Structural and functional insights of the human peroxisomal ABC transporter ALDP

  1. Yutian Jia
  2. Yanming Zhang
  3. Wenhao Wang
  4. Jianlin Lei
  5. Zhengxin Ying
  6. Guanghui Yang  Is a corresponding author
  1. China Agricultural University, China
  2. 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.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Yutian Jia

    Department of Nutrition and Health, China Agricultural University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Yanming Zhang

    Department of Nutrition and Health, China Agricultural University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Wenhao Wang

    Department of Nutrition and Health, China Agricultural University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Jianlin Lei

    Technology Center for Protein Sciences, Tsinghua University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9384-8742
  5. Zhengxin Ying

    Department of Nutrition and Health, China Agricultural University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  6. 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.
    ORCID icon "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.

Reviewing Editor

  1. David Drew, Stockholm University, Sweden

Version history

  1. Preprint posted: September 25, 2021 (view preprint)
  2. Received: October 28, 2021
  3. Accepted: November 10, 2022
  4. Accepted Manuscript published: November 14, 2022 (version 1)
  5. Version of Record published: November 23, 2022 (version 2)

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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  1. Yutian Jia
  2. Yanming Zhang
  3. Wenhao Wang
  4. Jianlin Lei
  5. Zhengxin Ying
  6. Guanghui Yang
(2022)
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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https://doi.org/10.7554/eLife.75039

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