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

<div class='caption-title'>Substrate-stimulated ATPase activity assays and structure determination of ABCD1.</div>
<div class='caption-title'>Overall structure of apo-form ABCD1.</div>
<div class='caption-title'>Structure of substrate-bound ABCD1 and the substrate binding pocket.</div>
Chen ZP, Xu D, Wang L, Mao YX, Li Y, Cheng MT, Zhou CZ, Hou WT, Chen Y
OpenAccess logo Nat Commun 13 3299 (2022)
Related entries: 7vx8, 7vzb

Cited: 7 times
EuropePMC logo PMID: 35676282

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.

Reviews citing this publication (2)

  1. The peroxisome: an update on mysteries 3.0. Kumar R, Islinger M, Worthy H, Carmichael R, Schrader M. Histochem Cell Biol 161 99-132 (2024)
  2. The Physiological and Pathological Role of Acyl-CoA Oxidation. Szrok-Jurga S, Czumaj A, Turyn J, Hebanowska A, Swierczynski J, Sledzinski T, Stelmanska E. Int J Mol Sci 24 14857 (2023)

Articles citing this publication (5)

  1. Structural basis for substrate and inhibitor recognition of human multidrug transporter MRP4. Huang Y, Xue C, Wang L, Bu R, Mu J, Wang Y, Liu Z. Commun Biol 6 549 (2023)
  2. Structural and functional insights of the human peroxisomal ABC transporter ALDP. Jia Y, Zhang Y, Wang W, Lei J, Ying Z, Yang G. Elife 11 e75039 (2022)
  3. Structural insights into substrate recognition and translocation of human peroxisomal ABC transporter ALDP. Xiong C, Jia LN, Xiong WX, Wu XT, Xiong LL, Wang TH, Zhou D, Hong Z, Liu Z, Tang L. Signal Transduct Target Ther 8 74 (2023)
  4. Transport mechanism of human bilirubin transporter ABCC2 tuned by the inter-module regulatory domain. Mao YX, Chen ZP, Wang L, Wang J, Zhou CZ, Hou WT, Chen Y. Nat Commun 15 1061 (2024)
  5. A novel ABCD1 gene mutation causes adrenomyeloneuropathy presenting with spastic paraplegia: A case report. Liu J, Wang X, Huang D, Qi Y, Xu L, Shao Y. Medicine (Baltimore) 103 e37874 (2024)


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