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PubMed1994

Cloning of two novel ABC transporters mapping on human chromosome 9.

The family of ATP binding cassette (ABC) transporters or traffic ATPases is composed of several membrane-associated proteins that transport a great variety of solutes across cellular membranes. Two novel mammalian members of the family, ABC1 and ABC2, have been identified by a PCR-based approach. They belong to a group of traffic ATPases encoded as a single multifunctional protein, such as CFTR, STE 6, and P-glycoproteins. Their peculiar structural features and close relationship to ABC transporters involved in nodulation suggest that ABC1 and ABC2 define a novel subgroup of mammalian traffic ATPases.

ATP Binding Cassette Transporter 1↗

PubMed1997

The cloning of a human ABC gene (ABC3) mapping to chromosome 16p13.3.

The ATP binding cassette (ABC) transporters, or traffic ATPases, constitute a large family of proteins responsible for the transport of a wide variety of substrates across cell membranes in both prokaryotic and eukaryotic cells. We describe a human ABC protein with regions of strong homology to the recently described murine ABC1 and ABC2 transporters. The gene for this novel protein, human ABC3, maps near the polycystic kidney disease type 1 (PKD1) gene on chromosome 16p13.3. The ABC3 gene is expressed at highest levels in lung compared to other tissues.

ATP-Binding Cassette Transporters↗

PubMed1998

ARA, a novel ABC transporter, is located at 16p13.1, is deleted in inv(16) leukemias, and is shown to be expressed in primitive hematopoietic precursors.

ATP-binding cassette (ABC), ATP-dependent transporters are a large superfamily of proteins that include the multidrug resistance proteins, P-glycoprotein and MRP (multidrug resistance protein). The ARA (anthracycline resistance-associated) gene that codes for a putative member of the ABC transporters has recently been cloned and shown to have high sequence homology to the gene for MRP. We have previously shown MRP to be deleted in a subset of inv(16) leukemic patients. The deletion of MRP was associated with an improved patient survival compared with inv(16) patients who did not have such a deletion. In this study, the ARA gene is mapped to 16p13.1, in the same physical interval as the inv(16) short-arm breakpoint. It is shown to be situated proximal to both MYH11, the gene involved in the primary breakpoint on the short arm of the inv(16), and MRP. A YAC clone has been isolated containing both MRP and ARA. FISH analysis of metaphase chromosomes from inv(16) patients has established the gene order as telomere-MYH11-MRP-ARA-centromere and demonstrated that both ARA and MRP are deleted in a subgroup of the inv(16) leukemias. ARA and MRP are both shown to be expressed in normal hematopoietic precursors including CD34(+) cells. The mapping of ARA to this region and its homology to MRP raises questions about its potential role in the biology of the inv(16) leukemias.

ATP-Binding Cassette Transporters↗

PubMed1997

Molecular and immunological analysis of an ABC transporter complex required for cytochrome c biogenesis.

The helABC genes are predicted to encode an ATP-binding cassette (ABC) transporter necessary for heme export for ligation in bacterial cytochrome c biogenesis. The recent discoveries of homologs of the helB and helC genes in plant mitochondrial genomes suggest this is a highly conserved transporter in prokaryotes and some eukaryotes with the HelB and HelC proteins comprising the transmembrane components. Molecular genetic analysis in the Gram-negative bacterium Rhodobacter capsulatus was used to show that the helABC and helDX genes are part of an operon linked to the secDF genes. To facilitate analysis of this transporter, strains with non-polar deletions in each gene, epitope and reporter-tagged HelABCD proteins, and antisera specific to the HelA and HelX proteins were generated. We directly demonstrate that this transporter is present in the cytoplasmic membrane as an HelABCD complex. The HelB and HelC but not HelD proteins are necessary for the binding and stability of the HelA protein, the cytoplasmic subunit containing the ATP-binding region. In addition we show that the HelA protein co-immunoprecipitates with either the HelC or HelD proteins. Thus, the HelABCD heme export complex is distinguished by the presence of four membrane-associated subunits and represents a unique subfamily of ABC transporters.

ATP-Binding Cassette Transporters↗

PubMed1990

Rapid and sensitive identification of human blood by an ELISA-ABC method using a biotinylated antibody against human HbA0.

A direct enzyme-linked immunosorbent assay (ELISA) using an avidin-biotin complex (ABC) system for the identification of human blood is described. In this ELISA-ABC method, in which biotin-labeled goat IgG antibody against human HbA0 was used, it was possible clearly to distinguish human blood from the blood of other species, including that of Japanese monkeys. It took about 3 h to obtain the results. Human Hb concentrations ranging from 22 ng to 169 micrograms produced a positive reaction, and the minimum detection limit in terms of the highest possible dilution of human blood was 1:640,000.

Animals↗

PubMed1996

An ABC transporter is essential for resistance to the antitumor agent mithramycin in the producer Streptomyces argillaceus.

Mithramycin is an antitumor antibiotic synthesized by Streptomyces argillaceus. This producer strain is highly resistant in vivo to mithramycin (MIC 100 micrograms/ml) but sensitive to the related drugs chromomycin and olivomycin (MIC 10 micrograms/ml). From a genomic library of S. argillaceus DNA two cosmid clones were isolated which confer a high level of resistance to mithramycin on S. albus. The resistance genes were mapped by subcloning to a 3.9-kb PstI-PvuII fragment. DNA sequence analysis of this fragment revealed one incomplete and three complete open reading frames. Subcloning experiments demonstrated that resistance to mithramycin is mediated by the genes mtrA and mtrB. The mtrA gene can potentially encode an ATP-binding protein of the ABC transporter superfamily, containing one nucleotide-binding domain and showing similarity with other ABC transporters involved in resistance to daunorubicin, oleandomycin and tetronasin in their respective producer strains. The mtrB gene codes for an integral membrane protein with six putative transmembrane helices. A mithramycin-sensitive mutant was generated in a gene replacement experiment by disrupting the mtrA gene, thus demonstrating that the system encoded by the mtrAB genes is essential for conferring resistance to mithramycin in S. argillaceus.

ATP-Binding Cassette Transporters↗

PubMed1990

Expression of HLA ABC and DR antigens in thyroid neoplasia and correlation with mononuclear leukocyte infiltration.

The rejection of tumor cells by the immune system depends on the production of tumor-associated antigens and the expression of HLA antigens on these cells. We therefore studied the expression of HLA ABC and DR antigens in malignant and benign thyroid disorders and correlated it with the types and extent of mononuclear cell infiltration. In the normal thyroid, HLA ABC expression was weak and focal, while it was diffusely present in benign disorders and in most but not all malignancies. HLA DR antigens, while absent or infrequently expressed in normal thyroid, were strongly but often focally expressed in all cases of autoimmune thyroid disease (AITD), as well as in most cases of malignant tumors and benign epithelium surrounding these tumors, and colloid nodule disease. There was a T cell predominance in all disorders, and the CD4+/CD8+ ratio was greater than 1 in most benign and malignant specimens. There was a direct correlation between the high expression of HLA antigens and dense inflammatory infiltration in AITD but not in most tumor specimens. Lack of such correlation suggests that the expression of HLA antigens is an autonomous event in tumors, independent of cellular infiltrate.

Antibodies, Monoclonal↗

PubMed2005

Pharmacogenomics of the human ABC transporter ABCG2: from functional evaluation to drug molecular design.

In the post-genome-sequencing era, emerging genomic technologies are shifting the paradigm for drug discovery and development. Nevertheless, drug discovery and development still remain high-risk and high-stakes ventures with long and costly timelines. Indeed, the attrition of drug candidates in preclinical and development stages is a major problem in drug design. For at least 30% of the candidates, this attrition is due to poor pharmacokinetics and toxicity. Thus, pharmaceutical companies have begun to seriously re-evaluate their current strategies of drug discovery and development. In that light, we propose that a transport mechanism-based design might help to create new, pharmacokinetically advantageous drugs, and as such should be considered an important component of drug design strategy. Performing enzyme- and/or cell-based drug transporter, interaction tests may greatly facilitate drug development and allow the prediction of drug-drug interactions. We recently developed methods for high-speed functional screening and quantitative structure-activity relationship analysis to study the substrate specificity of ABC transporters and to evaluate the effect of genetic polymorphisms on their function. These methods would provide a practical tool to screen synthetic and natural compounds, and these data can be applied to the molecular design of new drugs. In this review article, we present an overview on the genetic polymorphisms of human ABC transporter ABCG2 and new camptothecin analogues that can circumvent AGCG2-associated multidrug resistance of cancer.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

PubMed2006

Molecular characterisation of ABC transporter type FtsE and FtsX proteins of Mycobacterium tuberculosis.

Elicitation of drug resistance and various survival strategies inside host macrophages have been the hallmarks of Mycobacterium tuberculosis as a successful pathogen. ATP Binding Cassette (ABC) transporter type proteins are known to be involved in the efflux of drugs in bacterial and mammalian systems. FtsE, an ABC transporter type protein, in association with the integral membrane protein FtsX, is involved in the assembly of potassium ion transport proteins and probably of cell division proteins as well, both of which being relevant to tubercle bacillus. In this study, we cloned ftsE gene of M. tuberculosis, overexpressed and purified. The recombinant MtFtsE-6xHis protein and the native MtFtsE protein were found localized on the membrane of E. coli and M. tuberculosis cells, respectively. MtFtsE-6xHis protein showed ATP binding in vitro, for which the K42 residue in the Walker A motif was found essential. While MtFtsE-6xHis protein could partially complement growth defect of E. coli ftsE temperature-sensitive strain MFT1181, co-expression of MtFtsE and MtFtsX efficiently complemented the growth defect, indicating that the MtFtsE and MtFtsX proteins might be performing an associated function. MtFtsE and MtFtsX-6xHis proteins were found to exist as a complex on the membrane of E. coli cells co-expressing the two proteins.

ATP-Binding Cassette Transporters↗

PubMed2000

Molecular analysis of the ggtBCD gene cluster of Synechocystis sp. strain PCC6803 encoding subunits of an ABC transporter for osmoprotective compounds.

Genes encoding a substrate-binding protein (ggtB) and two integral membrane proteins (ggtC and ggtD) of the binding-protein-dependent ABC transporter for glucosylglycerol were identified in the genome of Synechocystis sp. strain PCC6803. These genes are clustered on the chromosome about 220 kb away from the previously identified ggtA gene, which encodes the ATP-binding protein of this transport system. The deduced amino acid sequences show significant similarities to corresponding subunits of ABC transporters mediating uptake of maltose and other di- and oligosaccharides in bacteria and archaea. Mutants were constructed by inserting an aphII gene cassette into the coding region of the ggtB, ggtC and ggtD genes. These mutants lost the ability to take up glucosylglycerol, sucrose and trehalose, proving that these compounds are transported by the same system. A truncated ggtB gene lacking the putative signal-peptide-encoding sequence was expressed in Escherichia coli yielding a histidine-tagged soluble protein. The recombinant GgtB protein bound glucosylglycerol with a KD of 0.45 microM and exhibited a somewhat lower affinity towards sucrose and a substantially lower affinity towards trehalose. Transcript analysis by RT-PCR indicated that the genes of the ggtBCD gene cluster form an operon. The transcript level estimated by RNA slot blot analysis using a ggtC-specific probe was very low in cells grown in basal medium but increased significantly after a salt shock.

ATP-Binding Cassette Transporters↗

PubMed1997

Molecular characterization of genes encoding a novel ABC transporter in Thermoanaerobacterium thermosulfurigenes EM1.

The nucleotide sequence of two open reading frames (ORFs) from Thermoanaerobacterium thermosulfurigenes EM1 was determined that encode proteins with similarity to components of ATP-binding cassette (ABC) transport systems. Sequence analysis suggests that the deduced proteins AbcA and AbcB consist of an NH2-terminal membrane-spanning domain and a COOH-terminal ATP-binding domain. The deduced proteins AbcA and AbcB showed highest similarity to proteins of the MsbA subfamily of ABC transporters. AbcA and AbcB probably function as a heterodimer. An ORF predicted to encode the primary sigma factor SigA was identified downstream of abcB.

ATP-Binding Cassette Transporters↗

PubMed2003

Evolutionary analysis of a cluster of ATP-binding cassette (ABC) genes.

To study the evolutionary history of ATP-binding cassette (ABC) transporters in mammals, we have characterized a cluster of five ABCA-subfamily genes localized on mouse Chromosome (Chr) 11. The genes, named Abca5, Abca6, Abca8a, Abca8b, and Abca9, are arranged in a head-to-tail fashion in a cluster that spans about 400 kb of the genomic DNA, each gene occupying about 70 kb. The transcripts of these genes contain an open reading frame from 4863 (for Abca8a and Abca8b) to 4929 (for Abca5) nucleotides, and have distinct tissue-specific expression pattern. The predicted proteins contain two transmembrane domains and two nucleotide binding domains, arranged similar to the other members of ABCA subfamily. Similarity of both the genomic organization and primary structure among the genes in this cluster suggests that the duplications generating the cluster occurred relatively recently compared with most of the ABC genes in present-day mammalian genomes. For instance, the Fugu rubripes genome contains an ortholog for only one gene, Abca5, from this cluster. Phylogenetic and comparative sequence analysis reveals that after the divergence of rodent and primate lineages, at least one gene has been lost in each genome. In addition, we found that both mouse and human clusters show evidence of a number of gene conversions, in several cases involving intron sequences.

AT Rich Sequence↗

PubMed2006

The peroxisomal ABC transporter family.

This review describes the current state of knowledge about the ABCD family of peroxisomal half adenosine-triphosphate-binding cassette (ABC) transporters. ABCDs are predicted to be present in a variety of eukaryotic organisms, although at present, only ABCDs in the yeast Saccharomyces cerevisiae, the plant Arabidopsis thaliana, and different mammalian species have been identified and characterized to any significant extent. The functional role of none of these ABCDs has been established definitively and awaits successful reconstitution of ABCDs, either as homo- or heterodimers into liposomes, followed by transport studies. Data obtained in S. cerevisiae suggest that the two ABCDs, which have been identified in this organism, form a heterodimer, which actually transports acyl coenzyme A esters across the peroxisomal membrane. In mammals, four ABCDs have been identified, of which one [adrenoleukodystrophy protein (ALDP)] has been implicated in the transport of the coenzyme A esters of very-long-chain fatty acids. Mutations in the gene (ABCD1) encoding ALDP are the cause of a severe X-linked disease, called X-linked adrenoleukodystrophy. The availability of mutant mice in which Abcd1, Abcd2, or Abcd3 have been disrupted will help to resolve the true role of the peroxisomal half-ABC transporters.

ATP Binding Cassette Transporter, Subfamily D, Mem↗

PubMed2002

Family business: the multidrug-resistance related protein (MRP) ABC transporter genes in Arabidopsis thaliana.

Despite the completion of the sequencing of the entire genome of Arabidopsis thaliana (L.) Heynh., the exact determination of each single gene and its function remains an open question. This is especially true for multigene families. An approach that combines analysis of genomic structure, expression data and functional genomics to ascertain the role of the members of the multidrug-resistance-related protein ( MRP) gene family, a subfamily of the ATP-binding cassette (ABC) transporters from Arabidopsis is presented. We used cDNA sequencing and alignment-based re-annotation of genomic sequences to define the exact genic structure of all known AtMRP genes. Analysis of promoter regions suggested different induction conditions even for closely related genes. Expression analysis for the entire gene family confirmed these assumptions. Phylogenetic analysis and determination of segmental duplication in the regions of AtMRP genes revealed that the evolution of the extraordinarily high number of ABC transporter genes in plants cannot solely be explained by polyploidisation during the evolution of the Arabidopsis genome. Interestingly MRP genes from Oryza sativa L. (rice; OsMRP) show very similar genomic structures to those from Arabidopsis. Screening of large populations of T-DNA-mutagenised lines of A. thaliana resulted in the isolation of AtMRP insertion mutants. This work opens the way for the defined analysis of a multigene family of important membrane transporters whose broad variety of functions expands their traditional role as cellular detoxifiers.

ATP-Binding Cassette Transporters↗

PubMed2002

The novel Streptomyces olivaceoviridis ABC transporter Ngc mediates uptake of N-acetylglucosamine and N,N'-diacetylchitobiose.

During cultivation in the presence of N-acetylglucosamine or chitin, Streptomyces olivaceoviridis mycelium efficiently takes up [(14)C]-labelled N-acetylglucosamine. Uptake of the labelled compound can be completely inhibited by unlabelled N-acetylglucosamine and partially by chitobiose. After extraction of the membrane with Triton X-100, two forms of a protein that binds to N-acetylglucosamine and N, N'-diacetylchitobiose (chitobiose) were purified to homogeneity by two consecutive rounds of anionic exchange chromatography. The protein was named NgcE. Using surface plasmon resonance, its binding parameters were determined. It showed highest affinity for N-acetylglucosamine (K(D)=8.28 x 10(-9) M) and for chitobiose (K(D)=2.87 x 10(-8) M). Varying equilibrium dissociation constants in the micromolecular range were ascertained for chitotetraose (K(D)=4.5 x 10(-6) M), chitopentaose (K(D)=1.03 x 10(-6) M) and chitohexaose (K(D)=3.02 x 10(-6) M); the lowest value was measured for chitotriose (K(D)=19.4 x 10(-6) M). After having determined the sequences of several internal peptides from the binding protein by Edman degradation, the corresponding ngcE gene, which encodes a predicted lipid-anchored protein, was identified by reverse genetics. Using a genomic phage library of S. olivaceoviridis genes encoding two other membrane proteins (named NgcF and NgcG) were identified adjacent to ngcE. Each of these is predicted to have six membrane-spanning helices and a consensus motif for integral membrane proteins characteristic of ABC transporters. In addition, the gene for a predicted regulator protein (NgcR) was detected. The ngcEFG operon lacks a gene for an ATP-hydrolysing protein. NgcE is a new member of the CUT-1 family of ABC transporters for carbohydrates. Comparative studies of the wild-type and a mutant strain carrying an insertion within the ngc operon clearly demonstrate that the Ngc system mediates the uptake of N-acetylglucosamine and chitobiose in vivo.

ATP-Binding Cassette Transporters↗

PubMed2002

A novel ABC transporter gene, PMR5, is involved in multidrug resistance in the phytopathogenic fungus Penicillium digitatum.

We have cloned a novel ABC transporter gene PMR5 from the phytopathogenic fungus Penicillium digitatum by RT-PCR using degenerate primers. The deduced amino acid sequence of PMR5 showed 37% identity to PMR1 from the same fungus, 71% identity to AtrB from Aspergillus nidulans, and 65% identity to BcatrB from Botrytis cinerea. Disruption mutants for PMR5 were generated in two independent P. digitatum strains and their phenotypes were characterized. These mutants displayed increased sensitivity to thiabendazole (a benzimidazole), benomyl (a benzimidazole), dithianon (a quinone), resveratrol (the phytoalexin of grape), and camptothecin (an alkaloid). Delta pmr1 disruption mutants were previously reported to show resistance to demethylation inhibitors (DMIs). These mutants were found also to display increased sensitivity to phloretin (the phytoanticipin of apples), camptothecin and oligomycin (an antibiotic). Transcription of PMR1 and PMR5 was strongly induced in response to several toxicants, including DMIs that specifically induced PMR1. In contrast, dithianon and resveratrol specifically induced PMR5 transcription. These findings indicate that expression of the two ABC transporter genes is regulated differently, and that they have complementary roles in multidrug resistance, with each having different substrate-specificities.

ATP-Binding Cassette Transporters↗

PubMed2004

Mutational analysis of the binding affinity and transport activity for N-acetylglucosamine of the novel ABC transporter Ngc in the chitin-degrader Streptomyces olivaceoviridis.

The highly differentiated bacterium Streptomyces olivaceoviridis efficiently hydrolyses chitin, a highly abundant natural polysaccharide, to low molecular weight products including N-acetylglucosamine (NAG) and N,N' -diacetylchitobiose (chitobiose). NAG is taken up by a PTS (phosphoenolpyruvate-dependent phosphotransferase system) which includes the PtsC2 protein, and via the ABC (ATP-binding cassette) transporter Ngc, which itself includes the substrate-binding protein NgcE. This is at present the only ABC transporter which is known to mediate specific uptake of NAG (K(m) 0.48 microM, V(max) 1.3 nmol/min/mg dry weight) and is competitively inhibited by chitobiose (K(i) 0.68 microM). The latter finding suggests that the Ngc system transports both NAG and chitobiose efficiently. To identify amino acid residues required for the function of NgcE, either the wild-type or one of several mutant forms of the ngcE gene was introduced into the strain S. olivaceoviridis DeltaNgcE/DeltaPtsC1/DeltaPtsC2, which lacks both functional transport systems for NAG, and chromosomal recombinants were selected. Based on the in vivo transport parameters of the recombinants, and the in vitro binding characteristics of the corresponding purified proteins, the following conclusions can be drawn. (1) Replacement of the C-terminally located residue Y396 by A (Y396A) has little effect on ligand-binding or transport parameters. The W395A mutation also induced little change in the substrate affinity in vitro, but it led in vivo to a marked increase (11 fold) in K(m), and enhanced V(max) (by 1.5 fold). (2) The amino acids Y201 and W280 both contribute (51% and 38%) to the ligand-binding capacity of NgcE. They are both very important for the in vivo function of the complete transport apparatus; strains expressing either Y201A or W280A show drastically (100 or 150 times) enhanced K(m) values. (3) The concomitant presence of either Y200 and W280 or Y201 and W280 is essential for the function of NgcE. (4) Y201 is located within a tyrosyl-rich motif. This has been found to share some features with the ligand-binding site of amelogenins (enamel matrix proteins), which interact with NAG residues in glycoconjugates. In addition, it is distantly related to the ligand-binding site(s) in the plant-lectins UDA ( Urtica dioicaagglutinin, specific for NAG and its oligomers) and WGA (wheat germ agglutinin, which recognises a motif comprising three consecutive NAG residues).

ATP-Binding Cassette Transporters↗

PubMed2001

Functional asymmetry of the two nucleotide binding domains in the ABC transporter Ste6.

The yeast a-factor transporter Ste6 is a member of the ABC transporter family and is closely related to human MDR1. We constructed a set of 26 Ste6 mutants using a random mutagenesis approach. Cell fractionation experiments demonstrated that most of the mutants, with the notable exception of those with alterations in TM1, are transported to the plasma membrane, the presumptive site of action of Ste6. Trafficking, therefore, does not seem to be affected in most of the mutants. To identify regions in Ste6 that interact with the ABC transporter "signature motif" (LSGGQ) we screened for intragenic revertants of the LSGGQ mutant M68 (S507N). Suppressor mutations were identified in TM12 and upstream of TM6. Surprisingly, these mutations also suppressed the Walker A mutation G397D, which should be defective in ATP-binding and hydrolysis at NBD1. Photoaffinity labeling experiments with 8-azido-[alpha-32P]ATP showed that ATP binding at NBD2 is reduced by the suppressor mutation in TM12. The experiments further suggest that the two NBDs of Ste6 are not equivalent and affect each other's ability to bind and hydrolyze ATP.

ATP Binding Cassette Transporter, Subfamily B, Mem↗