Human ABCG2: structure, function, and its role in multidrug resistance

Abstract

Human ABCG2 is a member of the ATP-binding cassette (ABC) transporter superfamily and is known to contribute to multidrug resistance (MDR) in cancer chemotherapy. Among ABC transporters that are known to cause MDR, ABCG2 is particularly interesting for its potential role in protecting cancer stem cells and its complex oligomeric structure. Recent studies have also revealed that the biogenesis of ABCG2 could be modulated by small molecule compounds. These modulators, upon binding to ABCG2, accelerate the endocytosis and trafficking to lysosome for degradation and effectively reduce the half-life of ABCG2. Hence, targeting ABCG2 stability could be a new venue for therapeutic discovery to sensitize drug resistant human cancers. In this report, we review recent progress on understanding the structure, function, biogenesis, as well as physiological and pathophysiological functions of ABCG2.

Keywords: ATP-binding cassette; Human ABCG2; cancer; chemotherapy; function; multidrug resistance; structure.

Figure 1

Membrane topology model of ABCG2. The schematic topological model was constructed on the basis of sequence analysis and the available experimental data. Nucleotide- binding domain (NBD), membrane-spanning domain (MSD), transmembrane (TM) segments, and extracellular loop 3 (ECL3) are indicated. The cysteine residues and N-linked glycosylation sites in ECL3 are also shown.

Figure 2

Schematic model of the dodecameric ABCG2. Three different possible interaction sites contributed by TM5 (5), TM6 (6), and ECL3 are shown.