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Author Spotlight: A Bicelle Crystallization Setup for ABC Transporter Membrane Proteins to Advance Drug Development
Published on: August 25, 2023
ATP-binding cassette transporters and sterol O-acyltransferases interact at membrane microdomains to modulate sterol
Sonia Gulati1, Dina Balderes1, Christine Kim1
1*Institute of Human Nutrition, Department of Neurology, **Department of Genetics and Development, and Department of Pediatrics, Columbia University Medical Center, New York, New York, USA; Department of Biological Sciences and Department of Chemistry, Columbia University, New York, New York, USA; Donnelly Center for Cellular and Biomolecular Research, Toronto, Ontario, Canada; Institute of Molecular Biosciences, BioTechMed Graz, University of Graz, Graz, Austria; Department of Biology, Providence College, Providence, Rhode Island, USA; and Marine Biological Laboratory, Woods Hole, Massachusetts, USA.
Abstract:
A key component of eukaryotic lipid homeostasis is the esterification of sterols with fatty acids by sterol O-acyltransferases (SOATs). The esterification reactions are allosterically activated by their sterol substrates, the majority of which accumulate at the plasma membrane. We demonstrate that in yeast, sterol transport from the plasma membrane to the site of esterification is associated with the physical interaction of the major SOAT, acyl-coenzyme A:cholesterol acyltransferase (ACAT)-related enzyme (Are)2p, with 2 plasma membrane ATP-binding cassette (ABC) transporters: Aus1p and Pdr11p. Are2p, Aus1p, and Pdr11p, unlike the minor acyltransferase, Are1p, colocalize to sterol and sphingolipid-enriched, detergent-resistant microdomains (DRMs). Deletion of either ABC transporter results in Are2p relocalization to detergent-soluble membrane domains and a significant decrease (53-36%) in esterification of exogenous sterol. Similarly, in murine tissues, the SOAT1/Acat1 enzyme and activity localize to DRMs. This subcellular localization is diminished upon deletion of murine ABC transporters, such as Abcg1, which itself is DRM associated. We propose that the close proximity of sterol esterification and transport proteins to each other combined with their residence in lipid-enriched membrane microdomains facilitates rapid, high-capacity sterol transport and esterification, obviating any requirement for soluble intermediary proteins.
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