the evidence for this specific localization will be evaluated and discussed in terms of relevance to ABC transporter function. We will focus on three ABC transporters of the A, B and C subfamily, respectively. Two of these transporters are relevant to multidrug resistance in tumor cells (Pgp/ABCB1 and MRP1/ABCC1), while the third (ABCA1) is extensively studied in relation to the reverse cholesterol pathway and cellular cholesterol homeostasis. We will attempt to derive a generalized model of lipid rafts to which they associate based on the use of various different lipid raft isolation procedures. In the context of lipid rafts, modulation of ABC transporter localization and function by two relevant lipid classes, i.e. sphingolipids and cholesterol, will be discussed.

Introduction

ATP-binding cassette transporters (ABC transporters) comprise a large family of transmembrane proteins. They function in the transport of a wide variety of substrates, including phospholipids, sterols, bile acids, peptides, metabolic products and various drugs. By binding and subsequent hydrolysis of ATP, the energy is supplied to pump these substrates against a concentration gradient across the membrane. In humans 48 ABC transporters are identified and these are divided into 7 groups (ABCA to ABCG). The presence of transmembrane domains and ATP-binding domains is a shared property of ABC transporters. The transmembrane domain consists of α-helices crossing the lipid bilayer multiple times forming usually 6 membrane-spanning regions. The specificity for the substrate is provided by these transmembrane domains. The ATP-binding domain is located on the cytoplasmic side of the membrane.

In view of their location in the membrane it is expected that surrounding lipids are important for ABC transporter function. Some of them, such as ABCA1 and Pgp/ABCB1 recognize phospholipids and cholesterol as substrates. These ABC transporters thus play a role in lipid homeostasis. Some ABC transporters play a crucial role in the development of multidrug resistance. In normal physiology they function by transporting various endogenous substances as well as effluxing foreign substances (e.g. drugs) from the cell. In tumor cells, however, an increased efflux of drugs by up regulated ABC transporters is observed upon prolonged drug medication. Transporters like Pgp/ABCB1, MRP1/ABCC1 or BCRP/ABCG2 are up regulated leading to resistance of the tumor cell for multiple drugs. The role for lipids is such that drugs are able to bind to the lipid phase on basis of their hydrophobicity and so become available for the transporter to be effluxed out of the cell. Moreover, it is considered that the direct membrane environment of the transporter is important for its functionality and the question subsequently arose whether lipid rafts are involved in localizing ABC transporters in a specific lipid environment in which they are functional.

Section snippets

Lipid rafts

In 2006 during The Keystone Symposium on Lipid Rafts and Cell Function the following definition was adopted: “Membrane rafts are small (10–200 nm), heterogeneous, highly dynamic, sterol- en sphingolipid-enriched domains that compartmentalize cellular processes. Small rafts can sometimes be stabilized to form larger platforms through protein-protein and protein–lipid interactions”.

The acyl chains of sphingolipids in lipid rafts are relatively long and highly saturated. This allows close packing

ABC transporters in lipid rafts

In this review we will evaluate the evidence for localization and function of the ABC transporters ABCA1, Pgp/ABCB1 and MRP1/ABCC1 in lipid rafts and discuss the modulating effect of raft-resident lipids, i.e. sphingolipids and cholesterol. We will attempt to derive a generalized model of lipid rafts to which these ABC transporters associate based on the use of various different lipid raft isolation procedures.

Models of ABC transporter localization in lipid rafts

Many methods of lipid raft isolation have been developed over time. Cold detergent extraction procedures are widespread, but detergent-free lipid raft isolation methods are gaining ground. These different methods are inherently different in selectivity and thus isolate different membrane domains. When the amount of cellular protein present in the lipid raft fractions is compared between methods, an ordered range of selectivities can be discerned. Triton-based DRMs contain about 1.5% of cellular

Lipids as substrates

So far we have discussed lipids and lipid rafts as modulators of ABC transporter localization and function. Finally we will briefly address the notion that vice versa ABC transporters can also modulate their lipid environment by acting as transporters/flippases for lipids. Upon expression of active ABCA1 in BHK cells, cholesterol, sphingomyelin and even the plasma membrane as a whole became less resistant to cold Triton X-100 extraction. Also caveolin, used as a lipid raft marker, redistributed

Concluding remarks

Different methodology for lipid raft isolation combined with the use of qualitative terminology – such as “enriched”, “partial” and “mainly” – to describe association of proteins with lipid rafts, makes it difficult to draw firm conclusions regarding the extent of lipid raft association of ABC transporters. In the future, more quantitative methods are required for measuring the amount and fraction of a protein that is lipid raft associated. In addition, recently developed biophysical techniques

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