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

Zhi-Peng Chen, Da Xu, Liang Wang, Yao-Xu Mao, Yang Li, Meng-Ting Cheng, Cong-Zhao Zhou (), Wen-Tao Hou () and Yuxing Chen ()
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Zhi-Peng Chen: University of Science and Technology of China
Da Xu: University of Science and Technology of China
Liang Wang: University of Science and Technology of China
Yao-Xu Mao: University of Science and Technology of China
Yang Li: University of Science and Technology of China
Meng-Ting Cheng: University of Science and Technology of China
Cong-Zhao Zhou: University of Science and Technology of China
Wen-Tao Hou: University of Science and Technology of China
Yuxing Chen: University of Science and Technology of China

Nature Communications, 2022, vol. 13, issue 1, 1-10

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-30974-5

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