Oligomerization of human ATP-binding cassette transporters and its potential significance in human disease

Abstract

Human ATP-binding cassette transporters (ABC transporter) belong to an extremely important superfamily of membrane transporters. They use energy from ATP hydrolysis to transport a wide variety of substrates across the cellular membrane. Due to the physiological and pharmacological importance of their diverse substrates, ABC transporters have been shown to have close relationship with various human diseases such as cystic fibrosis and multi-drug resistance in cancer chemotherapy. While it has been thought traditionally that functional ABC transporters exist as monomeric full or dimeric half transporters, emerging evidence indicates that some ABC transporters oligomerize on cellular membranes and this oligomerization seems to have functional relevance. Therefore, this oligomerization process might be a promising drug target for ABC transporter-related human diseases, especially in overcoming multi-drug resistance in cancer chemotherapy. In this review, we perform a critical analysis of the past studies on the oligomerization of ABC transporters.

Figure 1.. Domain structures of full and half ABC transporters.

Schematic domain structures of full (A, B) and half (C, D) ABC transporters are shown with cylinders representing transmembrane segments linked by loops. The gray boxes represent membrane lipid bilayers. ABC: ATP-binding cassette; MSD: Membrane-spanning domain; NBD: Nucleotide-binding domain.

Figure 2.. Schematic presentation of oligomeric ABCG2 molecules.

ABCG2 was shown to exist as a higher order of oligomers with either 12 (A) or 8 (B) subunits represented by solid balls. The dodecamer model consists of three stable tetrameric units (boxed) and three different possible interaction sites (asterisks) including a potential covalent disulfide bond. The octomer model consists of four dimeric units (boxed).