A close relative of the adrenoleukodystrophy (ALD) gene codes for a peroxisomal protein with a specific expression pattern.

Lombard-Platet, G; Savary, Stéphane; Sarde, Claude-Olivier; Mandel, Jean‐Louis; Chimini, Giovanna

doi:10.1073/pnas.93.3.1265

Cited by 205 publications

(141 citation statements)

References 33 publications

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“…The gene is believed to be involved in the transport of VLCFAs across peroxisome membranes. All the human ABCD subfamily members identified so far are peroxisome exclusive half ABC transporter genes but their transcript abundance varies with tissues (Lombard-Platet et al 1996). The ABCD genes are expected to be functional only after formation of homo-or hetrodimers.…”

Section: Discussionmentioning

confidence: 99%

Comparative Genomics and Adaptive Selection of the ATP-Binding-Cassette Gene Family in Caenorhabditis Species

et al. 2007

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ABC transporters constitute one of the largest gene families in all species. They are mostly involved in transport of substrates across membranes. We have previously demonstrated that the Caenorhabditis elegans ABC family shows poor one-to-one gene orthology with other distant model organisms. To address the evolution dynamics of this gene family among closely related species, we carried out a comparative analysis of the ABC family among the three nematode species C. elegans, C. briggsae, and C. remanei. In contrast to the previous observations, the majority of ABC genes in the three species were found in orthologous trios, including many tandemly duplicated ABC genes, indicating that the gene duplication took place before speciation. Species-specific expansions of ABC members are rare and mostly observed in subfamilies A and B. C. briggsae and C. remanei orthologous ABC genes tend to cluster on trees, with those of C. elegans as an outgroup, consistent with their proposed species phylogeny. Comparison of intron/exon structures of the highly conserved ABCE subfamily members also indicates a closer relationship between C. briggsae and C. remanei than between either of these species and C. elegans. A comparison between insect and mammalian species indicates lineage-specific duplications or deletions of ABC genes, while the family size remains relatively constant. Sites undergoing positive selection within subfamily D, which are implicated in very-long-chain fatty acid transport, were identified. The evolution of these sites might be driven by the changes in food source with time.

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Section: Discussionmentioning

confidence: 99%

Comparative Genomics and Adaptive Selection of the ATP-Binding-Cassette Gene Family in Caenorhabditis Species

et al. 2007

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“…ALDRP (encoded by the ABCD2 gene (5)), PMP70 (ABCD3 (6)), and PMP69 (ABCD4 (7,8)) cannot be excluded especially in the situation where these proteins are overexpressed. Although a mirror expression pattern is often observed between ALDP and ALDRP when specific cell types are analyzed (9), peroxisomal ABC transporters have overlapping expression patterns rendering possible such interactions (5,10). Coimmunoprecipitation experiments or FRET analysis have demonstrated heterodimerization in cells overexpressing the peroxisomal ABC transporters (11,12).…”

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confidence: 99%

Substrate Specificity Overlap and Interaction between Adrenoleukodystrophy Protein (ALDP/ABCD1) and Adrenoleukodystrophy-related Protein (ALDRP/ABCD2)

Génin

Geillon

Gondcaille

et al. 2011

Journal of Biological Chemistry

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X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disorder caused by mutations in the ABCD1 gene, which encodes a peroxisomal member of the ATP-binding cassette (ABC) transporter subfamily D called ALDP. ALDP is supposed to function as a homodimer allowing the entry of CoA-esters of very-long chain fatty acids (VLCFA) into the peroxisome, the unique site of their ␤-oxidation. ALDP deficiency can be corrected by overexpression of ALDRP, its closest homolog. However, the exact nature of the substrates transported by ALDRP and its relationships with ALDP still remain unclear. To gain insight into the function of ALDRP, we used cell models allowing the induction in a dose-dependent manner of a wild type or a mutated non-functional ALDRP-EGFP fusion protein. We explored the consequences of the changes of ALDRP expression levels on the fatty acid content (saturated, monounsaturated, and polyunsaturated fatty acids) in phospholipids as well as on the levels of ␤-oxidation of 3 suspected substrates: C26:0, C24:0, and C22:6n-3 (DHA). We found an inverse correlation between the fatty acid content of saturated (C26:0, C24:0) and monounsaturated (C26:1, C24:1) VLCFA and the expression level of ALDRP. Interestingly, we obtained a transdominant-negative effect of the inactive ALDRP-EGFP on ALDP function. This effect is due to a physical interaction between ALDRP and ALDP that we evidenced by proximity ligation assays and coimmunoprecipitation. Finally, the ␤-oxidation assays demonstrate a role of ALDRP in the metabolism of saturated VLCFA (redundant with that of ALDP) but also a specific involvement of ALDRP in the metabolism of DHA. X-linked adrenoleukodystrophy (X-ALD)2 (OMIM 300100) is a very complex neurodegenerative disorder whose physiopathogenesis remains to be clarified (1). X-ALD is caused by mutations in the ABCD1 gene located in Xq28, which encodes a peroxisomal member of the ATP-binding cassette (ABC) transporter subfamily D called ALDP (adrenoleukodystrophy-protein) (2). This protein has the structure of a half ABC transporter, which is supposed to function as a homodimer (3, 4). However, heterodimerization with one of the other members of the ABCD subfamily (i.e. ALDRP (encoded by the ABCD2 gene (5)), PMP70 (ABCD3 (6)), and PMP69 (ABCD4 (7, 8)) cannot be excluded especially in the situation where these proteins are overexpressed. Although a mirror expression pattern is often observed between ALDP and ALDRP when specific cell types are analyzed (9), peroxisomal ABC transporters have overlapping expression patterns rendering possible such interactions (5, 10). Coimmunoprecipitation experiments or FRET analysis have demonstrated heterodimerization in cells overexpressing the peroxisomal ABC transporters (11,12). Although the peroxisomal localization of ALDP, ALDRP, and PMP70 is clearly demonstrated, PMP69 has recently been described to be localized in the endoplasmic reticulum and was found to be absent in the peroxisome. This excludes a possible interaction at the peroxisomal membrane with the other ABC...

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“…To date, three ATP-binding cassette transporters have been identified on mammalian peroxisomal membranes: the 70-kDa peroxisomal membrane protein (PMP70) (21)(22)(23), adrenoleukodystrophy protein (24), and adrenoleukodystrophy protein related protein (25,26). A defect in adrenoleukodystrophy protein is known to be responsible for the X-linked neurodegeneration disorder, adrenoleukodystrophy.…”

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confidence: 99%

Identification of a Substrate-binding Site in a Peroxisomal β-Oxidation Enzyme by Photoaffinity Labeling with a Novel Palmitoyl Derivative

Kashiwayama

Tomohiro

Narita

et al. 2010

Journal of Biological Chemistry

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Peroxisomes play an essential role in a number of important metabolic pathways including ␤-oxidation of fatty acids and their derivatives. Therefore, peroxisomes possess various ␤-oxidation enzymes and specialized fatty acid transport systems. However, the molecular mechanisms of these proteins, especially in terms of substrate binding, are still unknown. In this study, to identify the substrate-binding sites of these proteins, we synthesized a photoreactive palmitic acid analogue bearing a diazirine moiety as a photophore, and performed photoaffinity labeling of purified rat liver peroxisomes. As a result, an 80-kDa peroxisomal protein was specifically labeled by the photoaffinity ligand, and the labeling efficiency competitively decreased in the presence of palmitoyl-CoA. Mass spectrometric analysis identified the 80-kDa protein as peroxisomal multifunctional enzyme type 2 (MFE2), one of the peroxisomal ␤-oxidation enzymes. Recombinant rat MFE2 was also labeled by the photoaffinity ligand, and mass spectrometric analysis revealed that a fragment of rat MFE2 (residues Trp 249 to Arg 251 ) was labeled by the ligand. MFE2 mutants bearing these residues, MFE2(W249A) and MFE2(R251A), exhibited decreased labeling efficiency. Furthermore, MFE2(W249G), which corresponds to one of the disease-causing mutations in human MFE2, also exhibited a decreased efficiency. Based on the crystal structure of rat MFE2, these residues are located on the top of a hydrophobic cavity leading to an active site of MFE2. These data suggest that MFE2 anchors its substrate around the region from Trp 249 to Arg 251 and positions the substrate along the hydrophobic cavity in the proper direction toward the catalytic center.Peroxisomes are organelles bound by a single membrane, which are present in almost all eukaryotic cells. Peroxisomes are involved in a variety of important metabolic processes including the ␤-oxidation of fatty acids, synthesis of plasmalogen, and bile acids (1). A specialized set of enzymes responsible for the peroxisomal functions are compartmentalized in the organelle, and the deficiency of peroxisomal enzymes causes severe metabolic disease such as acyl-CoA oxidase deficiency and D-bifunctional protein deficiency (2-4). Fibroblasts from patients with these deficiencies exhibit the disturbed peroxisomal ␤-oxidation of very long-chain fatty acids (VLCFAs), 4 and VLCFAs are accumulated in the plasma and tissues of these patients (5). Analyses of these peroxisomal diseases reflect the importance of the peroxisomal ␤-oxidation in organisms along with disclosing the enzymatic organization of the peroxisomal ␤-oxidation system. Peroxisomes are involved in the ␤-oxidation of VLCFAs, branched chain fatty acids such as pristanic acid, and bile acid intermediates such as dihydroxycholestanoic acid and trihydroxycholestanoic acid, which are incompatible with mitochondrial ␤-oxidation (6). Peroxisomal ␤-oxidation of fatty acids proceeds via a four-step pathway as in mitochondria, and multiple enzymes are involved in each step of the...

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A close relative of the adrenoleukodystrophy (ALD) gene codes for a peroxisomal protein with a specific expression pattern.

Cited by 205 publications

References 33 publications

Comparative Genomics and Adaptive Selection of the ATP-Binding-Cassette Gene Family in Caenorhabditis Species

Comparative Genomics and Adaptive Selection of the ATP-Binding-Cassette Gene Family in Caenorhabditis Species

Substrate Specificity Overlap and Interaction between Adrenoleukodystrophy Protein (ALDP/ABCD1) and Adrenoleukodystrophy-related Protein (ALDRP/ABCD2)

Identification of a Substrate-binding Site in a Peroxisomal β-Oxidation Enzyme by Photoaffinity Labeling with a Novel Palmitoyl Derivative

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