Organization of ABC Genes and Proteins
The classification of proteins as ABC transporters is based on the sequence and organization of ATP-binding domain(s), also known as nucleotide-binding domains (NBDs) or nucleotide-binding folds. Characteristic motifs, the Walker A motif and Walker B motif separated by ∼90–120 amino acids, are found in the nucleotide-binding fold of all ATP-binding proteins. In addition, the ABC genes contain an additional distinctive component referred to as the signature motif or the C-loop situated upstream of the Walker B site (Hyde et al., 1990).
The typical ABC protein contains two NBDs and two transmembrane domains (TMDs). The TM domains generally have 6-12 membrane-spanning alpha-helices, which determine substrate specificity. The eukaryotic ABC genes can be structured as full transporters containing two TMs and two NBDs, or as half transporters (Hyde et al., 1990). Half transporters need to form either homodimers or heterodimers to create a functional transporter. Specific mutations in ABC genes can contribute to several human genetic disorders, including cystic fibrosis, neurological disease, cholesterol/bile transport defects, retinal degeneration, anemia, and differential drug response (Dean, Hamon, & Chimini, 2001).
In bacteria, ABC transporters tend to be unidirectional. Most of them are importers, which import essential molecules involved in bacterial metabolism such as vitamins, metal ions, and sugars. However, several MDR-like transporters (primarily involved in drug resistance) and other ABC ATPases involved in cellular processes like DNA repair or other regulatory functions have also been identified (Lubelski, Konings, & Driessen, 2007). Eukaryotic ABC transporters are mainly engaged in the shuttling of hydrophobic compounds either within the cell as part of a metabolic process or outside the cell for transport to other organs or secretion from the body.
ABC genes exhibit evolutionary conservation from bacteria to humans, and multiple gene duplication and deletion events in the ABC genes point to the fact that gene evolution is still ongoing. ABC genes are dispersed widely in eukaryotic genomes. In humans, the ABC transporter superfamily contains 48 genes, divided into seven subfamilies ranging from A to G based on similarity in gene structure, order of the domains, and sequence homology in the NBD and TM domains (Dean, Rzhetsky, & Allikmets, 2001). To date, mutations in 21 of the 48 human ABC genes cause a Mendelian disease or an inherited phenotype (Table 1 )