Excerpt

The ATP-binding cassette (ABC) transporter superfamily contains membrane proteins that translocate a wide variety of substrates across extra- and intracellular membranes, including metabolic products, lipids and sterols, and drugs. Overexpression of certain ABC transporters occurs in cancer cell lines and tumors that are multidrug resistant. Genetic variation in these genes is the cause or contributor to a wide variety of human disorders with Mendelian and complex inheritance including cystic fibrosis, neurological disease, retinal degeneration, cholesterol and bile transport defects, anemia, and drug response phenotypes. Conservation of the ATP-binding domains of these genes has allowed the identification of new members of the superfamily based on nucleotide and protein sequence homology. Phylogenetic analysis places the 48 known human ABC transporters into seven distinct subfamilies of proteins. For each gene, the precise map location on human chromosomes, expression data, and localization within the superfamily have been determined. These data allow predictions to be made as to potential function(s) or disease phenotype(s) associated with each protein. Comparison of the human ABC superfamily to that of other sequenced eukaryotes including Drosophila indicated that there is a rapid rate of birth and death of ABC genes and that most members carry out highly specific functions that are not conserved across distantly related phyla.

Introduction to ABC Protein and Gene Organization

The ATP-binding cassette (ABC) genes represent the largest family of transmembrane (TM) proteins. These proteins bind ATP and use the energy to drive the transport of various molecules across all cell membranes (1–3) (Figure 1). Proteins are classified as ABC transporters based on the sequence and organization of their ATP-binding domain(s), also known as nucleotide-binding folds (NBFs). The NBFs contain characteristic motifs (Walker A and B), separated by approximately 90–120 amino acids, found in all ATP-binding proteins (Figure 1). ABC genes also contain an additional element, the signature (C) motif, located just upstream of the Walker B site (4). The functional protein typically contains two NBFs and two TM domains (Figure 2). The TM domains contain 6–11 membrane-spanning α-helices and provide the specificity for the substrate. The NBFs are located in the cytoplasm and transfer the energy to transport the substrate across the membrane. ABC pumps are mostly unidirectional. In bacteria, they are predominantly involved in the import of essential compounds that cannot be obtained by diffusion (sugars, vitamins, metal ions, etc.) into the cell. In eukaryotes, most ABC genes move compounds from the cytoplasm to the outside of the cell or into an intracellular compartment [endoplasmic reticulum (ER), mitochondria, peroxisome]. Most of the known functions of eukaryotic ABC transporters involve 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 for secretion from the body.

Figure 1

Diagram of a typical ABC transporter protein. A. A diagram of the structure of a representative ABC protein is shown with a lipid bilayer in yellow, the TM domains in blue, and the NBF in red. Although the most common arrangement is a full transporter (more...)

Figure 2

ABC gene structure. A diagram of an ABC half transporter and a full transporter. The half transporter can form homo- or heterodimers, whereas the entire full transporter is found in one transcript.

The eukaryotic ABC genes are organized either as full transporters containing two TMs and two NBFs, or as half transporters (4) (Figure 2). The latter must form either homodimers or heterodimers to form a functional transporter. ABC genes are widely dispersed in eukaryotic genomes and are highly conserved between species, indicating that most of these genes have existed since the beginning of eukaryotic evolution. The genes can be divided into subfamilies based on similarity in gene structure (half versus full transporters), order of the domains, and on sequence homology in the NBF and TM domains. There are seven mammalian ABC gene subfamilies, five of which are found in the Saccharomyces cerevisiae genome (5).

A list of Web resources on ABC genes and products can be found in Box 1.

Box 1

ABC transporter superfamily web resources.

A more detailed account of each of the human ABC genes is given below. For each gene, a concise description is given on the known function and disease involvement, and links to other databases, such as UniGene, OMIM, and GenBank, are given where appropriate. This is a comprehensive treatment: even genes that are very poorly characterized are included. For genes such as CFTR and ABCB1 /PGP/MDR that have been studied extensively, a brief review is given with links to other resources and review articles. Suggested corrections and additions are welcome for future updates of these pages and should be sent to the author (vog.frcficn@naed).

Nomenclature

All human and mouse ABC genes have standard nomenclature, developed by the Human Genome Organization (HUGO) at a meeting of ABC gene researchers. Details of the nomenclature scheme can be found at: http://www.genenames.org/genefamily/abc.html.

Researchers working on ABCC7 /CFTR, ABCB2 /TAP1, and ABCB3 /TAP2 have petitioned to keep their original gene designations. Official gene symbols are used in this monograph, but all known synonyms are also included to allow researchers to refer to the literature.

Overview of Human ABC Gene Subfamilies

A list of all known human ABC genes is displayed in Table 1. This list includes an analysis of the released genome sequences (6, 7). An analysis of the genome sequence indicates the presence of at least 19 pseudogenes (Dean, unpublished). There remain several sequences in the genome with homology to ABC genes that lie in incompletely sequenced regions and may represent additional pseudogenes or functional loci.

Table 1

List of human ABC genes, chromosomal location, and function.

By aligning the amino acid sequences of the NBF domains and performing phylogenetic analysis with a number of methods, the existing eukaryotic genes can be grouped into seven major subfamilies. A few genes do not fit into these subfamilies, and several of the subfamilies can be further divided into subgroups.

ABC Genes and Human Genetic Disease

Many ABC genes were originally discovered during the positional cloning of human genetic disease genes. To date, 14 ABC genes have been linked to disorders displaying Mendelian inheritance (19) (Table 2). As expected from the diverse functional roles of ABC genes, the genetic deficiencies that they cause also vary widely. Because ABC genes typically encode structural proteins, all of the disorders are recessive or X-linked recessive and are attributable to a severe reduction or lack of function of the protein. However, heterozygous variants in ABC gene mutations are being implicated in the susceptibility to specific complex disorders.

Table 2

Diseases and phenotypes caused by ABC genes.

Few ABC gene mutations are lethal. Untreated cystic fibrosis ( ABCC7 /CFTR) is typically lethal in the first decade, and adrenoleukodystrophy ( ABCD1 /ALD) can also be fatal in the first 10 years of life. The only mutations described in ABCB7 are missense alleles, and the yeast homolog is essential to mitochondria, suggesting that this gene is essential. The only developmental defect ascribed to an ABC gene is the congenital absence of the vas deferens that occurs in both cystic fibrosis patients and patients with less severe alleles that present male sterility as their only phenotype. Thus, most ABC genes do not play an essential role in development.

Mouse Knockouts

Most of the human genes have a clear mouse ortholog; however, there are several exceptions (Table 3). Several ABC genes have been disrupted in the mouse (Table 3). These include some of the genes mutated in human diseases, as well as several of the known drug transporters. The Abca1 and Cftr –/– mice show compromised viability; however, the remaining knockouts are viable and fertile, and many show either no phenotype or a phenotype only under stressed conditions.

Table 3

ABC genes: human and mouse orthologs.

Multidrug Resistance and Cancer Therapy

Cells exposed to toxic compounds can develop resistance by a number of mechanisms including decreased uptake, increased detoxification, alteration of target proteins, or increased excretion. Several of these pathways can lead to multidrug resistance (MDR) in which the cell is resistant to several drugs in addition to the initial compound. This is a particular limitation to cancer chemotherapy, and the MDR cell often displays other properties, such as genome instability and loss of checkpoint control, that complicate further therapy. ABC genes play an important role in MDR, and at least six genes are associated with drug transport.

Three ABC genes appear to account for nearly all of the MDR tumor cells in both human and rodent cells. These are ABCB1 /PGP/MDR1, ABCC1 /MRP1, and ABCG2 /MXR/BCRP (Table 4). No other genes have been found overexpressed in cells that display resistance to a wide variety of drugs and in cells from mice with disrupted Abcb1a , Abcb1b , and Abcc1 genes; the Abcg2 gene was overexpressed in all MDR cell lines derived from a variety of selections (20).

Table 4

ABC transporters involved in drug resistance.

Inhibitors of the major ABC genes contributing to MDR have been developed, and extensive experimentation and clinical research have been performed to attempt to block the development of drug resistance during chemotherapy (Table 4). The latest experiments with high-affinity and high-specificity ABCB1 inhibitors show that the gene is expressed in many primary tumors in human patients and that its activity can be blocked with doses of inhibitor that do not have adverse side effects or disrupt the pharmacology of the drug regimen (21). Thus, the development of highly specific inhibitors to the other major drug transporters could lead to the development of much more effective chemotherapy protocols.

Another limitation of chemotherapy is the narrow difference in sensitivity of the tumor cells to drugs and sensitivity of the patient's normal stem cells. ABC genes have also been used as tools to deliver drug transporters to early stem cells and to protect them from chemotherapeutic drugs. This strategy would allow high doses of drug to be given for longer periods of time.

Phylogenetic Analysis of Human ABC Genes

The identification of the complete set of human ABC genes allows a comprehensive phylogenetic analysis of the superfamily. Alignment of the NBFs from each gene and a neighbor-joining tree resulting from this analysis is displayed (Figure 3). The subclassification of ABC transporters is in excellent agreement with the phylogenetic trees obtained. In particular, all major ABC transporter families are represented in the human tree by stable clusters with high statistical significance.

Figure 3

Phylogenetic tree of the human ABC genes. ATP-binding domain proteins were identified using the model ABC_tran of the Pfam database (250). The HMMSEARCH program from the HMMER package (251) and a set of custom-made service scripts were used to extract (more...)

This analysis provides compelling evidence for frequent domain duplication of ATP-binding domains in ABC transporters. Virtually invariably, both ATP-binding domains within a gene are more closely related to each other than to ATP-binding domains from ABC transporter genes of other subfamilies. This could represent a concerted evolution of domains within the same gene, but this seems unlikely because the two domains within each gene are substantially diverged. Therefore, it appears that duplication of ATP-binding domains within major ABC families was a result of several independent duplication events rather than a single ancestral duplication.

Mouse ABC Genes

Analysis of the Celera assembly of the mouse genome was used to identify homologs of the human ABC genes. With only a few exceptions, there is concordance between the two mammalian species (Table 3). The exceptions are a duplicated copy of the ABCB1 /PGP/MDR gene ( Mdr1b ), an ABCG family gene related to ABCG2 that is present in the mouse and not in the human ( Abcg3 ) (22), loss of Abcc11 (Dean, unpublished), duplication of the ABCA8 gene in the mouse ( Abca8a ), and a loss in the mouse of ABCA10 (Annilo et al., submitted). In addition, mice have a cluster of three ABCA family genes that is not characterized in the human genome (Chen, Annilo, Shulenin, and Dean, unpublished). This region of the human genome is incompletely characterized and does not currently contain any described functional loci. Therefore, mice have 52 ABC genes and most of the human genes have a single homolog in the mouse genome, indicating that the functions of the mouse genes should be highly similar to human genes.

Drosophila ABC Genes

The organization and annotation of the Drosophila ABC genes have been determined from the Celera (23) and Flybase (5) databases. Initial subfamily classifications were assigned based on homology and BLAST scores, and the location of each gene is shown (Table 5). In total, there are 56 genes with at least one representative of each of the known mammalian subfamilies (Table 6). The subfamily groupings were confirmed by phylogenetic analyses. A representative tree is shown in Figure 4. As expected, genes from the same subfamily cluster together and confirm the initial assignments made by inspection.

Table 5

Drosophila ABC genes.

Table 6

ABC gene subfamilies in characterized eukaryotes.

Figure 4

Phylogenetic tree of the human and Drosophila G subfamily ABC genes. An alignment of the G family genes from Drosophila and human genomes were aligned. Analysis was performed as described for Figure 3 (Annilo and Dean, unpublished).

As in the human and yeast genomes, the Drosophila ABC genes are largely dispersed in the genome. There are four clusters of two genes and one cluster of four genes (Figure 5). One of these clusters (on chromosome 2L, band 37B9) is composed of an ABCB and an ABCC gene, indicating that this is a chance grouping of genes. The remaining clusters are composed of genes from the same subfamily and are arranged in a head-to-tail fashion, consistent with gene duplication. Because the clusters are themselves dispersed and involve different subfamilies, they presumably represent independent gene duplication events.

Figure 5

Map of the Drosophila ABC genes. A diagram of each Drosophila chromosome is shown with the location and gene subfamily designation of each gene.

The best-studied Drosophila ABC genes are the eye pigment precursor transporters white ( w ), scarlet ( st ), and brown ( bw ). These genes are part of the ABCG subfamily and have a unique NBF-TM organization. Surprisingly, there are 15 ABCG genes in the fly genome, making this the most abundant ABC subfamily. This is in sharp contrast to the five or six known ABCG genes in the human and mouse genomes, respectively. The Drosophila ABCG genes are highly dispersed in the genome with only two pairs of linked genes. In addition, they are very divergent phylogenetically, suggesting that there were many independent and ancient gene duplication events. The Atet gene is the only Drosophila ABCG family gene that has a close ortholog in the human genome ( ABCG1 and ABCG4 ) (Figure 4).

Several Drosophila ABCB genes, Mdr49 , Mdr50 , and Mdr65 , have also been well characterized. A fourth member of this group, CG10226 , found clustered with Mdr65 , was also identified (Table 5). These genes are closely related to the human and mouse P-glycoproteins ( ABCB1 and ABCB4), and disruption of Mdr49 results in sensitivity to colchicines (24).

Phenotypic mutants that are not assigned to genes and lie in the region of Drosophila ABC genes are shown (Table 5). The most promising connection is the identification of several eye phenotypes (vin, rose, cln) in the region of the CG7346 gene. Because CG7346 is part of the ABCG family and is therefore related to w , st , and bw , it is tempting to speculate that mutations in CG7346 cause one or more of these phenotypes. Because ABC genes perform very diverse functions and are associated with varied phenotypes, it is hard to gather much additional insight from this analysis.

Three genes, CG9990 , CG6162 , and CG11147 , were identified that do not fit into any of the known subfamilies and, in fact, are most closely related to ABC genes from bacteria. These genes are within large contigs and have introns and therefore do not represent contamination from bacterial sequences. This group forms a distinct cluster on the Drosophila tree. This new ABC transporter subfamily in Drosophila is significantly different from all known families of ABC transporters and might play an as-yet-unidentified functional role. These genes have been designated as subfamily H.

Because of the high rate of birth and death of ABC genes, very few Drosophila genes have a human ortholog. This indicates that the genes have evolved to carry out functions that are specialized to insects and mammals. This is borne out by the experimental data to date. For example, the insect and vertebrate eyes are convergent organs, and the eye pigment transporters in flies have no comparable functional homolog in vertebrates. Similarly, the vertebrate ABCA4 (photoreceptor-specific transporter), CFTR (chloride channel controlling exocrine secretion), and most other mammalian ABC genes have specialized functions that are not present in insects and nematodes. Therefore, the genetic and functional analysis of Drosophila genes is not likely to lead to the direct understanding of the function of the individual mammalian ABC genes.

ABCA Genes

ABCB Genes

ABCC Genes

ABCD Genes

ABCE Genes

ABCF Genes

ABCG Genes

ABCG5

The ABCG5 gene maps to chromosome 2p21 and is adjacent to and arranged head-to-head with the ABCG8 gene (237–239) (Figure 6). Both of these genes are mutated in families with sitosterolemia, a disorder characterized by defective transport of plant and fish sterols and cholesterol (238–243). Most likely, the two half transporters form a functional heterodimer, and they appear to be regulated by the same promoter (244).

Figure 6

Model of ABCG5 and ABCG8 dimers. A diagram of the potential dimers that can be formed from the ABCG5 and ABCG8 half transporters. Although the heterodimer is speculated to be the major transporter of sitosterol, the homodimers are proposed to transport (more...)

Patients mutated in either ABCG5 or ABCG8 have similarly elevated levels of sitosterol, suggesting that it is the heterodimer that is the principal transporter of sitosterol (245). However, Asian sitosterolemia patients have almost exclusive mutations in ABCG5 , and Caucasian patients have mutations in ABCG8 (245–247). This suggests that there are independent functions of the two genes, and that they may also form heterodimers to transport some of the wide variety of non-cholesterol sterols found in plants and shellfish.

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