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Structural insights into FSP1 catalysis and ferroptosis inhibition

Author

Listed:
  • Yun Lv

    (Shandong University)

  • Chunhui Liang

    (Shandong University)

  • Qichao Sun

    (Shandong University)

  • Jing Zhu

    (Shandong University)

  • Haiyan Xu

    (Shandong University)

  • Xiaoqing Li

    (Shandong University)

  • Yao-yao Li

    (Shandong University)

  • Qihai Wang

    (Jingchu University of Technology)

  • Huiqing Yuan

    (Shandong University
    Shandong University)

  • Bo Chu

    (Shandong University)

  • Deyu Zhu

    (Shandong University)

Abstract

Ferroptosis suppressor protein 1 (FSP1, also known as AIMF2, AMID or PRG3) is a recently identified glutathione-independent ferroptosis suppressor1–3, but its underlying structural mechanism remains unknown. Here we report the crystal structures of Gallus gallus FSP1 in its substrate-free and ubiquinone-bound forms. The structures reveal a FAD-binding domain and a NAD(P)H-binding domain, both of which are shared with AIF and NADH oxidoreductases4–9, and a characteristic carboxy-terminal domain as well. We demonstrate that the carboxy-terminal domain is crucial for the catalytic activity and ferroptosis inhibition of FSP1 by mediating the functional dimerization of FSP1, and the formation of two active sites located on two sides of FAD, which are responsible for ubiquinone reduction and a unique FAD hydroxylation respectively. We also identify that FSP1 can catalyze the production of H2O2 and the conversion of FAD to 6-hydroxy-FAD in the presence of oxygen and NAD(P)H in vitro, and 6-hydroxy-FAD directly inhibits ferroptosis in cells. Together, these findings further our understanding on the catalytic and ferroptosis suppression mechanisms of FSP1 and establish 6-hydroxy-FAD as an active cofactor in FSP1 and a potent radical-trapping antioxidant in ferroptosis inhibition.

Suggested Citation

  • Yun Lv & Chunhui Liang & Qichao Sun & Jing Zhu & Haiyan Xu & Xiaoqing Li & Yao-yao Li & Qihai Wang & Huiqing Yuan & Bo Chu & Deyu Zhu, 2023. "Structural insights into FSP1 catalysis and ferroptosis inhibition," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41626-7
    DOI: 10.1038/s41467-023-41626-7
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    References listed on IDEAS

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    1. Sebastian Doll & Florencio Porto Freitas & Ron Shah & Maceler Aldrovandi & Milene Costa Silva & Irina Ingold & Andrea Goya Grocin & Thamara Nishida Xavier da Silva & Elena Panzilius & Christina H. Sch, 2019. "FSP1 is a glutathione-independent ferroptosis suppressor," Nature, Nature, vol. 575(7784), pages 693-698, November.
    2. Yue Feng & Wenfei Li & Jian Li & Jiawei Wang & Jingpeng Ge & Duo Xu & Yanjing Liu & Kaiqi Wu & Qingyin Zeng & Jia-Wei Wu & Changlin Tian & Bing Zhou & Maojun Yang, 2012. "Structural insight into the type-II mitochondrial NADH dehydrogenases," Nature, Nature, vol. 491(7424), pages 478-482, November.
    3. Eikan Mishima & Junya Ito & Zijun Wu & Toshitaka Nakamura & Adam Wahida & Sebastian Doll & Wulf Tonnus & Palina Nepachalovich & Elke Eggenhofer & Maceler Aldrovandi & Bernhard Henkelmann & Ken-ichi Ya, 2022. "A non-canonical vitamin K cycle is a potent ferroptosis suppressor," Nature, Nature, vol. 608(7924), pages 778-783, August.
    4. Kirill Bersuker & Joseph M. Hendricks & Zhipeng Li & Leslie Magtanong & Breanna Ford & Peter H. Tang & Melissa A. Roberts & Bingqi Tong & Thomas J. Maimone & Roberto Zoncu & Michael C. Bassik & Daniel, 2019. "The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis," Nature, Nature, vol. 575(7784), pages 688-692, November.
    5. Chao Mao & Xiaoguang Liu & Yilei Zhang & Guang Lei & Yuelong Yan & Hyemin Lee & Pranavi Koppula & Shiqi Wu & Li Zhuang & Bingliang Fang & Masha V. Poyurovsky & Kellen Olszewski & Boyi Gan, 2021. "DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer," Nature, Nature, vol. 593(7860), pages 586-590, May.
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