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PubMed2003

Multidrug resistance ABC transporters.

Clinical multidrug resistance is caused by a group of integral membrane proteins that transport hydrophobic drugs and lipids across the cell membrane. One class of these permeases, known as multidrug resistance ATP binding cassette (ABC) transporters, translocate these molecules by coupling drug/lipid efflux with energy derived from the hydrolysis of ATP. In this review, we examine both the structures and conformational changes of multidrug resistance ABC transporters. Together with the available biochemical and structural evidence, we propose a general mechanism for hydrophobic substrate transport coupled to ATP hydrolysis.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2004

ABC transporter architecture and mechanism: implications from the crystal structures of BtuCD and BtuF.

ABC transporters are ubiquitous membrane proteins that facilitate unidirectional substrate translocation across the lipid bilayer. Over the past five years, new crystal structures have advanced our understanding of how ABC transporters couple adenosine triphosphate (ATP) hydrolysis to substrate transport. In the following, we will briefly review the results of these structural investigations and outline their mechanistic implications.

ATP-Binding Cassette Transporters↗

PubMed1997

Membrane topology distinguishes a subfamily of the ATP-binding cassette (ABC) transporters.

A group of ATP-binding cassette (ABC) transporters, including the yeast cadmium transporter (YCF1), the mammalian multidrug resistance-associated protein (MRP), the multispecific organic anion transporter and its congener (MOAT and EBCR), as well as the sulfonylurea receptor (SUR), group into a subfamily by sequence comparison. We suggest that these MRP-related proteins are also characterized by a special, common membrane topology pattern. The most studied ABC transporters, the cystic fibrosis transmembrane conductance regulator (CFTR) and the multidrug resistance (MDR) proteins, were shown to contain a tandem repeat of six transmembrane helices, each set followed by an ATP-binding domain. According to the present study, in contrast to various membrane topology predictions proposed for the different MRP-related proteins, they all seem to have a CFTR/MDR-like core structure, and an additional, large, N-terminal hydrophobic region. This latter domain is predicted to contain 4-6 (most probably 5) transmembrane helices, and is occasionally glycosylated on the cell surface. Since all the MRP-related transporters were shown to interact with anionic compounds, the N-terminal membrane-bound domain may have a key role in these interactions.

ATP-Binding Cassette Transporters↗

PubMed1997

The photoreceptor rim protein is an ABC transporter encoded by the gene for recessive Stargardt's disease (ABCR).

Rim protein (RmP) is a high-Mr membrane glycoprotein that has been localized to the rims of photoreceptor outer segment discs, but its molecular identity is unknown. Here, we describe the purification of RmP and present the sequence of its mRNA. RmP is a new member of the ATP-binding cassette (ABC) transporter superfamily. We show that RmP is expressed specifically in photoreceptors and predominantly in outer segments. Further, RmP is identical to the protein recently shown to be affected in recessive Stargardt's disease. RmP is the first ABC transporter observed in photoreceptors and may play a role in the photoresponse.

ATP-Binding Cassette Transporters↗

PubMed1997

Differential expression of genes coding for ABC transporters after treatment of Arabidopsis thaliana with xenobiotics.

ATP-binding cassette (ABC) transporters are thought to be involved in many cellular detoxification mechanisms. Performing a BLAST search, we found four distinct expressed sequence tags (EST) of Arabidopsis thaliana highly similar to the human and fungal glutathione-conjugate ABC transporters. We studied the expression of the corresponding genes in response to various xenobiotics in an effort to gain information on their function. The abundance of transcripts corresponding to one of the genes (EST1) was not affected by the various compounds tested, whereas the abundance of transcripts corresponding to the other three genes (EST2, EST3, EST4) was increased by 1-chloro-2,4-dinitrobenzene, primisulfuron and IRL 1803. Treatment of Arabidopsis with either primisufuron or IRL 1803 resulted in a more than 40-fold increase in EST2-specific transcripts.

ATP-Binding Cassette Transporters↗

PubMed1997

The yeast ATP binding cassette (ABC) protein genes PDR10 and PDR15 are novel targets for the Pdr1 and Pdr3 transcriptional regulators.

The yeast transcription factors Pdr1 and Pdr3 control pleiotropic drug resistance (PDR) development, since they regulate expression of ATP-binding cassette (ABC) drug efflux pumps through binding to cis-acting sites known as PDREs (PDR responsive elements). In this report, we show by Northern blotting, gel shift mobility assays and DNase I footprinting that transcription of the ABC genes PDR10 and PDR15 is also controlled by Pdr1 and Pdr3. In addition, in vitro band shift assays demonstrate that a GST-Pdr1 fusion protein can bind to the PDREs of PDR10 and PDR15. DNase I footprinting allowed the identification of the precise PDRE binding motifs, indicating the presence of a novel slightly degenerate PDRE motif in the PDR15 promoter. Finally, PDR10 and PDR15 mRNA levels vary dramatically in abundance in isogenic yeast strains carrying either deltapdr1, deltapdr3 and deltapdr1 deltapdr3 deletions or pdr1-3 and pdr3-2 gain-of-function mutations, demonstrating that both PDR10 and PDR15 are new members of the yeast PDR network.

ATP-Binding Cassette Transporters↗

PubMed1998

Identification of a human mitochondrial ABC transporter, the functional orthologue of yeast Atm1p.

We have sequenced the entire coding region of the human ABC transporter ABC7. The protein represents a 'half-transporter' and displays high sequence similarity to the mouse ABC7 protein and to the mitochondrial ABC transporter Atm1p of Saccharomyces cerevisiae. As shown by immunostaining using a specific antibody, the human ABC7 protein (hABC7) is a constituent of mitochondria. The N-terminus of hABC7 contains the information for targeting and import into the organelles. When synthesised in yeast cells defective in Atm1p (strain delta atm1/hABC7), hABC7 protein can revert the strong growth defect observed for delta atm1 cells to near wild-type behaviour. The known phenotypical consequences of inactivation of the ATM1 gene are almost fully amended by expression of hABC7 protein. delta atm1/hABC7 cells harbour wild-type levels of cytochromes and extra-mitochondrial heme-containing proteins, they contain normal levels of mitochondrial iron, and the cellular content of glutathione is substantially reduced relative to the high levels detected in delta atm1 cells. Our results suggest that hABC7 is a mitochondrial protein, and represents the functional orthologue of yeast Atm1p.

ATP-Binding Cassette Transporters↗

PubMed2003

Structure of MsbA from Vibrio cholera: a multidrug resistance ABC transporter homolog in a closed conformation.

The spread of multidrug resistance (MDR) is a world health crisis that presents a significant challenge to the treatment of cancer and infection. MDR can be caused by a group of ABC (MDR-ABC) transporters that move hydrophobic drug molecules and lipids across the cell membrane. To gain insight into the conformational changes these transporters undergo when flipping hydrophobic substrates across the lipid bilayer, we have determined the structure of the lipid flippase MsbA from Vibrio cholera (VC-MsbA) to 3.8A. Structural comparison of VC-MsbA to MsbA from Escherichia coli reveals that the transporters share a structurally conserved core of transmembrane alpha-helices, but differ in the relative orientations of their nucleotide-binding domains (NBD). The transmembrane domain of VC-MsbA is captured in a closed conformation and the structure supports a "power stroke" model of transporter dynamics where opposing NBDs associate upon ATP binding. The separation of the alpha and beta domains of the NBD suggests the possibility that their association could make them competent to bind ATP and gives further insight into the structural basis for catalytic regulation.

ATP-Binding Cassette Transporters↗

PubMed1985

Application of avidin-biotinized peroxidase (ABC) method for immunocytochemical localization of corticotropin-releasing factor (CRF) in rat hypothalamus.

Studies on immunocytochemical localization of corticotropin-releasing factor (CRF) were performed in the rat hypothalamus using avidin-biotinized peroxidase (ABC) and PAP techniques. In intact and control animals CRF-immunoreactive nerve fibers were observed within outer layer of median eminence. In the adrenalectomized animals, CRF was also demonstrated in perikarya of neurocytes and in their projections in paraventricular nucleus of the hypothalamus. In both immunocytochemical techniques identical localization of CRF was obtained. However, reaction intensity was greater with the ABC technique than with the PAP one. In bilateral adrenalectomized animals, a greater number of CRF-immunoreactive neural fibers were observed in the median eminence than in control rats and rats subjected to sham operation.

Adrenalectomy↗

PubMed1998

The C. elegans cell corpse engulfment gene ced-7 encodes a protein similar to ABC transporters.

The C. elegans gene ced-7 functions in the engulfment of cell corpses during programmed cell death. We report that the CED-7 protein has sequence similarity to ABC transporters, is broadly expressed during embryogenesis, and is localized to the plasma membrane. Mosaic analysis revealed that ced-7 functions in both dying cells and engulfing cells during the engulfment process. We propose that CED-7 functions to translocate molecules that mediate homotypic adhesion between the cell surfaces of the dying and engulfing cells. Like CED-7, the mammalian ABC transporter ABC1 has been implicated in the engulfment of cell corpses, suggesting that CED-7 and ABC1 may be functionally similar and that the molecular mechanism underlying cell corpse engulfment during programmed cell death may be conserved from nematodes to mammals.

ATP-Binding Cassette Transporters↗

PubMed2003

An intrinsic adenylate kinase activity regulates gating of the ABC transporter CFTR.

Cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel in the ATP binding cassette (ABC) transporter family. Like other ABC transporters, it can hydrolyze ATP. Yet while ATP hydrolysis influences channel gating, it has long seemed puzzling that CFTR would require this reaction because anions flow passively through CFTR. Moreover, no other ion channel is known to require the large energy of ATP hydrolysis to gate. We found that CFTR also has adenylate kinase activity (ATP + AMP <=> ADP + ADP) that regulates gating. When functioning as an adenylate kinase, CFTR showed positive cooperativity for ATP suggesting its two nucleotide binding domains may dimerize. Thus, channel activity could be regulated by two different enzymatic reactions, ATPase and adenylate kinase, that share a common ATP binding site in the second nucleotide binding domain. At physiologic nucleotide concentrations, adenylate kinase activity, rather than ATPase activity may control gating, and therefore involve little energy consumption.

ATP-Binding Cassette Transporters↗

PubMed2002

Combined effect of zidovudine (ZDV), lamivudine (3TC) and abacavir (ABC) antiretroviral therapy in suppressing in vitro FIV replication.

In view of close similarities at the molecular and clinical levels, feline immunodeficiency virus (FIV) infection of the domestic cat is subject of increasing attention as an animal model for human immunodeficiency virus (HIV) infection. A range of reverse transcriptase inhibitors effective against HIV are also active against FIV, allowing successful use of the cat model to investigate drug interactions and resistance development. Nevertheless, while combined nucleoside analog and protease inhibitor usage has proven remarkably effective in treating HIV infection, combination antiretroviral therapy of FIV infection has been hampered by lack of protease inhibitors specific for FIV. In an attempt to circumvent this problem, we have examined the feasibility of applying in the FIV system combination protocols lacking a protease inhibitor. We now report that, as observed during HIV infection, the nucleoside analog abacavir (ABC or 1592U89) is able to effectively block in vitro FIV-replication. Furthermore, we demonstrate that combined usage of ABC with the nucleoside analogs zidovudine (ZDV or AZT) and lamivudine (3TC) also blocks in vitro FIV replication in a synergistic manner. However, in contrast to its effect on HIV replication, the ribonucleotide reductase inhibitor hydroxyurea (HU) is unable to effectively control in vitro FIV replication.

Animals↗

PubMed2001

Wheat mitochondria ccmB encodes the membrane domain of a putative ABC transporter involved in cytochrome c biogenesis.

Assembly of cytochromes c is mediated by different proteins depending on the organism and organelle considered. In land plants, mitochondria follow a pathway distinct from that of yeast and animal mitochondria, more similar to that described for alpha- and gamma-proteobacteria. Indeed, in plant mitochondria, four genes were identified based on the similarities of their products with bacterial proteins involved in c-type cytochrome maturation. We report the characterisation of one of these mitochondrial genes in Triticum aestivum, TaccmB, which is proposed to encode a subunit of an ABC transporter. The transcript extremities were mapped and cDNA sequencing revealed 42 C to U editing positions in the 618 nucleotide long coding region. This high editing rate affects the identity of 32 amino acids out of 206. Antibodies directed against wheat CcmB recognise a 28 kDa protein in an enriched inner mitochondrial membrane protein fraction, a location which is in agreement with the high hydrophobicity of the protein and its function as a putative transmembrane domain of an ABC transporter involved in cytochrome c and c1 biogenesis in plant mitochondria.

ATP-Binding Cassette Transporters↗

PubMed1996

Molecular cloning and characterization of the ABC transporter expressed in Trachea (ATET) gene from Drosophila melanogaster.

A novel member of the ATP-binding cassette (ABC) transporter proteins has been cloned from Drosophila melanogaster. The gene is designated as ABC Transporter Expressed in Trachea (Atet), because the transcript was localized to the respiratory system by in situ hybridization analysis of whole-mount embryos using digoxigenin-labeled RNA probes. The hybridization signal was also observed in amnioserosa. Northern blot analysis identified a single 4.5 kb mRNA expressed in all developmental stages at a relatively constant level. The Atet gene mapped to 24E on the left arm of the second chromosome. The Atet protein shows extensive homology with the Drosophila white gene product, which is reported to form heterodimers with the brown or scarlet gene product to transport guanine or tryptophan into the pigment cells in the compound eye. By analogy, Atet is suggested to be involved in transporting a small molecule after dimerization with a partner protein.

ATP-Binding Cassette Transporters↗

PubMedDate not supplied

Comparison of the reaction time, the Berg Scale and the ABC in non-fallers and fallers.

Postural sway, reaction time, the Berg Scale and the Activities-specific Balance Confidence Scale (ABC) were administered to 80 elderly subjects (40 fallers and 40 healthy non-fallers) in order to determine reliable predictor for those at risk of falling. Non-fallers showed significantly faster reaction times when compared with fallers experimental group. Postural sway results show a higher oscillation displacement in the Y axis (lateral) than the X axis (anterior-posterior) and that fallers oscillate at a higher frequency than non-fallers. All variables were submitted to a multiple regression analysis. Only three of the four variables were found to be significant predictors of fall status. The variables in order of their inclusion are reaction time, Total Berg Balance Score and mean ABC. It was further determined that reaction time was indeed the best predictor of fall status in the present study.

Journal Article↗

PubMed2000

Hypoglycemia and the ABC'S (sugar) of pediatric resuscitation.

STUDY OBJECTIVE: The purpose of this study was to determine the prevalence of hypoglycemia and describe the clinical variables associated with hypoglycemia in children receiving resuscitation care. METHODS: A cross-sectional study of consecutive children receiving resuscitation care in an emergency department was performed. Rapid glucose testing was prospectively established as one of the initial resuscitation steps, and clinical variables were obtained from a retrospective chart review. The setting was an urban children's hospital ED (Level II trauma center) with a census of 31, 000 per year and a 10% admission rate. The patient population consisted of children (birth to 20 years of age) receiving resuscitation care for altered consciousness, status epilepticus, respiratory failure, cardiac failure, and cardiopulmonary arrest. RESULTS: Over a 1-year period, 49 nontrauma-related children received resuscitation care. Nine (18%; 95% confidence interval 8.7 to 32.2) were hypoglycemic (glucose level </=40 mg/dL). The median time from ED presentation to rapid glucose testing was 11 minutes (range, 0 to 65 minutes). Four of the hypoglycemic children had septic shock. The mortality rate was significantly greater (P =.015) in the hypoglycemic children. CONCLUSION: Because hypoglycemia occurs often in children requiring resuscitation and clinical signs are often unspecific, routine rapid assessment of serum glucose is recommended. To increase physician awareness, adding "S" (sugar) to the popular mnemonic A (airway), B (breathing), and C (circulation): ABC'S is recommended. [Losek JD. Hypoglycemia and the ABC'S (sugar) of pediatric resuscitation. Ann Emerg Med. January 2000;35:43-46.]

Abbreviations as Topic↗

PubMed2000

Molecular basis for K(ATP) assembly: transmembrane interactions mediate association of a K+ channel with an ABC transporter.

K(ATP) channels are large heteromultimeric complexes containing four subunits from the inwardly rectifying K+ channel family (Kir6.2) and four regulatory sulphonylurea receptor subunits from the ATP-binding cassette (ABC) transporter family (SUR1 and SUR2A/B). The molecular basis for interactions between these two unrelated protein families is poorly understood. Using novel trafficking-based interaction assays, coimmunoprecipitation, and current measurements, we show that the first transmembrane segment (M1) and the N terminus of Kir6.2 are involved in K(ATP) assembly and gating. Additionally, the transmembrane domains, but not the nucleotide-binding domains, of SUR1 are required for interaction with Kir6.2. The identification of specific transmembrane interactions involved in K(ATP) assembly may provide a clue as to how ABC proteins that transport hydrophobic substrates evolved to regulate other membrane proteins.

ATP Binding Cassette Transporter 1↗

PubMedDate not supplied

ABC transporters: physiology, structure and mechanism--an overview.

ABC transporters form one of the largest of all protein families with a diversity of physiological functions. In Escherichia coli almost 5% of the genome is occupied by genes encoding components of these transporters, and there are examples in all species from microbes to man. In this overview, the importance of studies on bacteria in elucidating many basic principles pertaining to ABC transporters is emphasised. The family is described and a general overview of the structure and function of these transporters is presented.

ATP Binding Cassette Transporter, Subfamily B, Mem↗