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Structure and mechanism of human diacylglycerol O-acyltransferase 1

Author

Listed:
  • Lie Wang

    (Baylor College of Medicine)

  • Hongwu Qian

    (Princeton University)

  • Yin Nian

    (Baylor College of Medicine
    Chinese Academy of Sciences)

  • Yimo Han

    (Princeton University
    Rice University)

  • Zhenning Ren

    (Baylor College of Medicine)

  • Hanzhi Zhang

    (Baylor College of Medicine)

  • Liya Hu

    (Baylor College of Medicine)

  • B. V. Venkataram Prasad

    (Baylor College of Medicine)

  • Arthur Laganowsky

    (Texas A&M University)

  • Nieng Yan

    (Princeton University)

  • Ming Zhou

    (Baylor College of Medicine)

Abstract

Diacylglycerol O-acyltransferase 1 (DGAT1) synthesizes triacylglycerides and is required for dietary fat absorption and fat storage in humans1. DGAT1 belongs to the membrane-bound O-acyltransferase (MBOAT) superfamily, members of which are found in all kingdoms of life and are involved in the acylation of lipids and proteins2,3. How human DGAT1 and other mammalian members of the MBOAT family recognize their substrates and catalyse their reactions is unknown. The absence of three-dimensional structures also hampers rational targeting of DGAT1 for therapeutic purposes. Here we present the cryo-electron microscopy structure of human DGAT1 in complex with an oleoyl-CoA substrate. Each DGAT1 protomer has nine transmembrane helices, eight of which form a conserved structural fold that we name the MBOAT fold. The MBOAT fold in DGAT1 forms a hollow chamber in the membrane that encloses highly conserved catalytic residues. The chamber has separate entrances for each of the two substrates, fatty acyl-CoA and diacylglycerol. DGAT1 can exist as either a homodimer or a homotetramer and the two forms have similar enzymatic activity. The N terminus of DGAT1 interacts with the neighbouring protomer and these interactions are required for enzymatic activity.

Suggested Citation

  • Lie Wang & Hongwu Qian & Yin Nian & Yimo Han & Zhenning Ren & Hanzhi Zhang & Liya Hu & B. V. Venkataram Prasad & Arthur Laganowsky & Nieng Yan & Ming Zhou, 2020. "Structure and mechanism of human diacylglycerol O-acyltransferase 1," Nature, Nature, vol. 581(7808), pages 329-332, May.
  • Handle: RePEc:nat:nature:v:581:y:2020:i:7808:d:10.1038_s41586-020-2280-2
    DOI: 10.1038/s41586-020-2280-2
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    Cited by:

    1. Yong Jiang & Zhong Zhuang & Wenqian Jia & Ming Xie & Zhengkui Zhou & Jing Tang & Hao Bai & Guobin Chang & Guohong Chen & Shuisheng Hou, 2022. "Comparative Transcriptome Analysis Reveals the Key Genes Involved in Lipid Deposition in Pekin Ducks ( Anas platyrhynchos domesticus )," Agriculture, MDPI, vol. 12(11), pages 1-19, October.
    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. 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.
    4. Lie Wang & Ming Zhou, 2023. "Structure of a eukaryotic cholinephosphotransferase-1 reveals mechanisms of substrate recognition and catalysis," Nature Communications, Nature, vol. 14(1), pages 1-8, 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. 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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