RGD Reference Report - Substrate specificity overlap and interaction between adrenoleukodystrophy protein (ALDP/ABCD1) and adrenoleukodystrophy-related protein (ALDRP/ABCD2).

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Substrate specificity overlap and interaction between adrenoleukodystrophy protein (ALDP/ABCD1) and adrenoleukodystrophy-related protein (ALDRP/ABCD2).
Authors:	Genin, Emmanuelle C Geillon, Flore Gondcaille, Catherine Athias, Anne Gambert, Philippe Trompier, Doriane Savary, Stéphane
Citation:	Genin EC, etal., J Biol Chem. 2011 Mar 11;286(10):8075-8084. doi: 10.1074/jbc.M110.211912. Epub 2011 Jan 5.
RGD ID:	127285396
Pubmed:	PMID:21209459 (View Abstract at PubMed)
PMCID:	PMC3048694 (View Article at PubMed Central)
DOI:	DOI:10.1074/jbc.M110.211912 (Journal Full-text)
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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Biological Process

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
Abcd2	Rat	very long-chain fatty acid metabolic process	involved_in	IMP	UniProtKB:D3ZHR2	PMID:21209459	UniProt

Molecular Function

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
Abcd1	Rat	protein binding	enables	IPI	UniProtKB:Q9QY44	PMID:21209459	UniProt
Abcd2	Rat	protein binding	enables	IPI	UniProtKB:D3ZHR2	PMID:21209459	UniProt

Objects Annotated

Genes (Rattus norvegicus)

Abcd1 (ATP binding cassette subfamily D member 1)

Abcd2 (ATP binding cassette subfamily D member 2)

Additional Information

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Substrate specificity overlap and interaction between adrenoleukodystrophy protein (ALDP/ABCD1) and adrenoleukodystrophy-related protein (ALDRP/ABCD2).