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Structural basis of substrate recognition and translocation by human very long-chain fatty acid transporter ABCD1

Author

Listed:
  • Zhi-Peng Chen

    (University of Science and Technology of China
    University of Science and Technology of China)

  • Da Xu

    (University of Science and Technology of China
    University of Science and Technology of China)

  • Liang Wang

    (University of Science and Technology of China
    University of Science and Technology of China)

  • Yao-Xu Mao

    (University of Science and Technology of China
    University of Science and Technology of China)

  • Yang Li

    (University of Science and Technology of China
    University of Science and Technology of China)

  • Meng-Ting Cheng

    (University of Science and Technology of China
    University of Science and Technology of China)

  • Cong-Zhao Zhou

    (University of Science and Technology of China
    University of Science and Technology of China)

  • Wen-Tao Hou

    (University of Science and Technology of China
    University of Science and Technology of China)

  • Yuxing Chen

    (University of Science and Technology of China
    University of Science and Technology of China)

Abstract

Human ABC transporter ABCD1 transports very long-chain fatty acids from cytosol to peroxisome for β-oxidation, dysfunction of which usually causes the X-linked adrenoleukodystrophy (X-ALD). Here, we report three cryogenic electron microscopy structures of ABCD1: the apo-form, substrate- and ATP-bound forms. Distinct from what was seen in the previously reported ABC transporters, the two symmetric molecules of behenoyl coenzyme A (C22:0-CoA) cooperatively bind to the transmembrane domains (TMDs). For each C22:0-CoA, the hydrophilic 3’-phospho-ADP moiety of CoA portion inserts into one TMD, with the succeeding pantothenate and cysteamine moiety crossing the inter-domain cavity, whereas the hydrophobic fatty acyl chain extends to the opposite TMD. Structural analysis combined with biochemical assays illustrates snapshots of ABCD1-mediated substrate transport cycle. It advances our understanding on the selective oxidation of fatty acids and molecular pathology of X-ALD.

Suggested Citation

  • Zhi-Peng Chen & Da Xu & Liang Wang & Yao-Xu Mao & Yang Li & Meng-Ting Cheng & Cong-Zhao Zhou & Wen-Tao Hou & Yuxing Chen, 2022. "Structural basis of substrate recognition and translocation by human very long-chain fatty acid transporter ABCD1," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30974-5
    DOI: 10.1038/s41467-022-30974-5
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    References listed on IDEAS

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    1. Yao-Xu Mao & Zhi-Peng Chen & Liang Wang & Jie Wang & Cong-Zhao Zhou & Wen-Tao Hou & Yuxing Chen, 2024. "Transport mechanism of human bilirubin transporter ABCC2 tuned by the inter-module regulatory domain," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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