Structural and functional insights of the human peroxisomal ABC transporter ALDP
Open accessPublished version of a preprint
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 structure of human ALDP with nominal resolution at 3.4 Å. ALDP exhibits a cytosolic-facing conformation. Compared to other lipid ATP-binding cassette transporters, ALDP has two substrate binding cavities formed by the transmembrane domains. 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.
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Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters
Mosser, J., Douar, A.-M., Sarde, C.-O., Kioschis, P., Feil, R., Moser, H., Poustka, A.-M., Mandel, J.-L., & Aubourg, P. (1993) · Nature · doi:10.1038/361726a0 · Cited by 1,202 · see citing works
Biochemistry of mammalian peroxisomes revisited
Wanders, R. J. A., & Waterham, H. R. (2006) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.74.082803.133329 · Cited by 995 · see citing works
Kemp, S., Pujol, A., Waterham, H. R., van Geel, B. M., Boehm, C. D., Raymond, G. V., Cutting, G. R., Wanders, R. J. A., & Moser, H. W. (2001) · Human Mutation · doi:10.1002/humu.1227 · Cited by 332 · see citing works
Differential substrate specificities of human ABCD1 and ABCD2 in peroxisomal fatty acid β-oxidation
van Roermund, C. W. T., Visser, W. F., IJlst, L., Waterham, H. R., & Wanders, R. J. A. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2010.11.010 · Cited by 128 · see citing works
A role for the human peroxisomal half-transporter ABCD3 in the oxidation of dicarboxylic acids
van Roermund, C. W. T., IJlst, L., Wagemans, T., Wanders, R. J. A., & Waterham, H. R. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2013.12.001 · Cited by 101 · see citing works
ABCD1 dysfunction alters white matter microvascular perfusion
Lauer, A., Da, X., Hansen, M. B., Boulouis, G., Ou, Y., Cai, X., Liberato Celso Pedrotti, A., Kalpathy-Cramer, J., Caruso, P., Hayden, D. L., et al. (2017) · Brain · doi:10.1093/brain/awx262 · Cited by 48 · see citing works
Chen, Z.-P., Xu, D., Wang, L., Mao, Y.-X., Li, Y., Cheng, M.-T., Zhou, C.-Z., Hou, W.-T., & Chen, Y. (2022) · Nature Communications · doi:10.1038/s41467-022-30974-5 · Cited by 37 · see citing works
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Chen, Z.-P., Xu, D., Wang, L., Mao, Y.-X., Li, Y., Cheng, M.-T., Zhou, C.-Z., Hou, W.-T., & Chen, Y. (2022) · Nature Communications · doi:10.1038/s41467-022-30974-5 · Cited by 37 · see citing works
Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy
Bougnères, P., & Le Stunff, C. (2025) · Genes · doi:10.3390/genes16050590 · Cited by 11 · see citing works
- Authors
- Jia, Y., Zhang, Y., Wang, W., Lei, J., Ying, Z., & Yang, G.
- Affiliations
- China Agricultural University (CN)
- Tsinghua University (CN)
- Corresponding author
- Ying, Zhengxin
- Yang, Guanghui
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2022-11-14
- Volume
- 11
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC9683791
- OpenAlex
- W4308952192
- Cited by
- 15
- References
- 8
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 3 · 2022: 1 · 2021: 1
- FWCI
- 1.74
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (3217110084, 32130081, 32100759)
- Chinese Universities Scientific Fund (15050004, 15051002, 15050017)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- ALDP, ABC transporters, X-linked adrenoleukodystrophy, very long chain fatty acids, cryo-EM structure, substrate-binding cavity, pathogenic variants, protein thermal stability, ATP hydrolysis, protein trafficking
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily D, Member 1, Adrenoleukodystrophy, Humans, ATP-Binding Cassette Transporters, Cryoelectron Microscopy, Peroxisomes
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