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Structure of nevanimibe-bound tetrameric human ACAT1

Author

Listed:
  • Tao Long

    (University of Texas Southwestern Medical Center)

  • Yingyuan Sun

    (University of Texas Southwestern Medical Center)

  • Abdirahman Hassan

    (University of Texas Southwestern Medical Center)

  • Xiaofeng Qi

    (University of Texas Southwestern Medical Center)

  • Xiaochun Li

    (University of Texas Southwestern Medical Center
    University of Texas Southwestern Medical Center)

Abstract

Cholesterol is an essential component of mammalian cell membranes, constituting up to 50% of plasma membrane lipids. By contrast, it accounts for only 5% of lipids in the endoplasmic reticulum (ER)1. The ER enzyme sterol O-acyltransferase 1 (also named acyl-coenzyme A:cholesterol acyltransferase, ACAT1) transfers a long-chain fatty acid to cholesterol to form cholesteryl esters that coalesce into cytosolic lipid droplets. Under conditions of cholesterol overload, ACAT1 maintains the low cholesterol concentration of the ER and thereby has an essential role in cholesterol homeostasis2,3. ACAT1 has also been implicated in Alzheimer’s disease4, atherosclerosis5 and cancers6. Here we report a cryo-electron microscopy structure of human ACAT1 in complex with nevanimibe7, an inhibitor that is in clinical trials for the treatment of congenital adrenal hyperplasia. The ACAT1 holoenzyme is a tetramer that consists of two homodimers. Each monomer contains nine transmembrane helices (TMs), six of which (TM4–TM9) form a cavity that accommodates nevanimibe and an endogenous acyl-coenzyme A. This cavity also contains a histidine that has previously been identified as essential for catalytic activity8. Our structural data and biochemical analyses provide a physical model to explain the process of cholesterol esterification, as well as details of the interaction between nevanimibe and ACAT1, which may help to accelerate the development of ACAT1 inhibitors to treat related diseases.

Suggested Citation

  • Tao Long & Yingyuan Sun & Abdirahman Hassan & Xiaofeng Qi & Xiaochun Li, 2020. "Structure of nevanimibe-bound tetrameric human ACAT1," Nature, Nature, vol. 581(7808), pages 339-343, May.
    • Handle: RePEc:nat:nature:v:581:y:2020:i:7808:d:10.1038_s41586-020-2295-8
    DOI: 10.1038/s41586-020-2295-8
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    Cited by:

    1. Pingfeng Zhang & Zheng Liu, 2024. "Structural insights into the transporting and catalyzing mechanism of DltB in LTA D-alanylation," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    2. Kun Wang & Chia-Wei Lee & Xuewu Sui & Siyoung Kim & Shuhui Wang & Aidan B. Higgs & Aaron J. Baublis & Gregory A. Voth & Maofu Liao & Tobias C. Walther & Robert V. Farese, 2023. "The structure of phosphatidylinositol remodeling MBOAT7 reveals its catalytic mechanism and enables inhibitor identification," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    3. Xuewu Sui & Kun Wang & Kangkang Song & Chen Xu & Jiunn Song & Chia-Wei Lee & Maofu Liao & Robert V. Farese & Tobias C. Walther, 2023. "Mechanism of action for small-molecule inhibitors of triacylglycerol synthesis," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    4. Zhi Lin & Jiao Liu & Fei Long & Rui Kang & Guido Kroemer & Daolin Tang & Minghua Yang, 2022. "The lipid flippase SLC47A1 blocks metabolic vulnerability to ferroptosis," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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