The human ATP-binding cassette (ABC) transporter superfamily

Abstract

The transport of specific molecules across lipid membranes is an essential function of all living organisms and a large number of specific transporters have evolved to carry out this function. The largest transporter gene family is the ATP-binding cassette (ABC) transporter superfamily. These proteins translocate a wide variety of substrates including sugars, amino acids, metal ions, peptides, and proteins, and a large number of hydrophobic compounds and metabolites across extra-and intracellular membranes. ABC genes are essential for many processes in the cell, and mutations in these genes cause or contribute to several human genetic disorders including cystic fibrosis, neurological disease, retinal degeneration, cholesterol and bile transport defects, anemia, and drug response. Characterization of eukaryotic genomes has allowed the complete identification of all the ABC genes in the yeast Saccharomyces cerevisiae , Drosophila , and C. elegans genomes. To date, there are 48 characterized human ABC genes. The genes can be divided into seven distinct subfamilies, based on organization of domains and amino acid homology. Many ABC genes play a role in the maintenance of the lipid bilayer and in the transport of fatty acids and sterols within the body. Here, we review the current knowledge of the human ABC genes, their role in inherited disease, and understanding of the topology of these genes within the membrane. -Dean, M., Y. Hamon, and G. Chimini. The human ATP-binding cassette (ABC) transporter superfamily.

Engineering a Cysteine-Deficient Functional Candida albicans Cdr1 Molecule Reveals a Conserved Region at the Cytosolic Apex of ABCG Transporters Important for Correct Folding and Trafficking of Cdr1

“…Substituting the four conserved EL6 cysteines led to an inactive protein in all EL6-containing variants despite reasonably good expression levels (20 to 70% of wild-type Cdr1; Table 2). In other words, any cysteine-deficient subdomain that was combined with the EL3-and/or EL6-deficient subdomains was almost (EL3) or completely (EL6) inactive (i.e., no detectable ATPase 5, and NT1 (6); C-terminal variants N2 (7), TS2 (8), EL6 (9), T2 (10), NTS2 (11), and NT2 (12); and variants of the indicated N-and C-terminal subdomain combinations N12 (13), TS12 (14), EL36 (15), T12 (16), NTS12 (17), and NTS12-S1 (18). In-gel fluorescence images of the same polyacrylamide gels before Coomassie blue staining are presented underneath; the fluorescence signals were used to quantify the Cdr1 expression levels ( Table 2).…”

“…What is conserved, however, is the GX 2[3] CPX 3 NPXD/E motif that appears to be an important pivot 24based on the ABCG5-G8 structure (18). The N-terminal (turquoise) and C-terminal (pink) halves are color coded, and the 23 cysteines (1 to 23) are shown as yellow dots, apart from C1106 (14), which is red. The model is viewed from the front (A) or back (B).…”

A High-Throughput Cell-Based Assay for Inhibitors of ABCG2 Activity

“…A variety of other compounds have been described as inhibitors of multidrug transporter activity, some with inhibitory activity against ABCG2 and others that are reported to not affect ABCG2 (see Dean et al, 2 Doyle and Ross, 3 and Dean et al 4 for general dis- For the remainder, IC 50 values could not be estimated because cellassociated fluorescence continued to increase at the highest concentration tested or compounds were cytotoxic at high concentrations (Table 1). By contrast, etoposide and verapamil have been identified as inhibitors of other multidrug resistance proteins but not ABCG2.…”

“…A BCG2, ALSO KNOWN AS BREAST CANCER RESISTANCE PROTEIN (BCRP) or mitoxantrone resistance protein (MXR), is a member of the adenosine triphosphate (ATP)-binding cassette (ABC) family of transporters. [1][2][3][4] ABCG2 is known to confer resistance to a wide range of chemotherapeutic agents such as mitoxantrone, topotecan, irinotecan, flavopiridol, and methotrexate, thus making it a potential mediator of drug resistance in cancer. 3 Transport of natural substrates, among which are plant polyphenols, 5,6 may reflect a physiologic function of ABCG2 in normal cells.…”

“…1 ABCG2 is highly expressed in normal and cancer stem cells. [2][3][4] Although the clinical relevance of ABCG2 has yet to be established, it does appear to play a role in drug resistance in acute myelogenous leukemia, although conflicting data exist. 3 In addition, ABCG2 expression has been reported in a wide variety of untreated human solid tumors.…”