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Structural basis of tethered agonism of the adhesion GPCRs ADGRD1 and ADGRF1

Author

Listed:
  • Xiangli Qu

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

  • Na Qiu

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

  • Mu Wang

    (Chinese Academy of Sciences
    ShanghaiTech University)

  • Bingjie Zhang

    (ShanghaiTech University)

  • Juan Du

    (University of Chinese Academy of Sciences)

  • Zhiwei Zhong

    (Nanjing University of Chinese Medicine)

  • Wei Xu

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

  • Xiaojing Chu

    (Chinese Academy of Sciences)

  • Limin Ma

    (Chinese Academy of Sciences)

  • Cuiying Yi

    (Chinese Academy of Sciences)

  • Shuo Han

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

  • Wenqing Shui

    (ShanghaiTech University)

  • Qiang Zhao

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    Shanghai Institute of Materia Medica, Chinese Academy of Sciences)

  • Beili Wu

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

Abstract

Adhesion G protein-coupled receptors (aGPCRs) are essential for a variety of physiological processes such as immune responses, organ development, cellular communication, proliferation and homeostasis1–7. An intrinsic manner of activation that involves a tethered agonist in the N-terminal region of the receptor has been proposed for the aGPCRs8,9, but its molecular mechanism remains elusive. Here we report the G protein-bound structures of ADGRD1 and ADGRF1, which exhibit many unique features with regard to the tethered agonism. The stalk region that proceeds the first transmembrane helix acts as the tethered agonist by forming extensive interactions with the transmembrane domain; these interactions are mostly conserved in ADGRD1 and ADGRF1, suggesting that a common stalk–transmembrane domain interaction pattern is shared by members of the aGPCR family. A similar stalk binding mode is observed in the structure of autoproteolysis-deficient ADGRF1, supporting a cleavage-independent manner of receptor activation. The stalk-induced activation is facilitated by a cascade of inter-helix interaction cores that are conserved in positions but show sequence variability in these two aGPCRs. Furthermore, the intracellular region of ADGRF1 contains a specific lipid-binding site, which proves to be functionally important and may serve as the recognition site for the previously discovered endogenous ADGRF1 ligand synaptamide. These findings highlight the diversity and complexity of the signal transduction mechanisms of the aGPCRs.

Suggested Citation

  • Xiangli Qu & Na Qiu & Mu Wang & Bingjie Zhang & Juan Du & Zhiwei Zhong & Wei Xu & Xiaojing Chu & Limin Ma & Cuiying Yi & Shuo Han & Wenqing Shui & Qiang Zhao & Beili Wu, 2022. "Structural basis of tethered agonism of the adhesion GPCRs ADGRD1 and ADGRF1," Nature, Nature, vol. 604(7907), pages 779-785, April.
  • Handle: RePEc:nat:nature:v:604:y:2022:i:7907:d:10.1038_s41586-022-04580-w
    DOI: 10.1038/s41586-022-04580-w
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    Cited by:

    1. Szymon P. Kordon & Przemysław Dutka & Justyna M. Adamska & Sumit J. Bandekar & Katherine Leon & Satchal K. Erramilli & Brock Adams & Jingxian Li & Anthony A. Kossiakoff & Demet Araç, 2023. "Isoform- and ligand-specific modulation of the adhesion GPCR ADGRL3/Latrophilin3 by a synthetic binder," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Xinyan Zhu & Yu Qian & Xiaowan Li & Zhenmei Xu & Ruixue Xia & Na Wang & Jiale Liang & Han Yin & Anqi Zhang & Changyou Guo & Guangfu Wang & Yuanzheng He, 2022. "Structural basis of adhesion GPCR GPR110 activation by stalk peptide and G-proteins coupling," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    3. Jiale Liang & Asuka Inoue & Tatsuya Ikuta & Ruixue Xia & Na Wang & Kouki Kawakami & Zhenmei Xu & Yu Qian & Xinyan Zhu & Anqi Zhang & Changyou Guo & Zhiwei Huang & Yuanzheng He, 2023. "Structural basis of lysophosphatidylserine receptor GPR174 ligand recognition and activation," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    4. Daniel T. D. Jones & Andrew N. Dates & Shaun D. Rawson & Maggie M. Burruss & Colin H. Lipper & Stephen C. Blacklow, 2023. "Tethered agonist activated ADGRF1 structure and signalling analysis reveal basis for G protein coupling," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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