Substrate Specificity Overlap and Interaction between Adrenoleukodystrophy Protein (ALDP/ABCD1) and Adrenoleukodystrophy-related Protein (ALDRP/ABCD2)
Open accessAbstract
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 β-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 β-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 β-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.
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A further explanation for the lack of compensation in vivo may be different affinities toward VLCFAs.
“A further explanation for the lack of compensation in vivo may be different affinities toward VLCFAs.”
From The genetic landscape of X-linked adrenoleukodystrophy: inheritance, mutations, modifier genes, and diagnosis (2015) · cites this paper as [122]
The Discussion (page unavailable) describes different substrate preferences for ALDP and ALDRP, which supports the possibility of a functional difference toward VLCFAs. But it says there are no clear data on differences in affinity toward C24:0 and C26:0, and it does not establish affinity differences as an explanation for the lack of compensation in vivo. (LLM, conf=0.82)
Experimental — accuracy not yet measuredDifferent substrate preferences were suggested for ABCD1-3: straight-chain VLCFAs for ABCD1, unsaturated VLCFAs for ABCD2, and branched-chain fatty acids, dicarboxylic acids, and bile acid precursors for ABCD3.
“Different substrate preferences were suggested for ABCD1-3: straight-chain VLCFAs for ABCD1, unsaturated VLCFAs for ABCD2, and branched-chain fatty acids, dicarboxylic acids, and bile acid precursors for ABCD3.122–124”
From The genetic landscape of X-linked adrenoleukodystrophy: inheritance, mutations, modifier genes, and diagnosis (2015) · cites this paper as [122]
The Discussion (page unavailable) describes a preference for saturated VLCFAs in ABCD1 and polyunsaturated fatty acids in ABCD2, while emphasizing that their substrate specificities overlap. The passage labeled Abstract (page unavailable) suggests that ABCD3 preferentially transports branched-chain fatty acids and bile acid precursors. Our copy does not support the additional attribution of dicarboxylic acids to ABCD3. (LLM, conf=0.88)
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“Experiments in mammalian cells confirmed such substrate preference [19,20].”
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Structure-Function Analysis of Peroxisomal ATP-binding Cassette Transporters Using Chimeric Dimers
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Immune response of BV-2 microglial cells is impacted by peroxisomal beta-oxidation
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Self-citationPeroxisomal defects in microglial cells induce a disease-associated microglial signature
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Self-citation
- Authors
- Genin, E. C., Geillon, F., Gondcaille, C., Athias, A., Gambert, P., Trompier, D., & Savary, S.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Corresponding author
- Savary, Stéphane
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2011-03
- Volume
- 286
- Issue
- 10
- Pages
- 8075-8084
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3048694
- OpenAlex
- W2015577087
- Cited by
- 53
- References
- 8
- Citations by year
- 2024: 2 · 2023: 2 · 2022: 3 · 2021: 2 · 2020: 2 · 2019: 3 · 2018: 1 · 2017: 5 · 2016: 3 · 2015: 5 · 2014: 6 · 2013: 7 · 2012: 8
- FWCI
- 4.63
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by)
- ORBi (University of Liège) (submittedVersion, other-oa)
- Funders
- Conseil régional de Bourgogne-Franche-Comté
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Keywords
- X-linked adrenoleukodystrophy, ABCD1, ABCD2, ALDP, very long chain fatty acids, peroxisomal beta-oxidation, docosahexaenoic acid, substrate specificity, protein-protein interaction, phospholipid fatty acid composition
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily D, Adrenoleukodystrophy, Animals, Fatty Acids, Oxidation-Reduction, ATP-Binding Cassette Transporters, Peroxisomes, Cell Line, Tumor, Rats
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