Adrenoleukodystrophy protein enhances association of very long-chain acyl-coenzyme A synthetase with the peroxisome

Yamada, Takeshi; Taniwaki, Takayuki; Shinnoh, Nobue; Uchiyama, Atsushi; Shimozawa, Nobuyuki; Ohyagi, Yasumasa; Asahara, Hideaki; Kira, Jun Ichi

doi:10.1212/wnl.52.3.614

Cited by 23 publications

(16 citation statements)

References 21 publications

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“…If it is located within peroxisomes, this would rather support that ALDP transports VLCFA or a substrate necessary to VLACS activation. It is unlikely that ALDP transports the VLACS enzyme across the peroxisomal membrane because VLACS is normally expressed in the liver from ALDP-deficient mice and normally localized in peroxisomes (35).…”

Section: Discussionmentioning

confidence: 99%

Homo- and Heterodimerization of Peroxisomal ATP-binding Cassette Half-transporters

Liu¹,

Janvier²,

Berteaux‐Lecellier³

et al. 1999

Journal of Biological Chemistry

129

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The peroxisomal membrane is equipped with four ATP-binding cassette (ABC) 1 transporters, which include the adrenoleukodystrophy protein (ALDP) (1), the adrenoleukodystrophyrelated protein (ALDRP) (2), the 70-kDa peroxisomal membrane protein (PMP70) (3), and the PMP70-related protein (4, 5). Typical mammalian ABC transporters, like the multidrug-resistant P-glycoprotein, are single functional proteins with two related halves comprised of one hydrophobic transmembrane domain and one hydrophilic nucleotide-binding fold (NBF) (6). In contrast, the peroxisomal ABC transporters, as well as TAP1/TAP2 (7) and ABC7 (8), which are respectively located within the endoplasmic reticulum or mitochondria, are half-transporters with only one hydrophobic domain and one NBF.X-linked adrenoleukodystrophy (X-ALD) is the only genetic disease known to result from a peroxisomal ABC transporter gene defect. This neurodegenerative disorder is characterized by progressive demyelination within the central nervous system, adrenal insufficiency, and accumulation of very long-chain fatty acids because of an impaired peroxisomal ␤-oxidation (9 -12). Although it is firmly established that the loss of ALDP function is responsible for the abnormality in VLCFA metabolism, its precise role is unknown. Similarly, no precise function has been assigned to ALDRP, PMP70, or PMP70-related proteins. ALDRP, PMP70, and PMP70-related protein present 66, 38, and 27% amino acid identity with ALDP, respectively, suggesting functional similarity of these four transporters. These proteins display specific but sometimes overlapping patterns of expression in different cell types (13-15). Because it is likely that half-transporters need to dimerize to exert their function (6), this raises the possibility that different types of peroxisomal ABC dimers could allow the import of distinct substrates. Few ABC transporters are known to dimerize. Genetic evidence suggests that the bacterial hemolysin transporter B ABC half-transporter forms homodimers (16), whereas the Drosophila white, brown, and scarlet gene products form heterodimers (17). Heterodimerization of ABC transporters has also been reported for the transporters of antigenic peptides, TAP1 and TAP2 (18), and the two yeast peroxisomal ABC proteins, Pxa1 and Pxa2 (19,20).This study used the yeast two-hybrid assay to show that the carboxyl-terminal half of ALDP, ALDRP, and PMP70 can engage in homo-and heterodimerization. These two processes were confirmed by co-immunoprecipitation methods. We examined the effect of four different ALD patient mutations upon these interactions and attempted to map the carboxyl-terminal subdomains of ALDP allowing dimerization of the protein. EXPERIMENTAL PROCEDURESAntibodies, Yeast Strains, and Cell Lines-Monoclonal antibody 1D6 against human ALDP (hALDP) and polyclonal antibodies 1664 and 7373 raised against mouse ALDP (mALDP) and mouse ALDRP (mALDRP), respectively, have been described previously (13,15,21).

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Section: Discussionmentioning

confidence: 99%

Homo- and Heterodimerization of Peroxisomal ATP-binding Cassette Half-transporters

Liu¹,

Janvier²,

Berteaux‐Lecellier³

et al. 1999

Journal of Biological Chemistry

129

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“…All of these enzymes have been localized to both peroxisomes and endoplasmic reticulum, sites of VLCS activity in the cell, and shown to have VLCS activity as well as the ability to activate long chain fatty acids. Vlcs has been identified as a mouse gene with a high degree of identity to these enzymes (20,21) and, as such, warrants investigation in X-ALD.…”

mentioning

confidence: 99%

Mouse Very Long-chain Acyl-CoA Synthetase in X-linked Adrenoleukodystrophy

Heinzer¹,

Kemp²,

Lu³

et al. 2002

Journal of Biological Chemistry

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X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disorder characterized by accumulation of very long-chain fatty acids (VLCFA). This accumulation has been attributed to decreased VLCFA ␤-oxidation and peroxisomal very long-chain acyl-CoA synthetase (VLCS) activity. The X-ALD gene, ABCD1, encodes a peroxisomal membrane ATP binding cassette transporter, ALDP, that is hypothesized to affect VLCS activity in peroxisomes by direct interaction with the VLCS enzyme. Recently, a VLCS gene that encodes a protein with significant sequence identity to known rat and human peroxisomal VLCS protein has been identified in mice. We find that the mouse VLCS gene (Vlcs) encodes an enzyme (Vlcs) with VLCS activity that localizes to peroxisomes and is expressed in X-ALD target tissues. We show that the expression of Vlcs in the peroxisomes of X-ALD mouse fibroblasts improves VLCFA ␤-oxidation in these cells, implying a role for this enzyme in the biochemical abnormality of X-ALD. X-ALD mice, which accumulate VLCFA in tissues, show no change in the expression of Vlcs, the subcellular localization of Vlcs, or general peroxisomal VLCS activity. These observations imply that ALDP is not necessary for the proper expression or localization of Vlcs protein, and the control of VLCFA levels does not depend on the direct interaction of Vlcs and ALDP.

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“…Yamada et al [99] suggested that ALDP is required for correct targeting of the activating enzyme very-long-chain acyl-CoA synthetase (VLACS) to peroxisomes. Apart from the fact that the reduction in the amount of Vlacs protein in peroxisomes isolated from livers of Abcd1 (−/−) mice was only minimal (30% reduction), it is now known that VLACS plays no role in VLCFA activation nor betaoxidation.…”

Section: Abcd1 (Aldp)mentioning

confidence: 99%

The peroxisomal ABC transporter family

Wanders

Visser

Roermund

et al. 2006

Pflugers Arch - Eur J Physiol

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This review describes the current state of knowledge about the ABCD family of peroxisomal half adenosine-triphosphate-binding cassette (ABC) transporters. ABCDs are predicted to be present in a variety of eukaryotic organisms, although at present, only ABCDs in the yeast Saccharomyces cerevisiae, the plant Arabidopsis thaliana, and different mammalian species have been identified and characterized to any significant extent. The functional role of none of these ABCDs has been established definitively and awaits successful reconstitution of ABCDs, either as homo-or heterodimers into liposomes, followed by transport studies. Data obtained in S. cerevisiae suggest that the two ABCDs, which have been identified in this organism, form a heterodimer, which actually transports acyl coenzyme A esters across the peroxisomal membrane. In mammals, four ABCDs have been identified, of which one [adrenoleukodystrophy protein (ALDP)] has been implicated in the transport of the coenzyme A esters of very-long-chain fatty acids. Mutations in the gene (ABCD1) encoding ALDP are the cause of a severe X-linked disease, called X-linked adrenoleukodystrophy. The availability of mutant mice in which Abcd1, Abcd2, or Abcd3 have been disrupted will help to resolve the true role of the peroxisomal half-ABC transporters.

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Adrenoleukodystrophy protein enhances association of very long-chain acyl-coenzyme A synthetase with the peroxisome

Abstract: ALDP plays a role in the peroxisomal localization of VLACS, and VLACS does not function unless localized in the peroxisome.

Cited by 23 publications

References 21 publications

Homo- and Heterodimerization of Peroxisomal ATP-binding Cassette Half-transporters

Homo- and Heterodimerization of Peroxisomal ATP-binding Cassette Half-transporters

Mouse Very Long-chain Acyl-CoA Synthetase in X-linked Adrenoleukodystrophy

The peroxisomal ABC transporter family

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