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Structural basis of FPR2 in recognition of Aβ42 and neuroprotection by humanin

Author

Listed:
  • Ya Zhu

    (Chinese Academy of Sciences)

  • Xiaowen Lin

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Xin Zong

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Shuo Han

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Mu Wang

    (Chinese Academy of Sciences
    ShanghaiTech University)

  • Yuxuan Su

    (China Pharmaceutical University)

  • Limin Ma

    (Chinese Academy of Sciences)

  • Xiaojing Chu

    (Chinese Academy of Sciences)

  • Cuiying Yi

    (Chinese Academy of Sciences)

  • Qiang Zhao

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, CAS)

  • Beili Wu

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    ShanghaiTech University)

Abstract

Formyl peptide receptor 2 (FPR2) has been shown to mediate the cytotoxic effects of the β amyloid peptide Aβ42 and serves as a receptor for humanin, a peptide that protects neuronal cells from damage by Aβ42, implying its involvement in the pathogenesis of Alzheimer’s disease (AD). However, the interaction pattern between FPR2 and Aβ42 or humanin remains unknown. Here we report the structures of FPR2 bound to Gi and Aβ42 or N-formyl humanin (fHN). Combined with functional data, the structures reveal two critical regions that govern recognition and activity of Aβ42 and fHN, including a polar binding cavity within the receptor helical bundle and a hydrophobic binding groove in the extracellular region. In addition, the structures of FPR2 and FPR1 in complex with different formyl peptides were determined, providing insights into ligand recognition and selectivity of the FPR family. These findings uncover key factors that define the functionality of FPR2 in AD and other inflammatory diseases and would enable drug development.

Suggested Citation

  • Ya Zhu & Xiaowen Lin & Xin Zong & Shuo Han & Mu Wang & Yuxuan Su & Limin Ma & Xiaojing Chu & Cuiying Yi & Qiang Zhao & Beili Wu, 2022. "Structural basis of FPR2 in recognition of Aβ42 and neuroprotection by humanin," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29361-x
    DOI: 10.1038/s41467-022-29361-x
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    References listed on IDEAS

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    Cited by:

    1. Geng Chen & Xiankun Wang & Qiwen Liao & Yunjun Ge & Haizhan Jiao & Qiang Chen & Yezhou Liu & Wenping Lyu & Lizhe Zhu & Gydo C. P. Zundert & Michael J. Robertson & Georgios Skiniotis & Yang Du & Hongli, 2022. "Structural basis for recognition of N-formyl peptides as pathogen-associated molecular patterns," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Yan Chen & Qingtong Zhou & Jiang Wang & Youwei Xu & Yun Wang & Jiahui Yan & Yibing Wang & Qi Zhu & Fenghui Zhao & Chenghao Li & Chuan-Wei Chen & Xiaoqing Cai & Ross A .D. Bathgate & Chun Shen & H. Eri, 2023. "Ligand recognition mechanism of the human relaxin family peptide receptor 4 (RXFP4)," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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