Structural and functional insights of the human peroxisomal ABC transporter ALDP
- China Agricultural University, China
- Tsinghua University, China
Abstract
Adrenoleukodystrophy protein (ALDP) is responsible for the transport of very-long-chain fatty acids (VLCFAs) and corresponding CoA-esters across the peroxisomal membrane. Dysfunction of ALDP leads to peroxisomal metabolic disorder exemplified by X-linked adrenoleukodystrophy (ALD). Hundreds of ALD-causing mutations have been identified on ALDP. However, the pathogenic mechanisms of these mutations are restricted to clinical description due to limited structural and biochemical characterization. Here we report the cryo-electron microscopy (cryo-EM) structure of human ALDP with nominal resolution at 3.4 Å. ALDP exhibits a cytosolic-facing conformation. Compared to other lipid ATP-binding cassette (ABC) transporters, ALDP has two substrate binding cavities formed by the transmembrane domains (TMD). Such structural organization may be suitable for the coordination of VLCFAs. Based on the structure, we performed integrative analysis of the cellular trafficking, protein thermostability, ATP hydrolysis and the transport activity of representative mutations. These results provide a framework for understanding the working mechanism of ALDP and pathogenic roles of disease-associated mutations.
Data availability
1）Cryo-EM data have been deposited in PDB under the accession code 7VR12）All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures supplement 6A.
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The ABCD1 Variant DatabaseThe ABCD1 Variant Database.
Article and author information
Author details
Funding
National Natural Science Foundation of China (3217110084)
- Guanghui Yang
Chinese Universities Scientific Fund (15050004,15050017,15051002)
- Guanghui Yang
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2022, Jia et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Structural and functional insights of the human peroxisomal ABC transporter ALDP
eLife 11:e75039.
https://doi.org/10.7554/eLife.75039
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