ABCMdb

ABCD1 p.Leu78Phe

Predicted by SNAP2:	A: D (53%), C: N (57%), D: D (80%), E: D (75%), F: D (63%), G: D (75%), H: D (71%), I: N (82%), K: D (75%), M: N (72%), N: D (66%), P: D (80%), Q: D (66%), R: D (75%), S: D (63%), T: D (63%), V: N (66%), W: D (59%), Y: D (66%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: N, K: D, M: N, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] Mammalian peroxisomal ABC transporters: from endog... Br J Pharmacol. 2011 Dec;164(7):1753-66. doi: 10.1111/j.1476-5381.2011.01435.x. Kemp S, Theodoulou FL, Wanders RJ
Mammalian peroxisomal ABC transporters: from endogenous substrates to pathology and clinical significance.
Br J Pharmacol. 2011 Dec;164(7):1753-66. doi: 10.1111/j.1476-5381.2011.01435.x., [PMID:21488864]

Abstract [show]
Peroxisomes are indispensable organelles in higher eukaryotes. They are essential for a number of important metabolic pathways, including fatty acid alpha- and beta-oxidation, and biosynthesis of etherphospholipids and bile acids. However, the peroxisomal membrane forms an impermeable barrier to these metabolites. Therefore, peroxisomes need specific transporter proteins to transfer these metabolites across their membranes. The mammalian peroxisomal membrane harbours three ATP-binding cassette (ABC) transporters. In recent years, significant progress has been made in unravelling the functions of these ABC transporters. There is ample evidence that they are involved in the transport of very long-chain fatty acids, pristanic acid, di- and trihydroxycholestanoic acid, dicarboxylic acids and tetracosahexaenoic acid (C24:6omega3). Surprisingly, only one disease is associated with a deficiency of a peroxisomal ABC transporter. Mutations in the ABCD1 gene encoding the peroxisomal ABC transporter adrenoleukodystrophy protein are the cause for X-linked adrenoleukodystrophy, an inherited metabolic storage disorder. This review describes the current state of knowledge on the mammalian peroxisomal ABC transporters with a particular focus on their function in metabolite transport.

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162 For example, the missense mutation p.Leu78Phe significantly reduced the targeting efficiency and an in-frame deletion of three amino acids (p.Arg80_Leu82del) resulted in the mislocalization of ALDP to the nucleus, cytosol and mitochondria (Landgraf et al., 2003). Login to comment

[hide] Targeting of the human adrenoleukodystrophy protei... Eur J Cell Biol. 2003 Aug;82(8):401-10. Landgraf P, Mayerhofer PU, Polanetz R, Roscher AA, Holzinger A
Targeting of the human adrenoleukodystrophy protein to the peroxisomal membrane by an internal region containing a highly conserved motif.
Eur J Cell Biol. 2003 Aug;82(8):401-10., [PMID:14533738]

Abstract [show]
In this study we addressed the targeting requirements of peroxisomal ABC transporters, in particular the human adrenoleukodystrophy protein. This membrane protein is defective or missing in X-linked adrenoleukodystrophy, a neurodegenerative disorder predominantly presenting in childhood. Using adrenoleukodystrophy protein deletion constructs and green fluorescent protein fusion constructs we identified the amino acid regions 1-110 and 67-164 to be sufficient for peroxisomal targeting. However, the minimal region shared by these constructs (amino acids 67-110) is not sufficient for peroxisomal targeting by itself. Additionally, the NH2-terminal 66 amino acids enhance targeting efficiency. Green fluorescent protein-labeled fragments of human peroxisomal membrane protein 69 and Saccharomyces cerevisiae Pxa1 corresponding to the amino acid 67-164 adrenoleukodystrophy protein region were also directed to the mammalian peroxisome. The required region contains a 14-amino-acid motif (71-84) conserved between the adrenoleukodystrophy protein and human peroxisomal membrane protein 69 and yeast Pxa1. Omission or truncation of this motif in the adrenoleukodystrophy protein abolished peroxisomal targeting. The single amino acid substitution L78F resulted in a significant reduction of targeting efficiency. The in-frame deletion of three amino acids (del78-80LLR) within the proposed targeting motif in two patients suffering from X-linked adrenoleukodystrophy resulted in the mislocalization of a green fluorescent protein fusion protein to nucleus, cytosol and mitochondria. Our data define the targeting region of human adrenoleukodystrophy protein containing a highly conserved 14-amino-acid motif.

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7 The single amino acid substitution L78F resulted in a significant reduction of targeting efficiency. Login to comment
127 Construct name n Strictly peroxisomal targeting (%) 1 ± 281 ALDP-GFP1 361 313 (86.7) * 1 ± 164 ALDP-GFP1 331 277 (83.7) * 1 ± 110 ALDP-GFP1 132 108 (81.8) * 282 ± 745 ALDP-GFP 218 0 (0) * 67 ± 164 ALDP-GFP 176 90 (51.1) 67 ± 134 ALDP-GFP 275 0 (0) * 78 ± 164 ALDP-GFP2 247 2 (0.8) * 87 ± 164 ALDP-GFP2 206 1 (0.5) * 67 ± 164 ALDP(F71S)-GFP3 363 143 (39.4) 67 ± 164 ALDP(F71V)-GFP3 203 90 (44.3) 67 ± 164 ALDP(R74W)-GFP3 218 89 (40.8) 67 ± 164 ALDP(R74G)-GFP3 277 123 (44.4) 67 ± 164 ALDP(L78F)-GFP3 315 103 (32.7) * 67 ± 164 ALDP(L81V)-GFP3 363 199 (54.8) 67 ± 164 ALDP(P84A)-GFP3 413 196 (47.5) 67 ± 164 ALDP-delLLR-GFP4 224 0 (0) * Total number of cells (n) analysed that were transfected with various ALDP-GFP fusion constructs. Login to comment
149 The percentage of 67 ± 164 ALDP(L78F)-GFP-transfected cells exhibiting a strictly peroxisomal pattern significantly (p < 0.01) differed as compared to the wild-type 67 ± 164 ALDP-GFP (Table II) suggesting a decrease in targeting efficiency. Login to comment
179 Among several single-amino-acid substitutions of conserved residues only the 67 ± 164 ALDP(L78F)-GFP construct significantly reduced targeting efficiency. Login to comment