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At least 217 records · Page 12Linked to original sources

PubMed2005

X-ray structure of RLI, an essential twin cassette ABC ATPase involved in ribosome biogenesis and HIV capsid assembly.

The ABC ATPase RNase-L inhibitor (RLI) emerges as a key enzyme in ribosome biogenesis, formation of translation preinitiation complexes, and assembly of HIV capsids. To help reveal the structural mechanism of RLI, we determined the Mg2+-ADP bound crystal structure of the twin cassette ATPase of P. furiosus RLI at 1.9 A resolution and analyzed functional motifs in yeast in vivo. RLI shows similarities but also differences to known ABC enzyme structures. Twin nucleotide binding domains (NBD1 and NBD2) are arranged to form two composite active sites in their interface cleft, indicating they undergo the ATP-driven clamp-like motion of the NBDs of ABC transporters. An unusual "hinge" domain along the NBD1:NBD2 interface provides a frame for association and possibly ATP-driven conformational changes of the NBDs. Our results establish a first structural basis for ABC domain heterodimers and suggest that RLI may act as mechanochemical enzyme in ribosome and HIV capsid biogenesis.

Adenosine Triphosphatases↗

PubMed2006

X-linked adrenoleukodystrophy: very long-chain fatty acid metabolism, ABC half-transporters and the complicated route to treatment.

X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene that encodes a peroxisomal membrane located ABC half-transporter named ALDP. Mutations in ALDP result in elevated levels of very long-chain fatty acids (VLCFA) and reduced VLCFA beta-oxidation in peroxisomes. The peroxisomal membrane harbors three additional closely related ABC half-transporters, ALDRP, PMP70 and PMP69 (PMP70R). ABC half-transporters must dimerize to form a functional full-transporter. Whether ALDP forms a homodimer or a heterodimer has not yet been resolved, but most indirect evidence favors homodimerization. The peroxisomal ABC half-transporters are functionally related. Over-expression of ALDRP can correct the biochemical defect both in X-ALD patients cells and the Abcd1 knockout mouse, providing an exciting new possibility for treatment of X-ALD patients. This paper provides an overview of current knowledge and the problems that have been encountered.

ATP Binding Cassette Transporter, Subfamily D↗

PubMed2005

Reversal of different drug-resistant phenotypes by an autocatalytic multitarget multiribozyme directed against the transcripts of the ABC transporters MDR1/P-gp, MRP2, and BCRP.

A "multitarget multiribozyme" (MTMR) was constructed. It consists of three trans-acting hammerhead ribozymes directed against the transcripts of the ABC transporters MDR1/P-gp, BCRP, and MRP2; three cis-acting MDR1/P-gp-specific ribozymes; and three MDR1/P-gp-homologous spacer sequences. The trans-acting hammerhead ribozymes are liberated from the MTMR through autocatalytic self-cleavage by the cis-acting ribozymes. The MTMR was characterized with regard to its kinetic parameters. Comparison of the MTMR-specific kinetic values with those of the corresponding monoribozymes demonstrated that MTMR fragments could cleave their specific substrates without loss of efficiency. The MTMR was applied to three cell models, each overexpressing another ABC transporter, i.e., the gastric carcinoma cell line EPG85-257RDB expresses MDR1/P-gp, the cell variant EPG85-257RNOV synthesizes BCRP, and the ovarian carcinoma line A2780RCIS produces MRP2. In all cellular systems, the MTMR could specifically decrease the expression of the respective ABC transporter at the mRNA level (97% decrease in the MDR1/P-gp mRNA, 80% decrease in the BCRP mRNA, 96% decrease in the MRP2 mRNA) and the protein level. Resistance against the selection drug was reversed completely (100% in EPG85-257RDB) or by 94 (EPG85-257RNOV) or 63% (A2780RCIS). Thus, the MTMR technology provides a novel tool for gene therapeutic applications to reverse different ABC-transporter-dependent drug-resistant phenotypes.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1994

The sulphation pattern in chondroitin sulphate chains investigated by chondroitinase ABC and ACII digestion and reactivity with monoclonal antibodies.

We have used progressive chondroitinase digestion of pig aggrecan in conjunction with ELISA assays and disaccharide analysis to derive information about the pattern of 4- and 6-sulphation in chondroitin sulphate chains. Digestion with chondroitinase ABC resulted in the release of mainly disaccharides from the nonreducing terminal of chondroitin sulphate chains but there was also the release of some tetra- and hexa-saccharides which were degraded to disaccharides with more extensive digestion. Chondroitinase ACII, in contrast, released only disaccharides. Analysis of the disaccharide composition of the intact and digested products at different stages of digestion showed that there was a slight increase in 6-sulphate content of the chains as they were shortened. Reaction of the partially digested proteoglycans with monoclonal antibodies 3-B-3 and 3-D-5 which recognise chains terminating in 6- or 4-sulphated disaccharides, respectively, showed major differences between chondroitinase ABC and ACII products. The results suggested that chondroitinase ABC preferentially cleaved next to 4-sulphated, rather than 6-sulphated disaccharides and this resulted in some oligosaccharides as well as disaccharide being released. Chondroitinase ACII also cleaved an additional disaccharide next to the linkage to protein of chondroitin sulphate, which was not removed by chondroitinase ABC and this disaccharide was mainly nonsulphated.

Aggrecans↗

PubMed1998

Identification of an ABC transporter gene that exhibits mRNA level overexpression in fluoroquinolone-resistant Mycobacterium smegmatis.

We describe here the PCR amplification of a DNA fragment (mtp1) from Mycobacterium smegmatis using primers derived from consensus sequences of the ABC family of transporters. The fragment encodes amino acid sequences that exhibited significant homology with different ABC transporters. Amino acid sequence alignment of the full length gene with other transporters identified the ABC protein as the B-subunit of the phosphate specific transporter. Strikingly, a M. smegmatis colony which exhibited a high level of ciprofloxacin resistance showed mRNA level overexpression of mtp1. Thus this is the first report in any prokaryote indicating differential expression of an ABC transporter in a fluoroquinolone resistant colony.

ATP-Binding Cassette Transporters↗

PubMed2003

Role of farnesoid X receptor in determining hepatic ABC transporter expression and liver injury in bile duct-ligated mice.

BACKGROUND & AIMS: Cholestasis induces changes in hepatic adenosine triphosphate-binding cassette (ABC) transporter expression. We aimed to investigate the role of the nuclear bile acid receptor (farnesoid X receptor [FXR]) in mediating changes in ABC transporter expression and in determining liver injury. METHODS: Hepatic ABC transporter (multidrug resistance-associated proteins [Mrp] 2-4 and bile salt export pump [Bsep]) expression and localization were studied in common bile duct-ligated (CBDL) FXR knockout (FXR(-/-)), wild-type (FXR(+/+)), and sham-operated mice. Serum alanine aminotransferase, alkaline phosphatase, bilirubin and bile acid levels, hepatic bile acid composition, and liver histology were investigated. Cholangiomanometry and bile duct morphometry were performed. RESULTS: CBDL induced expression of Mrp 3 and Mrp 4 in FXR(+/+) and even more in FXR(-/-), whereas Mrp 2 expression remained unchanged. Bsep expression was maintained in CBDL FXR(+/+) but remained undetectable in CBDL FXR(-/-). Alanine aminotransferase levels and mortality rates did not differ between CBDL FXR(+/+) and FXR(-/-). CBDL increased biliary pressure and induced bile ductular proliferation and bile infarcts in FXR(+/+), whereas FXR(-/-) had lower biliary pressures, less ductular proliferation, and developed disseminated liver cell necroses. CONCLUSIONS: Overexpression of Mrp 3 and Mrp 4 in CBDL mice is FXR independent and could play an important role in the adaptive hepatic ABC transporter response to cholestasis. Maintenance of Bsep expression strictly depends on FXR and is a critical determinant of the cholestatic phenotype. Lack of bile infarcts in CBDL FXR(-/-) suggests that development of bile infarcts is related to bile acid-dependent bile flow and biliary pressure. This information is relevant for the potential use of FXR modulators in the treatment of cholestatic liver diseases.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

Detection and localization of non-HLA-ABC antigenic sites relevant to kidney rejection on endothelial cells.

Immunological rejection of kidney allografts is usually attributed to presensitization to HLA antigens. However, data on HLA identical transplant rejections indicate that non-HLA antigens may also be involved, and it has been suggested that vascular endothelium represents the main target cell. The purpose of the present study is to describe a method of detecting non-HLA antibodies immunocytochemically. We showed the molecular independence between HLA-ABC molecules identified by the monoclonal antibody w6/32, and antigenic sites identified by a kidney rejection patient serum, previously characterized, on cultured endothelial cells isolated from human umbilical cords by collagenase digestion. Single immunofluorescence staining indicated the molecular independence between these antigenic sites, as the first serum showed a granular pattern, diffused throughout the cytoplasm and the other a reticular pattern restricted to the same cytoplasmic region. This result was confirmed by double labeling. Immunoelectronmicroscopy study also confirmed site independence, showing labeling patterns with different intensities and distinct localizations, using 10- and 20-nm colloidal gold particles to reveal HLA-ABC and non-HLA-ABC determinants, respectively. In conclusion, cultured endothelial cells may be used immunocytochemically to detect non-HLA-ABC determinants of antibody reactivity in renal graft recipients, and the indirect immunofluorescence may be the methodology of choice, since it is easy, reliable and low cost.

Adult↗

PubMed1992

Monoclonal antibody Due ABC 3 directed against transitional cell carcinoma. I. Production, specificity analysis, and preliminary characterization of the antigen.

The development of the hybridoma technology allows the identification of tumor associated antigens with monoclonal antibodies (mAbs). Employing this technology mAb Due ABC 3 was obtained by immunization of a BALB/c mouse with bladder tumor cell line SW 1710 and subsequent cell fusion of spleen cells with P3. X63.Ag8.653 mouse myeloma cells. MAb Due ABC 3, an IgM antibody, was found to recognize an antigen present in the membrane of tumor cells in 25 out of 28 (89%) transitional cell carcinoma specimens but rarely (three out of 25 specimens, 12%) on normal urothelial cells. Cross reactions were seen with proximal tubular epithelium of the kidney and seven out of 12 renal cell carcinomas examined. Furthermore, the antigen was expressed by granulocytes, some gastrointestinal epithelia, ovarian and breast carcinoma. The antigen recognized by mAb Due ABC 3 was stable to fixation with formaldehyde and paraffin emmbedding, different proteases, alkaline treatment and heat exposure up to 70C. Antigenicity was abandoned by incubation with periodate but not with neuraminidase treatment. The antigen could be extracted with chloroform/methanol suggesting the involvement of a glycolipid. Immuno-thin layer chromatography revealed a single lipid band reacting with mAb Due ABC 3 but not with anti-CD15, directed against the Lewis X antigen. Although not tumor-specific, mAbs directed against differentiation antigens may be of value for the investigation of cell transformations as well as for diagnostic use.

Animals↗

PubMed2003

Thalictrum minus cell cultures and ABC-like transporter.

Cultured Thalictrum minus cells produce a benzylisoquinoline alkaloid, berberine, in the presence of benzyladenine, and excrete it into the culture medium. T. minus cells excluded berberine, even if berberine was exogenously added to the medium, without benzyladenine treatment. Similarly, T. minus cells excluded a heterocyclic dye (neutral red) and calcein AM, which is used as a fluorescent probe to detect the drug efflux pump activity by ABC transporters. The addition of several inhibitors of P-glycoprotein, a representative ABC transporter, induced the accumulation in of both berberine and calcein AM ATP-dependent manner. The expression of P-glycoprotein-like ABC transporter genes was also demonstrated. The involvement of ABC transporter in the secretion of berberine in T. minus cells is discussed.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMedDate not supplied

Predicting falls within the elderly community: comparison of postural sway, reaction time, the Berg balance scale and the Activities-specific Balance Confidence (ABC) scale for comparing fallers and non-fallers.

Simple reaction time, the Berg balance scale, the Activities-specific Balance Confidence (ABC) scale and postural sway were studied in order to determine cut-off scores as well as develop a model used in the prevention of fallers within the elderly community. One hundred and twenty-five subjects, 45 fallers and 80 non-fallers were evaluated throughout the study and results indicated that non-fallers have significantly faster reaction times, have higher scores on the Berg balance scale and the ABC scale as well as sway at slower frequencies when compared to fallers. Furthermore, all risk factors were subsequently entered into a logistic regression analysis and results showed that reaction time, the total Berg score and the total ABC score contributed significantly to the prediction of falls with 89% sensitivity and 96% specificity. A second logistic regression was carried out with the same previous variables as well as all questions of the Berg and ABC scales. Results from the logistic analysis revealed that three variables were associated with fall status with 91% sensitivity and 97% specificity. Results from the following study would seem rather valuable as an assessment tool for health care professionals in the identification and monitoring of potential fallers within nursing homes and throughout the community.

Accidental Falls↗

PubMed2003

Role of nuclear bile acid receptor, FXR, in adaptive ABC transporter regulation by cholic and ursodeoxycholic acid in mouse liver, kidney and intestine.

BACKGROUND/AIMS: Adaptive changes in transporter expression in liver and kidney provide alternative excretory pathways for biliary constituents during cholestasis and may thus attenuate liver injury. Whether adaptive changes in ATP-binding cassette (ABC) transporter expression are stimulated by bile acids and their nuclear receptor FXR is unknown. METHODS: Hepatic, renal and intestinal ABC transporter expression was compared in cholic acid (CA)- and ursodeoxycholic acid (UDCA)-fed wild-type (FXR(+/+)) and FXR knock-out mice (FXR(-/-)). Expression was assessed by reverse transcription-polymerase chain reaction, immunoblotting and immunofluorescence microscopy. RESULTS: CA feeding stimulated hepatic Mrp2, Mrp3, Bsep and renal Mrp2 as well as intestinal Mrp2 and Mrp3 expression. Lack of Bsep induction by CA in FXR(-/-) was associated with disseminated hepatocyte necrosis which was not prevented by compensatory induction of Mrp2 and Mrp3. With the exception of Bsep, UDCA stimulated expression of hepatic, renal and intestinal ABC transporters independent of FXR without inducing liver toxicity. CONCLUSIONS: Toxic CA and non-toxic UDCA induce adaptive ABC transporter expression, independent of FXR with the exception of Bsep. Stimulation of hepatic Mrp3 as well as intestinal and renal Mrp2 by UDCA may contribute to its therapeutic effects by inducing alternative excretory routes for bile acids and other cholephiles.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1997

Protein secretion by Gram-negative bacterial ABC exporters--a review.

One of the strategies used by Gram-negative bacteria to secrete proteins across the two membranes which delimit the cells is sec-independent and dedicated to proteins lacking an N-terminal signal peptide. Most of these proteins display a C-terminal secretion signal located in the last 60 amino acids (aa). Using one Erwinia chrysanthemi protease, PrtG, secreted by such a pathway it was shown that the smallest C-terminal sequence allowing efficient secretion contains the last 29 aa of PrtG and that low but significant secretion can be promoted by the last 15 aa of PrtG. Moreover, the extreme C-terminal motif, consisting of a negatively charged aa followed by several hydrophobic aa must be exposed and is conserved amongst many proteins following this pathway. This secretion system depends on ABC protein-mediated exporters, which consist of three cell envelope proteins: two inner membrane proteins, an ATPase (the ABC protein), a membrane fusion protein (MFP) and an outer membrane polypeptide. These Gram-negative bacterial protein exporters are dedicated to the secretion of one or several closely related proteins belonging to the toxin, protease and lipase families. The genes encoding the three secretion proteins and the exoproteins are usually all linked, consistent with the specificity of the systems. Er. chrysanthemi metalloproteases B and C and Serratia marcescens hemoprotein HasA are secreted by such homologous pathways and interact with the ABC protein. Interaction between the ABC protein and its substrate has also been evidenced by studies on protease and HasA hybrid transporters obtained by combining components from each system. Association between hemoprotein HasA and the three exporter secretion proteins was demonstrated by affinity chromatography on hemin agarose on which the substrate remained bound with the three secretion proteins. The three components' association was ordered and substrate binding was required for the formation of this multiprotein complex.

ATP-Binding Cassette Transporters↗

PubMed2003

ABC transporters and drug resistance in parasitic protozoa.

Parasitic protozoa are responsible for a wide spectrum of diseases in humans and domestic animals. The main line of defence available against these organisms is chemotherapy. However, the application of chemotherapeutic drugs has resulted in the development of resistance mechanisms, which limit the number of antiprotozoal drugs that are effective in the treatment and control of parasitic diseases. Knowledge about the resistance mechanisms involved may allow the development of new drugs that minimise or circumvent drug resistance or may identify new targets for drug development. This review focuses on the role of protozoal ATP-binding cassette (ABC) transporters in drug resistance. These membrane proteins mediate the ATP-dependent transport of a wide variety of chemotherapeutic drugs away from their targets inside the parasites. The genome sequence of Plasmodium falciparum and Plasmodium yoelii has recently been completed, and the sequencing of other parasitic genomes are now underway. As a result, many new membrane transporters belonging to the ABC superfamily are being discovered. We review the ABC transporters in major parasitic protozoa, including Plasmodium, Leishmania, Trypanosoma and Entamoeba species. Transporters with an established role in drug resistance have been emphasised, but newly discovered transporters with a significant amino acid sequence identity to established ABC drug transporters have also been included.

ATP-Binding Cassette Transporters↗

PubMed2003

A new dimer interface for an ABC transporter.

The crystallization of MsbA, an ATP-binding cassette (ABC) transporter involved in the transport of Lipid A in Escherichia coli, provided a fascinating glimpse into the high-resolution structure of an ABC transporter at 4.8 A. The E. coli crystal structure of MsbA reveals a dimer. Although the structure of the MsbA monomer is consistent with the biochemistry of ABC transporters, including the human multidrug resistance P-glycoprotein, the interface between the monomers in the MsbA dimer may not reflect the biologically relevant interface. We considered the interface in a two-armed MsbA dimer, named spiral. Our findings indicate that (i) the spiral MsbA dimer may have biological relevance for ABC transporters that interact with lipophilic substrates, and (ii) the dimer interface observed in the crystal structure of E. coli MsbA represents a crystallization artefact. A comparison of the spiral MsbA dimer with the recently published structure of MsbA in Vibrio cholera is also described.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

A common mechanism for ATP hydrolysis in ABC transporter and helicase superfamilies.

ABC (ATP-binding cassette) transporters and helicases are large superfamilies of seemingly unrelated proteins, whose functions depend on the energy provided by ATP hydrolysis. Comparison of the 3D structures of their nucleotide-binding domains reveals that, besides two well-characterized ATP-binding signatures, the folds of their nucleotide-binding sites are similar. Furthermore, there are striking similarities in the positioning of residues thought to be important for ATP binding or hydrolysis. Interestingly, structures have recently been obtained for two ABC proteins that are not involved in transport activities, but that have a function related to DNA modification. These ABC proteins, which contain a nucleotide-binding site akin to those of typical ABC transporters, might constitute the missing link between the two superfamilies.

ATP-Binding Cassette Transporters↗

PubMed2003

Pharmacogenomics of ABC transporters and its role in cancer chemotherapy.

ATP-binding cassette (ABC) genes play a role in the resistance of malignant cells to anticancer agents. The ABC gene products, including ABCB1 (P-glycoprotein), ABCC1 (MRP1), ABCC2 (MRP2, cMOAT), and ABCG2 (BCRP, MXR, ABCP) are also known to influence oral absorption and disposition of a wide variety of drugs. As a result, the expression levels of these proteins in humans have important consequences for an individual's susceptibility to certain drug-induced side effects, interactions, and treatment efficacy. Naturally occurring variants in ABC transporter genes have been identified that might affect the function and expression of the protein. This review focuses on recent advances in the pharmacogenomics of ABC transporters, and discusses potential implications of genetic variants for the chemotherapeutic treatment of cancer.

ATP-Binding Cassette Transporters↗

PubMed1998

ABC transporters in Leishmania and their role in drug resistance.

ABC transporters have been found in several parasitic protozoa including Leishmania. At least two Leishmania ABC transporters are involved in drug resistance. One is PgpA, which is involved in resistance to arsenic and antimony-containing compounds. Antimonials are the drug of choice against Leishmania infections. Transfection and biochemical studies suggest that PgpA recognizes metals conjugated to thiols. The second ABC transporter is closely related to mammalian P-glycoproteins and confers resistance to anticancer drugs by a mechanism that remains to be elucidated. Additional ABC transporters are likely to be present in Leishmania and these are discussed in relation to the phenomenon of antimony resistance.

Journal Article↗

PubMed2004

Characterization of YvcC (BmrA), a multidrug ABC transporter constitutively expressed in Bacillus subtilis.

The involvement of transporters in multidrug resistance of bacteria is an increasingly challenging problem, and most of the pumps identified so far use the protonmotive gradient as the energy source. A new member of the ATP-binding cassette (ABC) family, known in Bacillus subtilis as YvcC and homologous to each half of mammalian P-glycoprotein and to LmrA of Lactococcus lactis, has been studied here. The yvcC gene was constitutively expressed in B. subtilis throughout its growth, and a knockout mutant showed a lower rate of ethidium efflux than the wild-type strain. Overexpression of yvcC in Escherichia coli allowed the preparation of highly enriched inverted-membrane vesicles that exhibited high transport activities of three fluorescent drugs, namely, Hoechst 33342, doxorubicin, and 7-aminoactinomycin D. After solubilization with n-dodecyl beta-D-maltoside, the hexahistidine-tagged YvcC was purified by a one-step affinity chromatography, and its ability to bind many P-glycoprotein effectors was evidenced by fluorescence spectroscopy experiments. Collectively, these results showed that YvcC is a multidrug ABC transporter functionally active in wild-type B. subtilis, and YvcC was therefore renamed BmrA for Bacillus multidrug resistance ATP. Besides, reconstitution of YvcC into liposomes led to the highest, vanadate-sensitive, ATPase activity reported so far for an ABC transporter. Interestingly, such a high ATP hydrolysis proceeds with a positive cooperativity mechanism, a property only found so far with ABC importers.

ATP-Binding Cassette Transporters↗