Abstract
The peroxisomal very long chain fatty acid (VLCFA) transporter ABCD1 is central to fatty acid catabolism and lipid biosynthesis. Its dysfunction underlies toxic cytosolic accumulation of VLCFAs, progressive demyelination, and neurological impairments including X-linked adrenoleukodystrophy (X-ALD). We present cryo-EM structures of ABCD1 in phospholipid nanodiscs in a nucleotide bound conformation open to the peroxisomal lumen and an inward facing conformation open to the cytosol at up to 3.5 Å resolution, revealing details of its transmembrane cavity and ATP dependent conformational spectrum. We identify features distinguishing ABCD1 from its closest homologs and show that coenzyme A (CoA) esters of VLCFAs modulate ABCD1 activity in a species dependent manner. Our data suggest a transport mechanism where the CoA moieties of VLCFA-CoAs enter the hydrophilic transmembrane domain while the acyl chains extend out into the surrounding membrane bilayer. The structures help rationalize disease causing mutations and may aid ABCD1 targeted structure-based drug design.
| Original language | English (US) |
|---|---|
| Article number | 7 |
| Journal | Communications biology |
| Volume | 5 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 2022 |
Bibliographical note
Funding Information:We would like to thank the cryo-EM and shared instruments core facilities at the Hormel Institute for help with experimental setup and Dr. Rhoderick Brown, Dr. Jarrod French, and Dr. Jeppe Olsen for critical reading and discussion during manuscript preparation. This work was supported in part by the Hormel Foundation (Institutional research funds to A.A.), the United Leukodystrophy Foundation (ULF research grant to A.A.), and the EAGLES Cancer Telethon Postdoctoral Fellowship (to L.T.M.L.).
Publisher Copyright:
© 2022, The Author(s).
PubMed: MeSH publication types
- Journal Article
- Research Support, Non-U.S. Gov't