Skip Navigation

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (72)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Shani, N.
Right arrow Articles by Valle, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Shani, N.
Right arrow Articles by Valle, D.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Human Molecular Genetics Pages 1925-1931

Identification of a fourth half ABC transporter in the human peroxisomal membrane
Introduction
Results
   Cloning P70R cDNAs
   Mapping and expression of the P70R gene
   Immunoblot analysis and subcellular localization of the P70R protein
Discussion
Materials And Methods
   Cloning human P70R cDNAs
   Northern blot analysis and chromosomal location
   Production and purification of antibodies
   Immunoblots and immunofluorescence
   Cell lines and cultures
Acknowledgements
Abbreviations
References

Identification of a fourth half ABC transporter in the human peroxisomal membrane

Identification of a fourth half ABC transporter in the human peroxisomal membrane Noam Shani1,2, Gerardo Jimenez-Sanchez3, Gary Steel4, Michael Dean5 and David Valle2,4,*

1Kennedy Krieger Institute, 2Department of Pediatrics, 3Predoctoral Training Program, 4Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA and 5National Cancer Research and Development Center, Frederick, MD 21702, USA

Received June 3, 1997; Revised and Accepted August 5, 1997

Three half ATP-binding cassette transporters (ALDP, ALDR, PMP70) are known to be present in the human peroxisome membrane. Mutations in the gene encoding ALDP cause X-linked adrenoleukodystrophy; the role of ALDR and PMP70 in human disease is unclear. We report the cloning and characterization of a fourth human gene encoding a peroxisomal half ABC transporter. The gene, designated P70R, maps to chromosome 14q24, encodes a 73 kDa transporter most similar to PMP70, and is expressed in all human tissues examined. Because half ABC transporters heterodimerize to form functional transporters, the identification of a fourth member of this family in the peroxisome membrane has implications for our understanding of mammalian peroxisomes and the genetic disorders of peroxisomal function.

INTRODUCTION

Peroxisomes are single membrane bound organelles present in virtuallyall eukaryotic cells. They contain >50 matrix enzymes which play important roles in a variety of metabolic pathways (1 ,2 ). The peroxisomal membrane contains multiple organelle-specific proteins involved in the transport of matrix proteins into the organelle(3 ,4 )and others whose function is required for transport of small molecule substrates and products across the peroxisome membrane (5 ,6 ). The peroxisomal ATP-binding cassette (ABC) transporters are in this latter category.

ABC transporters are a superfamily of integral membrane proteins involved in the transport of a wide variety of molecules across biological membranes (7 ,8 ). ABC transporters are comprised of two homologous halves, each with two parts: a membrane spanning domain with multiple transmembrane segments; and a nucleotide binding domain with Walker A and B consensus sequences (7 ,9 ,10 ). Eukaryotic ABC transporter proteins are either full-size transporters of ~140 kDa [e.g. the multiple-drug-resistance (MDR) and the cystic fibrosis transmembrane regulator (CFTR) proteins] or half-transporters of ~70 kDa which dimerize to form the active transporter (7 ). Although there is a formal possibility of half ABC transporters assembling as homodimers, only heterodimeric associations have been observed. For example, the transporter of antigenic peptides (TAP) in the mammalian endoplasmic reticulum membrane (11 ) and the PXA transporter in Saccharomyces cerevisiae peroxisome membrane (12 ) are heterodimers of the TAP1/TAP2 proteins and Pxa1p/Pxa2p, respectively. Interestingly, the white/scarlet/brown subfamily of half ABC transporters in Drosophila eye pigment cells have been shown to assemble in different heteromeric combinations each with a different substrate preference (13 ).

Three half ABC transporters are known in the human peroxisome membrane: the 70 kDa peroxisomal membrane protein, PMP70 (14 ,15 ); the adrenoleukodystrophy protein, ALDP (16 ); and the adrenoleukodystrophy-related protein, ALDR (17 ). Both PMP70 and ALDP have been implicated in genetic diseases. Mutations in the PMP70 gene were found in two patients with Zellweger syndrome, a peroxisome biogenesis disorder (PBD) (15 ). The functional consequence of these mutations, however, and the role of PMP70 in Zellweger syndrome, if any, is uncertain (18 ). Indeed, a recent survey of 12 PBD complementation group 1 probands for PMP70 mutations by Southern blotting and SSCP of RT-PCR fragments failed to detect mutations (19 ). By contrast, mutations in the gene (ALD) encoding ALDP are clearly responsible for X-linked adrenoleukodystrophy, a neurodegenerative disorder characterized by defective peroxisomal [beta]-oxidation of very long chain fatty acids (C24 and longer) (20 -24 ). Adrenoleukodystrophy has extreme phenotypic variability ranging from the lethal childhood cerebral form to isolated Addison's disease in adults (21 ). This phenotypic variability is not explained by the genotype at the ALD locus and may be the result of a polymorphic modifier gene (25 ). The third known peroxisomal half ABC transporter, ALDR, is most similar to ALDP (66% amino acid identity) and has been proposed as a candidate for the ALD modifier gene (17 ).

Here we report the cloning and characterization of P70R, a fourth mammalian peroxisomal half ABC transporter.

RESULTS

Cloning P70R cDNAs


Figure 1. Alignment of mammalian peroxisomal ABC transporters. The amino acid sequences of human P70R, PMP70 and ALDP and murine ALDR were aligned using the MegAlign program (DNASTAR Inc.). The complete sequence of human ALDR is not available. Amino acids identical in two or more of the transporters are boxed in black. The six putative transmembrane domains are indicated by the labeled overlines (TMD1-6). The EAA-like motif, as well as the Walker A, Walker B and the C sequence of the nucleotide binding fold also are indicated by labeled overlines.

Utilizing the amino acid sequence of two human peroxisomal ABC transporters (PMP70 and ALDP) as probes in a homology search of the dbEST (26 ,27 ), we identified a human expressed sequence tag (EST) clone (H50978) encoding the C-terminal 149 amino acids of an unidentified homolog. Using the EST insert as the initial probe, we screened several human cDNA libraries to isolate a cDNA clone (P70R-hr3). P70R-hr3 has a 5' untranslated sequence of 6 bp, followed by an open reading frame of 1818 bp and a 3' untranslated sequence of 137 bp. Additional cDNA sequence extending 5'-ward (to -44) and 3' to the poly-A (+2311) was obtained from other overlappingcDNA clones. In Figure 1 , we aligned the 606 amino acid sequence of P70R with that of the other three mammalian half ABC transporters PMP70, ALDP and ALDR. The overall amino acid identity of P70R is 27.4% to PMP70, 24.5% to ALDP and 24.9% to ALDR. Like these proteins, P70R has the structure of a half ABC transporter. A hydrophilicity graph of the P70R protein shows six putative transmembrane domains (TMD) which align with the putative TMD of PMP70, ALDP and ALDR (Fig. 1 ). A database search using the P70R protein sequence shows the highest similarity to a Caenorhabditis elegans open reading frame (Z75532, 36.8% amino acid identity) and to a murine EST clone (518750). The sequence of this EST encodes the C-terminal 144 amino acids of the murine P70R ortholog and is 92% identical to the corresponding amino acid sequence of the human protein (not shown).

Mapping and expression of the P70R gene

To map the P70R structural gene we used the full P70R cDNA to probe a human monochromosomal hybrid somatic cell mapping panel. The probe hybridized to fragments of chromosome 14 (not shown). A more precise chromosomal location was achieved using the P70R cDNA in a homology search of the sequence tag site (STS) database (28 ). Two STSs were found to contain P70R sequences (WI-9601 and A006I12). A UniGene database search (29 ) mapped these STSs between two chromosome 14 markers (D14S71 and D14S76) localizing the P70R structural gene to 14q24.

Northern blot analysis of mRNA isolated from multiple human tissues shows that the P70R gene encodes a transcript of ~2.6 kb which is expressed in all tissues examined (Fig. 2 ).


Figure 2.Expression of P70R in human tissues. A Northern blot of mRNA isolated from the various human tissues, was probed with a P70R cDNA fragment (top panel). The same membrane was reprobed with a human [beta]-actin cDNA fragment to control for the quality and quantity of RNA (bottom panel). Arrows on the right indicate the position of the single P70R transcript and the two alternatively-spliced actin mRNAs.

Immunoblot analysis and subcellular localization of the P70R protein


Figure 3.Immunoblot of chimeric and intact P70R and PMP70 proteins. (a) Lanes 1 and 4 were loaded with 1 [mu]l of a bacterial lysate expressing the 67 kDa MBP-P70R fusion protein. Lanes 2, 3, and 5 were loaded with 0.1, 1 and 0.1 [mu]l, respectively, of a bacterial lysate expressing the 49 kDa T7G10-PMP70 fusion protein. The left panel was analyzed by immunoblotting with anti-P70R antibodies, and the right panel with anti-PMP70. Note that the anti-P70R does not detect the PMP70 fusion protein even in amounts of lysate 10-fold higher than that required to detect the fusion protein with anti-PMP70 (compare lanes 3 and 5). The extra bands in lane 3 reflect non-specific interaction of the anti-P70R antibody due to the overloading of this lane with bacterial lysate. (b) Lanes 1 and 2 were loaded with 30 or 10 [mu]l, respectively, of the organelle enriched fraction of DEHP-induced rat liver cells. Lane 1 was analyzed by immunoblotting with anti-P70R antiserum and lane 2 with immunopurified anti-PMP70.

Although P70R and PMP70 share only 38% amino acid identity in the region of overlap for the segment of P70R used as antigen (see Materials and Methods), we first determined that our immunoadsorbed P70R antibody did not cross-react with PMP70. As shown in Figure 3 a, our P70R antibody does not detect a fusion protein containing the corresponding segment of PMP70 even at amounts of bacterial lysate 10-fold greater than that required for the fusion protein to be recognized by anti-PMP70 antibody (compare lane 3 with lane 5). Additionally, in extracts of liver from rats fed the peroxisome-inducing agent [DHEP, (30 )], the anti-P70R antibody detects a single protein of 73 kDa, clearly different from PMP70 which migrates as a 70 kDa protein (Fig. 3 b). Similarly, in extracts of total human hepatoma cell (Hep G2) protein, anti-P70R antibody also detects a protein of 73 kDa clearly distinct from PMP70 (not shown). We conclude that in the range of dilutions utilized in these studies, our anti-P70R antibody does not cross-react with PMP70.


Figure 4.Cellular localization of the P70R protein. (a)A control cultured skin fibroblast co-stained with Texas Red-labeled anti-P70R antiserum (left) or FITC-labeled anti-catalase antibody (right). Note the punctate structures detected by the anti-P70R antiserum co-localize with catalase, a peroxisomal marker. (b) Cultured skin fibroblasts from a complementation group 9 PBD patient stained as in (a). Note punctate structures are not detected by either antibody. (c) Control cultured skin fibroblasts stained with Texas Red-labeled anti-P70R antiserum (left) or Texas Red-labeled anti-ALDP (right). (d) Cultured skin fibroblasts from a patient with X-linked adrenoleukodystrophy caused by deletion of the 3' end of the ALD gene (see Materials and Methods) stained with Texas Red-labeled anti-P70R (left) or Texas Red-labeled anti-ALDP (right). Note that in these cells normal punctate peroxisomal staining is detected with anti-P70R despite the absence of ALDP.

To determine the subcellular distribution of the P70R protein, we performed immunofluorescence studies of human fibroblasts (Fig. 4 ). The anti-P70R antibody stains punctuate structures identical in shape and number to peroxisomes. These structures also stain with antibodies to catalase, a peroxisomal marker (Fig. 4 a) and are not detected by either anti-P70R or anti-catalase in fibroblasts from a Zellweger syndrome patient (PBD061, complementation group 9) which lacks recognizable peroxisomes (31 ) (Fig. 4 b). These results localize the P70R protein to peroxisomes. Furthermore, P70R is present in apparently normal amounts in the peroxisomes of fibroblasts from an X-linked adrenoleukodystrophy patient (patient O in ref. 16 ) who has been shown to lack ALDP as a consequence of a deletion which removes the 3' half of the ALD gene (20 ). This result confirms that the peroxisomal staining detected with our anti-P70R antiserum is not due to cross reaction with ALDP and suggests that the presence of ALDP in the peroxisomal membrane is not required for accumulation of P70R.

DISCUSSION

Using homology probing, we identified a human cDNA (P70R) that encodes for a 606 amino acid protein whose sequence is most similar to those of the peroxisomal ABC transporters. Alignment of the P70R amino acid sequence with that from the three known human members of this subgroup of the ABC protein superfamily shows that P70R is slightly more similar to PMP70 than to ALDP or ALDR (27.4, 24.5 and 24.9% overall amino acid identity, respectively, Fig. 1 ). Like PMP70 and ALDP, but unlike ALDR (14 ,16 ,17 ), the P70R gene is expressed at variable levels in all human tissues examined (Fig. 2 ) and immunofluorescence analysis of cultured fibroblasts localizes it to peroxisomes (Fig. 4 ). We conclude that P70R is a fourth human peroxisomal half ABC transporter.

Peroxisomes are present in all eukaryotic organisms but are not found in prokaryotes (2 ). In earlier work, we showed that S.cerevisiae has only two peroxisomal half ABC transporters (12 ,32 ) and that C.elegans has a pair of transporters highly similar to PMP70 and ALDP (33 ). A database search using the human P70R amino acid sequence detects a C.elegans open reading frame (accession # Z75532) with 36.8% overall amino acid identity which is likely the worm ortholog of P70R. Interestingly, we found a second open reading frame possessing high similarity to P70R (30.4% overall amino acid identity) in a prokaryotic cyanobacterium Synechocystis sp. (accession #D64002). Cyanobacteria are thought to be the endosymbiotic source of chloroplasts in modern plants (34 ). A phylogenetic tree of these half ABC transporters places P70R and the putative C.elegans ortholog in a separate branch, closer to the prokaryotic transporter (Fig. 5 ). This relationship suggests that P70R resembles the evolutionary precursor of mammalian peroxisomal half ABC transporters more closely than any of the other known members of this subfamily.


Figure 5. Phylogenetic tree of peroxisomal ABC transporters. A phylogenetic tree of peroxisomal ABC transporters was constructed with the MegAlign program (DNASTAR Inc.). Analyzed proteins include the four known mammalian peroxisomal half ABC transporters (human P70R, PMP70 and ALDP and murine ALDR), open reading frames in C.elegans encoding a putative P70R ortholog (CeZ75532) and homologs of PMP70 and ALDP (CeC44B7.8 and CeC44B7.9) and a cyanobacterium Synechocystis sp. protein (D64002). The length of each pair of branches represents the distance between protein pairs. The scale below the tree measures the distance between sequences. The units reflect the number of substitution events. An alignment was also produced with the PILEUP program in the University of Wisconsin Genetics Computer Group package and used to build a neighbor joining tree. The same topology of the sequences was obtained (data not shown).

As is the case for other half ABC transporters, the P70R protein must dimerize to form a functional transporter (7 ). Interestingly, genetic studies of the Drosophila white, brown and scarlet proteins show that these half ABC transporters assemble in various combinations to form dimeric transporters that transport different substrates: a white/brown dimer transports guanine; conversely, a white/scarlet dimer transports tryptophan (13 ). Based on this precedent and the known heterodimeric structure of the PXA peroxisomal transporter in S.cerevisiae (12 ), we and others have suggested that the human peroxisomal half ABC transporters also heterodimerize in various combinations to form transporters with different functions (12 ,17 ). Identification of a fourth member of this subfamily of ABC transporters (P70R) increases the number of possible heterodimeric combinations and, accordingly, the number of functions these transporters could perform. Our results also show that P70R, like PMP70, is present in roughly normal amounts in cells lacking ALDP (Fig. 4 d) (20 ). Thus, the absence of ALDP does not prevent accumulation of these transporters in the peroxisomal membrane. Although this result does not preclude interaction of ALDP with P70R, it does not support this possibility.

Although the substrates of the human peroxisomal ABC transporters are not known, their yeast homologs (PXA1 and PXA2) are necessary for transport of long chain (C16-18) fatty acids into the organelle (12 ,32 ,35 ). Similarly, the biochemical phenotype of patients with ALD mutations [accumulation of very long chain (>C24) fatty acids] suggests one or more of the possible human transporters is required for transport of these compounds into the peroxisome. Members of another subgroup of ABC transporters, the multiple drug resistance transporters, are known to transport lipids, phospholipids and steroids (36 -39 ). Based on these observations, we and others have suggested that the human peroxisomal ABC transporters mediate the transport of fatty acids into the peroxisome matrix (12 ,32 ,35 ). It is possible that different heterodimers formed by various combinations of the four half transporters transport fatty acids of different saturation states and/or chain lengths into the peroxisome.

Like the other human peroxisomal ABC transporters (14 ,16 ,17 ), P70R is also a candidate modifier gene contributing to the phenotypic variability of X-linked adrenoleukodystrophy.

MATERIALS AND METHODS

Cloning human P70R cDNAs

We probed the dbEST (26 ) withPMP70 and ALDP protein sequences and identified EST clone H50978 with similarity to both proteins. Utilizing standard methods (40 ) we screened a human liver cDNA library (Stratagene) using H50978 as a probe and isolated several cDNA clones. We PCR-amplified a 216 bp DNA fragment (+757 to +973, when +1 is the A of the ATG start codon) from the most 5' of the longest of these (P70R-hl3) to probe a second cDNA library [human fetal brain (41 )]. The longest clone isolated from this second screen (P70R-hfb4) extended 6 bp upstream of the ATG start codon. We screened a third cDNA library (human retina, kindly provided by J. Nathans) with a PCR amplified DNA fragment (-6 to +241) as probe and isolated a clone (P70R-hr3) which contained the full open reading frame (-6 to +1961) of the gene. The entire sequence of this cDNA was confirmed by sequencing both strands. A second clone from the third library (P70R-hr17) extended to -44 bp upstream of the ATG. This extension of the 5' untranslated sequence was confirmed by an independent amplification and cloning using a Marathon-Ready kit of liver and kidney cDNA (Clontech).

Northern blot analysis and chromosomal location

We probed a multiple tissue Northern blot with a 1.2 kb P70R cDNA fragment and a 2 kb human [beta]-actin cDNA (Clontech). Both probes were labeled by the random primer method (40 ) and hybridized according to the company's protocol. The membrane was probed with the P70R fragment, exposed for 10 days, stripped and reprobed with the [beta]-actin and exposed for 3 h. We mapped the P70R structural gene to a specific chromosome using a monochromosomal somatic cell hybrid panel (Oncor) and the full length P70R cDNA as probe. Regional localization was obtained from the STS/Unigene project (29 ).

Production and purification of antibodies

We cloned cDNAs encoding the C-terminal 194 amino acids of P70R or the C-terminal 117 amino acids of PMP70 into the pMal-c2 plasmid (BioLabs) to produce chimeric proteins consisting of an N-terminal maltose binding protein (MBP) fused to C-terminal sequences of either P70R or PMP70 (MBP-P70R or MBP-PMP70, respectively). The same PMP70 cDNA fragment was also cloned into the pGEMEX plasmid (Promega) to produce a chimeric protein consisting of an N-terminal T7 gene 10 protein (T7G10) fused to the C-terminal 117 residues of PMP70 (T7G10-PMP70). The MBP-P70R and MBP-PMP70 chimeric proteins were expressed in Escherichia coli (BL21) and purified by affinity chromatography using an amylose resin column (New England Biolabs). The T7G10-PMP70 chimeric protein was purified by SDS-PAGE. Rabbit antisera were raised against MBP-P70R and T7G10-PMP70 (HRP Inc., Denver, PA) and antibodies against P70R and PMP70 were affinity purified (ImmunoPure, Pierce) using MBP-P70R or MBP-PMP70, respectively, as the binding antigen.

Immunoblots and immunofluorescence

An organelle enriched fraction was prepared from di(ethyl-hexyl)phthalate (DEHP) induced rat liver (kindly provided by Dr Paul Watkins) as described (42 ). DEHP induces rodent peroxisomes and their components (30 ). The proteins in the organelle fraction were separated by SDS-PAGE and transferred to a nitrocellulose membrane (40 ). For immunoblot analysis (ECL, Amersham) we used a 1/200 or a 1/500 dilution of the affinity purified anti-P70R or anti-PMP70 antibodies, respectively. Immunofluorescence localization of P70R in human fibroblasts was performed as described (31 ). For primary antibody we used the immunoadsorbed anti-P70R antibody which we detected with Texas Red-labeled goat anti-rabbit as a secondary antibody (Vector). This secondary antibody used alone does not detect peroxisome-like structures (not shown). Co-localization with catalase, a peroxisomal matrix marker protein, was performed using sheep anti-human catalase antibodies (The Binding Site) detected with fluorescein isothiocyanate (FITC)-labeled donkey anti-sheep (The Binding Site). To detect ALDP, we used the rabbit anti-ALDP antiserum described in ref. 20 .

Cell lines and cultures

Human fibroblasts were cultured in Eagles' MEM with 10% fetal calf serum. The cellular phenotype of the complementation group 9 Zellweger patient (PBD061) is described by Slawecki et al. (31 ). The ALD fibroblasts are from patient O who lacks ALDP secondary to a deletion removing the 3' four exons of the 10 exon ALD gene (16 ,20 ,43 ).

ACKNOWLEDGEMENTS

Computing resources were provided by the Frederick Biomedical Supercomputing Center. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. Government. This work was supported in part by NIH grant 2P01HD10981 to the Kennedy Krieger Institute (NS). D.V. is an Investigator in The Howard Hughes Medical Institute. G.J.S. is supported in part by a fellowship from the Instituto de Investigaciones Biomedicas/DGAPA, UNAM.

ABBREVIATIONS

ABC, ATP-binding cassette; ALDP, adrenoleukodystrophy protein; ALDR, adrenoleukodystrophy-related protein; CFTR, cystic fibrosis transmembrane regulator; DEHP, di(ethyl-hexyl)phthalate; EST, expressed sequence tag; MBP, maltose binding protein; MDR, multiple-drug-resistance; PBD, peroxisome biogenesis disorder; PMP, peroxisomal membrane protein; STS, sequence tag site; TAP, transporter of antigenic peptides.

REFERENCES

1 van den Bosch, H., Schutgens, R. B. H., Wanders, R. J. A. and Tager, J. M. (1992) Biochemistry of peroxisomes. Annu. Rev. Biochem., 61, 157-197. MEDLINE Abstract

2 Lazarow, P. B. and Moser, H. W. (1995). Disorders of peroxisome biogenesis. In C. Scriver, A. Beaudet, W. Sly and D. Valle, eds, The Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill, New York, pp. 2287-2324.

3 Subramani, S. (1997) PEX genes on the rise. Nature Genet., 15, 331-333. MEDLINE Abstract

4 Rachubinski, R. A. and Subramani, S. (1995) How proteins penetrate peroxisomes. Cell, 83, 525-528.

5 Subramani, S. (1993) Protein import into peroxisomes and biogenesis of the organelle. Annu. Rev. Cell Biol., 9, 445-478. MEDLINE Abstract

6 Valle, D. and Gartner, J. (1993) Penetrating the peroxisome: News and Views. Nature, 361, 682-683. MEDLINE Abstract

7 Higgins, C. F. (1992) ABC transporters: From microorganisms to man. Annu. Rev. Cell Biol., 8, 67-113.

8 Allikmets, R., Gerrard, B., Hutchinson, A. and Dean, M. (1996) Characterization of the human ABC superfamily: isolation and mapping of 21 new genes using the expressed sequence tags database. Hum. Mol. Genet., 5, 1649-1655. MEDLINE Abstract

9 Michaelis, S. and Berkower, C. (1995) Sequence comparison of yeast ATP-binding cassette proteins. In Cold Spring Harbor Symposia on Quantitative Biology, LX, Cold Spring Harbor Press, Cold Spring Harbor.

10 Dean, M. and Allikmets, R. (1995) Evolution of ATP-binding cassette transporter genes. Curr. Opin. Genet. Dev., 5, 779-785. MEDLINE Abstract

11 Kelly, A., Powis, S. H., Kerr, L. A., Mockridge, I., Elliott, T., Bastin, J., Ziegler, B. U., Ziegler, A., Trowsdale, J. and Townsend, A. (1992) Assembly and function of the two ABC transporter proteins encoded in the human major histocompatibility complex. Nature, 355, 641-644. MEDLINE Abstract

12 Shani, N. and Valle, D. (1996) A Saccharomyces cerevisiae homolog of the human adrenoleukodystrophy transporter is a heterodimer of two half ATP-binding cassette transporter. Proc. Natl. Acad. Sci. USA, 93, 11901-11906. MEDLINE Abstract

13 Ewart, G. D., Cannell, D., Cox, G. B. and Howell, A. J. (1994) Mutational analysis of the traffic ATPase (ABC) transporters involved in uptake of eye pigment precursors in Drosophila melanogaster. J. Biol. Chem., 269, 10370-10377.

14 Kamijo, K., Taketani, S., Yokata, S., Osumi, T. and Hashimoto, T. (1990) The 70 kDa peroxisomal membrane protein is a member of the Mdr (P-glycoprotein)-related ATP-binding protein superfamily. J. Biol. Chem., 265, 4534-4540. MEDLINE Abstract

15 Gärtner, J., Moser, H. and Valle, D. (1992) Mutations in the 70 kD peroxisomal membrane protein gene in Zellweger syndrome. Nature Genet., 1, 16-23. MEDLINE Abstract

16 Mosser, J., Lutz, Y., Stoeckel, M. E., Sarde, C. O., Kretz, C., Douar, A. M., Lopez, J., Aubourg, P. and Mandel, J. L. (1994) The gene responsible for adrenoleukodystrophy encodes a peroxisomal membrane protein. Hum. Mol. Genet., 3, 265-271. MEDLINE Abstract

17 Lombard-Platet, G., Savary, S., Sarde, C.-O. and Mandel, J.-L. (1996) A close relative of the adrenoleukodystrophy (ALD) gene codes for a peroxisomal protein with a specific expression pattern. Proc. Natl. Acad. Sci. USA, 93, 1265-1269. MEDLINE Abstract

18 Braverman, N., Dodt, G., Gould, S. J. and Valle, D. (1995) Disorders of peroxisome biogenesis. Hum. Mol. Genet., 4, 1791-1798. MEDLINE Abstract

19 Paton, B. C., Heron, S. E., Nelson, P. V., Morris, C. P. and Poulos, A. (1997) Absence of mutations raises doubts about the role of the 70 kDa peroxisomal membrane protein in Zellweger syndrome. Am. J. Hum. Genet., 60, 1535-1539.

20 Watkins, P. A., Gould, S. J., Smith, M. A., Braiterman, L. T., Wei, H.-M., Kok, F., Moser, A. B., Moser, H. W. and Smith, K. D. (1995) Altered expression of ALDP in X-linked adrenoleukodystrophy. Am. J. Hum. Genet., 57, 292-301.

21 Moser, H., Smith, K. and Moser, A. (1995). Adrenoleukodystrophy (X-linked). In C. Scriver, A. Beaudet, W. Sly and D. Valle, eds, The Metabolic and Molecular Bases of Inherited Disease. McGraw Hill, New York, pp. 2325-2349.

22 Ligtenberg, M. J. L., Kemp, S., Sarde, C.-O., van Geel, B. M., Kleijer, W. J., Barth, P. G., Mandel, J.-L., van Oost, B. A. and Bolhuis, P. A. (1995) Spectrum of mutations in the gene encoding the adrenoleukodystrophy protein. Am. J. Hum. Genet., 56, 44-50.

23 Kok, F., Neumann, S., Sarde, C.-O., Zheng, S., Wu, K.-H., Wei, H.-M., Bergin, J., Watkins, P., Gould, S., Sack, G., Moser, H., Mandel, J.-L. and Smith, K. (1995) Mutational analysis of patients with X-linked adrenoleukodystrophy. Hum. Mut., 6, 104-115. MEDLINE Abstract

24 Mosser, J., Douar, A. M., Sarde, C. O., Kioschis, P., Feil, R., Moser, H., Poustka, A. M., Mandel, J. L. and Aubourg, P. (1993) Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters. Nature, 361, 726-730. MEDLINE Abstract

25 Moser, H. W., Moser, A. B., Smith, K. D., Bergin, A., Borel, J., Shankroff, J., Stine, O. C., Merette, C., Ott, J., Krivit, W. and Shapiro, E. (1992) Adrenoleukodystrophy: Phenotypic variability and implications for therapy. J. Inher. Metab. Dis., 15, 645-664.

26 Boguski, M., Lowe, T. M. J. and Tolstoshev, C. M. (1993) dbEST-database for `expressed sequence tags'. Nature Genet., 4, 332-333. MEDLINE Abstract

27 Dodt, G., Braverman, N., Valle, D. and Gould, S. J. (1996) From expressed sequence tags to peroxisome biogenesis disorder genes. Ann. NY Acad. Sci., 804, 516-523. MEDLINE Abstract

28 Olson, M., Hood, L., Cantor, C. and Botstein, D. (1989) A common language for physical mapping of the human genome. Science, 245, 1434-1435. MEDLINE Abstract

29 Boguski, M. S. (1995) The turning point in genome research. Trends Biol. Sci., 20, 295-296.

30 Watanabe, T., Lalwani, N. D. and Reddy, J. K. (1985) Specific changes in the protein composition of rat liver in response to the peroxisome proliferators ciprofibrate, WY-14,643 and di-(2-ethylhexyl)phthalate. Biochem J., 227, 767-775.

31 Slawecki, M., Dodt, G., Steinberg, S., Moser, A. B., Moser, H. W. and Gould, S. J. (1995) Identification of three distinct peroxisomal protein import defects in patients with peroxisome biogenesis disorders. J. Cell. Sci., 108, 1817-1829. MEDLINE Abstract

32 Shani, N., Watkins, P. A. and Valle, D. (1995) PXA1, a putative S. cerevisiae homolog of the human adrenoleukodystrophy gene. Proc. Natl. Acad. Sci. USA, 92, 6012-6016. MEDLINE Abstract

33 Shani, N., Sapag, A. and Valle, D. (1996) Characterization and analysis of conserved motifs in a peroxisomal ATP-binding cassette transporter. J. Biol. Chem., 271, 8725-8730. MEDLINE Abstract

34 Pace, N. R. (1997) A molecular view of microbial diversity and the biosphere. Science, 276, 734-740.

35 Hettema, E. H., van Roermund, C. W. T., Distel, B., van den Berg, M., Vilela, C., Rodrigues-Pousada, C., Wanders, R. J. A. and Tabak, H. F. (1996) The ABC transporter proteins Pat1 and Pat2 are required for import of long-chain fatty acids into peroxisomes of Saccharomyces cerevisiae. EMBO J., 15, 3813-3822.

36 Gottesman, M. M., Hrysyna, C. A., Schoenlein, P. V., Germann, U. A. and Pastan, I. (1995) Genetic analysis of the multidrug transporter. Annu. Rev. Genet., 29, 607-649.

37 Ruetz, S. and Gros, P. (1994) Phosphatidylcholine translocase: a physiological role for the mdr2 gene. Cell, 77, 1071-1081. MEDLINE Abstract

38 van Helvoort, A., Smith, A. J., Sprong, H., Fritzsche, I., Schinkel, A. H., Borst, P. and van Meer, G. (1996) MDR1 P-glycoprotein is a lipid translocase of broad specificity, while MDR3 P-glycoprotein specifically translocates phosphatidylcholine. Cell, 87, 507-517. MEDLINE Abstract

39 Mahé, Y., Lemoine, Y. and Kuchler, K. (1996) The ATP binding cassette transporters Pdr5 and Snq2 of Saccharomyces cerevisiae can mediate transport of steroids in vivo. J. Biol. Chem., 271, 25167-25172. MEDLINE Abstract

40 Ausubel, F. M., Brent, R., Kingston, R. E., Moore, D. D., Seidman, G. J., Smith, J. A. and Struhl, K. (1991) Current Protocols in Molecular Biology. John Wiley & Sons, New York.

41 Braverman, N., Steel, G., Obie, C., Moser, A., Moser, H., Gould, S. J. and Valle, D. (1997) Human PEX7 encodes the peroxisomal PTS2 receptor and is responsible for rhizomelic chondrodysplasia punctata. Nature Genet., 15, 369-376. MEDLINE Abstract

42 Ghosh, M. K. and Hajra, A. K. (1986) A rapid method for the isolation of peroxisomes from rat liver. Anal. Biochem., 159, 169-174.

43 Sarde, C. O., Mosser, J., Kioschis, P., Kretz, C., Vicaire, S., Aubourg, P., Poustka, A. and Mandel, J. L. (1994) Genomic organization of the adrenoleukodystrophy gene. Genomics, 22, 13-20.

*To whom correspondence should be addressed. Tel: +1 410 955 4260; Fax: +1 410 955 7397; Email: david.valle@qmail.bs.jhu.edu
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 J Child NeurolHome page
I. Singh, A. K. Singh, and M. A. Contreras
Peroxisomal Dysfunction in Inflammatory Childhood White Matter Disorders: An Unexpected Contributor to Neuropathology
J Child Neurol, September 1, 2009; 24(9): 1147 - 1157.
[Abstract] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
S. Fourcade, M. Ruiz, C. Camps, A. Schluter, S. M. Houten, P. A. W. Mooyer, T. Pampols, G. Dacremont, R. J. A. Wanders, M. Giros, et al.
A key role for the peroxisomal ABCD2 transporter in fatty acid homeostasis
Am J Physiol Endocrinol Metab, January 1, 2009; 296(1): E211 - E221.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M. Hillebrand, S. E. Verrier, A. Ohlenbusch, A. Schafer, H.-D. Soling, F. S. Wouters, and J. Gartner
Live Cell FRET Microscopy: HOMO- AND HETERODIMERIZATION OF TWO HUMAN PEROXISOMAL ABC TRANSPORTERS, THE ADRENOLEUKODYSTROPHY PROTEIN (ALDP, ABCD1) AND PMP70 (ABCD3)
J. Biol. Chem., September 14, 2007; 282(37): 26997 - 27005.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
M. Asheuer, I. Bieche, I. Laurendeau, A. Moser, B. Hainque, M. Vidaud, and P. Aubourg
Decreased expression of ABCD4 and BG1 genes early in the pathogenesis of X-linked adrenoleukodystrophy
Hum. Mol. Genet., May 15, 2005; 14(10): 1293 - 1303.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
I. Oezen, W. Rossmanith, S. Forss-Petter, S. Kemp, T. Voigtlander, K. Moser-Thier, R. J. Wanders, R. E. Bittner, and J. Berger
Accumulation of very long-chain fatty acids does not affect mitochondrial function in adrenoleukodystrophy protein deficiency
Hum. Mol. Genet., May 1, 2005; 14(9): 1127 - 1137.
[Abstract] [Full Text] [PDF]

Home page
 J BiochemHome page
M. Une, Y. Iguchi, T. Sakamoto, T. Tomita, Y. Suzuki, M. Morita, and T. Imanaka
ATP-Dependent Transport of Bile Acid Intermediates across Rat Liver Peroxisomal Membranes
J. Biochem., August 1, 2003; 134(2): 225 - 230.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
A. R. Tanaka, K. Tanabe, M. Morita, M. Kurisu, Y. Kasiwayama, M. Matsuo, N. Kioka, T. Amachi, T. Imanaka, and K. Ueda
ATP Binding/Hydrolysis by and Phosphorylation of Peroxisomal ATP-binding Cassette Proteins PMP70 (ABCD3) and Adrenoleukodystrophy Protein (ABCD1)
J. Biol. Chem., October 11, 2002; 277(42): 40142 - 40147.
[Abstract] [Full Text] [PDF]

Home page
 JCBHome page
X. Li and S. J. Gould
PEX11 promotes peroxisome division independently of peroxisome metabolism
J. Cell Biol., February 18, 2002; 156(4): 643 - 651.
[Abstract] [Full Text] [PDF]

Home page
 Plant Cell PhysiolHome page
M. Hayashi, K. Nito, R. Takei-Hoshi, M. Yagi, M. Kondo, A. Suenaga, T. Yamaya, and M. Nishimura
Ped3p is a Peroxisomal ATP-Binding Cassette Transporter that might Supply Substrates for Fatty Acid {beta}-Oxidation
Plant Cell Physiol., January 1, 2002; 43(1): 1 - 11.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
L. X. Liu, K. Janvier, V. Berteaux-Lecellier, N. Cartier, R. Benarous, and P. Aubourg
Homo- and Heterodimerization of Peroxisomal ATP-binding Cassette Half-transporters
J. Biol. Chem., November 12, 1999; 274(46): 32738 - 32743.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
B. V. Geisbrecht and S. J. Gould
The Human PICD Gene Encodes a Cytoplasmic and Peroxisomal NADP+-dependent Isocitrate Dehydrogenase
J. Biol. Chem., October 22, 1999; 274(43): 30527 - 30533.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
B. V. Geisbrecht, D. Zhang, H. Schulz, and S. J. Gould
Characterization of PECI, a Novel Monofunctional Delta 3,Delta 2-Enoyl-CoA Isomerase of Mammalian Peroxisomes
J. Biol. Chem., July 30, 1999; 274(31): 21797 - 21803.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
T. Imanaka, K. Aihara, T. Takano, A. Yamashita, R. Sato, Y. Suzuki, S. Yokota, and T. Osumi
Characterization of the 70-kDa Peroxisomal Membrane Protein, an ATP Binding Cassette Transporter
J. Biol. Chem., April 23, 1999; 274(17): 11968 - 11976.
[Abstract] [Full Text] [PDF]

Home page
 NeurologyHome page
T. Yamada, T. Taniwaki, N. Shinnoh, A. Uchiyama, N. Shimozawa, Y. Ohyagi, H. Asahara, and J. Kira
Adrenoleukodystrophy protein enhances association of very long-chain acyl-coenzyme A synthetase with the peroxisome
Neurology, February 1, 1999; 52(3): 614 - 614.
[Abstract] [Full Text] [PDF]

Home page
 JCBHome page
X. Li and S. J. Gould
PEX11 promotes peroxisome division independently of peroxisome metabolism
J. Cell Biol., February 18, 2002; 156(4): 643 - 651.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (72)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Shani, N.
Right arrow Articles by Valle, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Shani, N.
Right arrow Articles by Valle, D.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?