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Structure and catalytic mechanism of a human triacylglycerol-synthesis enzyme

Author

Listed:
  • Xuewu Sui

    (Harvard T. H. Chan School of Public Health
    Harvard Medical School)

  • Kun Wang

    (Harvard T. H. Chan School of Public Health
    Harvard Medical School)

  • Nina L. Gluchowski

    (Harvard T. H. Chan School of Public Health
    Harvard Medical School
    Hepatology, and Nutrition, Boston Children’s Hospital)

  • Shane D. Elliott

    (Harvard T. H. Chan School of Public Health
    Harvard Medical School)

  • Maofu Liao

    (Harvard Medical School)

  • Tobias C. Walther

    (Harvard T. H. Chan School of Public Health
    Harvard Medical School
    Broad Institute of MIT and Harvard
    Howard Hughes Medical Institute)

  • Robert V. Farese

    (Harvard T. H. Chan School of Public Health
    Harvard Medical School
    Broad Institute of MIT and Harvard)

Abstract

Triacylglycerols store metabolic energy in organisms and have industrial uses as foods and fuels. Excessive accumulation of triacylglycerols in humans causes obesity and is associated with metabolic diseases1. Triacylglycerol synthesis is catalysed by acyl-CoA diacylglycerol acyltransferase (DGAT) enzymes2–4, the structures and catalytic mechanisms of which remain unknown. Here we determined the structure of dimeric human DGAT1, a member of the membrane-bound O-acyltransferase (MBOAT) family, by cryo-electron microscopy at approximately 3.0 Å resolution. DGAT1 forms a homodimer through N-terminal segments and a hydrophobic interface, with putative active sites within the membrane region. A structure obtained with oleoyl-CoA substrate resolved at approximately 3.2 Å shows that the CoA moiety binds DGAT1 on the cytosolic side and the acyl group lies deep within a hydrophobic channel, positioning the acyl-CoA thioester bond near an invariant catalytic histidine residue. The reaction centre is located inside a large cavity, which opens laterally to the membrane bilayer, providing lipid access to the active site. A lipid-like density—possibly representing an acyl-acceptor molecule—is located within the reaction centre, orthogonal to acyl-CoA. Insights provided by the DGAT1 structures, together with mutagenesis and functional studies, provide the basis for a model of the catalysis of triacylglycerol synthesis by DGAT.

Suggested Citation

  • Xuewu Sui & Kun Wang & Nina L. Gluchowski & Shane D. Elliott & Maofu Liao & Tobias C. Walther & Robert V. Farese, 2020. "Structure and catalytic mechanism of a human triacylglycerol-synthesis enzyme," Nature, Nature, vol. 581(7808), pages 323-328, May.
  • Handle: RePEc:nat:nature:v:581:y:2020:i:7808:d:10.1038_s41586-020-2289-6
    DOI: 10.1038/s41586-020-2289-6
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    Citations

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    Cited by:

    1. Dianne Lumaquin-Yin & Emily Montal & Eleanor Johns & Arianna Baggiolini & Ting-Hsiang Huang & Yilun Ma & Charlotte LaPlante & Shruthy Suresh & Lorenz Studer & Richard M. White, 2023. "Lipid droplets are a metabolic vulnerability in melanoma," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Qing Zhang & Deqiang Yao & Bing Rao & Liyan Jian & Yang Chen & Kexin Hu & Ying Xia & Shaobai Li & Yafeng Shen & An Qin & Jie Zhao & Lu Zhou & Ming Lei & Xian-Cheng Jiang & Yu Cao, 2021. "The structural basis for the phospholipid remodeling by lysophosphatidylcholine acyltransferase 3," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    3. Shuhui Wang & Kun Wang & Kangkang Song & Zon Weng Lai & Pengfei Li & Dongying Li & Yajie Sun & Ye Mei & Chen Xu & Maofu Liao, 2024. "Structures of the Mycobacterium tuberculosis efflux pump EfpA reveal the mechanisms of transport and inhibition," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    4. 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.
    5. Xinli Dai & Xuanzhong Liu & Jialu Li & Hui Chen & Chuangye Yan & Yaozong Li & Hanmin Liu & Dong Deng & Xiang Wang, 2024. "Structural insights into the inhibition mechanism of fungal GWT1 by manogepix," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    6. 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.
    7. 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.
    8. 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.

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