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Structural basis for catalysis and substrate specificity of human ACAT1

Author

Listed:
  • Hongwu Qian

    (Princeton University)

  • Xin Zhao

    (Tsinghua University)

  • Renhong Yan

    (Westlake University
    Westlake Institute for Advanced Study)

  • Xia Yao

    (Princeton University)

  • Shuai Gao

    (Princeton University)

  • Xue Sun

    (Peking University)

  • Ximing Du

    (The University of New South Wales)

  • Hongyuan Yang

    (The University of New South Wales)

  • Catherine C. L. Wong

    (Peking University)

  • Nieng Yan

    (Princeton University)

Abstract

As members of the membrane-bound O-acyltransferase (MBOAT) enzyme family, acyl-coenzyme A:cholesterol acyltransferases (ACATs) catalyse the transfer of an acyl group from acyl-coenzyme A to cholesterol to generate cholesteryl ester, the primary form in which cholesterol is stored in cells and transported in plasma1. ACATs have gained attention as potential drug targets for the treatment of diseases such as atherosclerosis, Alzheimer’s disease and cancer2–7. Here we present the cryo-electron microscopy structure of human ACAT1 as a dimer of dimers. Each protomer consists of nine transmembrane segments, which enclose a cytosolic tunnel and a transmembrane tunnel that converge at the predicted catalytic site. Evidence from structure-guided mutational analyses suggests that acyl-coenzyme A enters the active site through the cytosolic tunnel, whereas cholesterol may enter from the side through the transmembrane tunnel. This structural and biochemical characterization helps to rationalize the preference of ACAT1 for unsaturated acyl chains, and provides insight into the catalytic mechanism of enzymes within the MBOAT family8.

Suggested Citation

  • Hongwu Qian & Xin Zhao & Renhong Yan & Xia Yao & Shuai Gao & Xue Sun & Ximing Du & Hongyuan Yang & Catherine C. L. Wong & Nieng Yan, 2020. "Structural basis for catalysis and substrate specificity of human ACAT1," Nature, Nature, vol. 581(7808), pages 333-338, May.
    • Handle: RePEc:nat:nature:v:581:y:2020:i:7808:d:10.1038_s41586-020-2290-0
    DOI: 10.1038/s41586-020-2290-0
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    Cited by:

    1. 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.
    2. Iris D. Zelnik & Beatriz Mestre & Jonathan J. Weinstein & Tamir Dingjan & Stav Izrailov & Shifra Ben-Dor & Sarel J. Fleishman & Anthony H. Futerman, 2023. "Computational design and molecular dynamics simulations suggest the mode of substrate binding in ceramide synthases," Nature Communications, Nature, vol. 14(1), pages 1-6, December.
    3. Yang, Ruiyue & Hong, Chunyang & Liu, Wei & Wu, Xiaoguang & Wang, Tianyu & Huang, Zhongwei, 2021. "Non-contaminating cryogenic fluid access to high-temperature resources: Liquid nitrogen fracturing in a lab-scale Enhanced Geothermal System," Renewable Energy, Elsevier, vol. 165(P1), pages 125-138.

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