Structural and functional insights of the human peroxisomal ABC transporter ALDP

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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.

The following data sets were generated

1. Yang GH
2. Jia YT
3. Zhang
4. YM
(2022) Cryo-EM structure of the ATP-binding cassette sub-family D member 1 from Homo sapiens
PDB, 7VR1.

https://www.rcsb.org/structure/7VR1

The following previously published data sets were used

1. Stephan Kemp
(2022) The ABCD1 Variant Database
The ABCD1 Variant Database.

https://adrenoleukodystrophy.info/mutations-and-variants-in-abcd1

Article and author information

Author details

Yutian Jia

Department of Nutrition and Health, China Agricultural University, Beijing, China

Competing interests
The authors declare that no competing interests exist.
Yanming Zhang

Department of Nutrition and Health, China Agricultural University, Beijing, China

Competing interests
The authors declare that no competing interests exist.
Wenhao Wang

Department of Nutrition and Health, China Agricultural University, Beijing, China

Competing interests
The authors declare that no competing interests exist.
Jianlin Lei

Technology Center for Protein Sciences, Tsinghua University, Beijing, China

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-9384-8742
Zhengxin Ying

Department of Nutrition and Health, China Agricultural University, Beijing, China

Competing interests
The authors declare that no competing interests exist.
Guanghui Yang

Department of Nutrition and Health, China Agricultural University, Beijing, China

For correspondence
guanghuiyang@cau.edu.cn

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-6835-1611

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.

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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.