Structural and functional insights of the human peroxisomal ABC transporter ALDP
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-c...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-11-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/75039 |
| _version_ | 1811186777910673408 |
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| author | Yutian Jia Yanming Zhang Wenhao Wang Jianlin Lei Zhengxin Ying Guanghui Yang |
| author_facet | Yutian Jia Yanming Zhang Wenhao Wang Jianlin Lei Zhengxin Ying Guanghui Yang |
| author_sort | Yutian Jia |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T13:51:52Z |
| format | Article |
| id | doaj.art-d5af0d551d624ebaa4f0c358e3da57b6 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T13:51:52Z |
| publishDate | 2022-11-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-d5af0d551d624ebaa4f0c358e3da57b62022-12-22T04:20:36ZengeLife Sciences Publications LtdeLife2050-084X2022-11-011110.7554/eLife.75039Structural and functional insights of the human peroxisomal ABC transporter ALDPYutian Jia0https://orcid.org/0000-0001-6921-7222Yanming Zhang1Wenhao Wang2Jianlin Lei3https://orcid.org/0000-0002-9384-8742Zhengxin Ying4https://orcid.org/0000-0003-0948-4948Guanghui Yang5https://orcid.org/0000-0002-6835-1611State Key Laboratory for Agrobiotechnology, Department of Nutrition and Health, College of Biological Sciences, China Agricultural University, Beijing, ChinaState Key Laboratory for Agrobiotechnology, Department of Nutrition and Health, College of Biological Sciences, China Agricultural University, Beijing, ChinaState Key Laboratory for Agrobiotechnology, Department of Nutrition and Health, College of Biological Sciences, China Agricultural University, Beijing, ChinaTechnology Center for Protein Sciences, Ministry of Education Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, ChinaState Key Laboratory for Agrobiotechnology, Department of Nutrition and Health, College of Biological Sciences, China Agricultural University, Beijing, ChinaState Key Laboratory for Agrobiotechnology, Department of Nutrition and Health, College of Biological Sciences, China Agricultural University, Beijing, ChinaAdrenoleukodystrophy 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.https://elifesciences.org/articles/75039ALDPcryo-EMmutations |
| spellingShingle | Yutian Jia Yanming Zhang Wenhao Wang Jianlin Lei Zhengxin Ying Guanghui Yang Structural and functional insights of the human peroxisomal ABC transporter ALDP eLife ALDP cryo-EM mutations |
| title | Structural and functional insights of the human peroxisomal ABC transporter ALDP |
| title_full | Structural and functional insights of the human peroxisomal ABC transporter ALDP |
| title_fullStr | Structural and functional insights of the human peroxisomal ABC transporter ALDP |
| title_full_unstemmed | Structural and functional insights of the human peroxisomal ABC transporter ALDP |
| title_short | Structural and functional insights of the human peroxisomal ABC transporter ALDP |
| title_sort | structural and functional insights of the human peroxisomal abc transporter aldp |
| topic | ALDP cryo-EM mutations |
| url | https://elifesciences.org/articles/75039 |
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