The ABCG family of membrane-associated transporters: you don't have to be big to be mighty

Abstract

Along with many other mammalian ATP-binding cassette (ABC) transporters, members of the ABCG group are involved in the regulated transport of hydrophobic compounds across cellular membranes. In humans, five ABCG family members have been identified, encoding proteins ranging from 638 to 678 amino acids in length. All five have been the subject of intensive investigation to better understand their physiological roles, expression patterns, interactions with substrates and inhibitors, and regulation at both the transcript and protein level. The principal substrates for at least four of the ABCG proteins are endogenous and dietary lipids, with ABCG1 implicated in particular in the export of cholesterol, and ABCG5 and G8 forming a functional heterodimer responsible for plant sterol elimination from the body. ABCG2 has a much broader substrate specificity and its ability to transport numerous diverse pharmaceuticals has implications for the absorption, distribution, metabolism, excretion and toxicity (ADMETOx) profile of these compounds. ABCG2 is one of at least three so-called multidrug resistant ABC transporters expressed in humans, and its activity is associated with decreased efficacy of anti-cancer agents in several carcinomas. In addition to its role in cancer, ABCG2 also plays a role in the normal physiological transport of urate and haem, the implications of which are described. We summarize here data on all five human ABCG transporters and provide a current perspective on their roles in human health and disease.

Figure 1

Architecture of human ABC proteins. Each of the five subfamilies of human ABC proteins involved in transmembrane transport is listed at the top of a panel with the number of members identified in the human genome in parenthesis. The transmembrane architecture is then shown in schematic fashion, with the N- and C-terminus of the primary sequence indicated. The approximate position of the membrane is denoted by a dotted line. Where members of a subfamily show different architectures (e.g. ABCB and ABCC), two alternatives are shown for illustrative purposes. Several ABCA proteins are distinct in having large extracellular domains not seen in any other ABC protein sequences (and with no homology to other known sequences).Underneath each topology diagram the spectrum of substrates (where characterized) is indicated, followed by the size range of the proteins (in amino acids; a.a.), followed by the highest resolution structural data obtained to date. For more information refer to other review articles in this series. The two non-transport associated families ABCE (1 member) and ABCF (2 members) are not shown here for clarity.

Figure 2

Principal functions of human ABCG transporters. Major functions of several transport systems as described in the text. Clockwise from top left: ABCG2 homodimer (blue) exports drugs into capillary lumen, preventing their crossing the blood–brain barrier. The reverse cholesterol transport pathway in macrophages – ABCA1 (black) activity results in formation of spherical or discoid HDL particles, which are then substrates for cholesterol export by ABCG1 homodimer (purple). A less well understood pathway involving cholesterol transport in the brain is proposed for ABCG4. ABCG2 (blue) in the proximal tubule expels urate into the kidney lumen. ABCG5/G8 (orange/red) in the small intestine prevent plant sterol absorption. ABCG5/G5 (orange/red) combine with ABCB4 (grey) in biliary lipid secretion.