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Updated: Jun 14, 2025
11:03
Measurement of Fatty Acid β-Oxidation in a Suspension of Freshly Isolated Mouse Hepatocytes
Published on: September 9, 2021
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Structural insights into human ABCD3-mediated peroxisomal acyl-CoA translocation
Yang Li1,2, Zhi-Peng Chen1, Da Xu1,2
1Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, and Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
Cell Discovery
|September 2, 2024
Summary
Human ABCD3 transporters facilitate fatty acid breakdown in peroxisomes. Cryo-EM structures reveal how ABCD3 binds substrates and ATP, offering insights into fatty acid oxidation and related liver diseases.
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Biology
Background:
- Human ATP-binding cassette (ABC) transporters ABCD1-3 are peroxisomal membrane proteins crucial for fatty acyl-CoA β-oxidation.
- ABCD3 specifically transports branched-chain fatty acids, and its dysfunction leads to severe liver diseases like hepatosplenomegaly.
Purpose of the Study:
- To elucidate the molecular mechanism of human ABCD3 in fatty acid transport.
- To determine the structural basis of ABCD3 substrate specificity and ATP-dependent transport.
Main Methods:
- Cryogenic electron microscopy (cryo-EM) to obtain high-resolution structures of ABCD3.
- Biochemical assays, including substrate-stimulated ATPase activity assays.
Main Results:
- Two cryo-EM structures of ABCD3 bound to phytanoyl-CoA and ATP were determined at 2.9 Å and 3.2 Å resolution.
- Phytanoyl-CoA binding sites in ABCD3 differ from ABCD1, with each molecule binding to a single transmembrane domain.
- ATP binding induces a matrix-open conformation of ABCD3, with CoA molecules within the translocation cavity, suggesting distinct transport states.
Conclusions:
- The determined structures provide unprecedented insights into the transport cycle of ABCD3.
- These findings advance the understanding of fatty acid oxidation pathways and the molecular pathology of ABCD3-related liver diseases.
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