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Tethered agonist activated ADGRF1 structure and signalling analysis reveal basis for G protein coupling

Author

Listed:
  • Daniel T. D. Jones

    (Harvard Medical School)

  • Andrew N. Dates

    (Harvard Medical School)

  • Shaun D. Rawson

    (Harvard Medical School)

  • Maggie M. Burruss

    (Harvard Medical School)

  • Colin H. Lipper

    (Harvard Medical School)

  • Stephen C. Blacklow

    (Harvard Medical School
    Dana Farber Cancer Institute)

Abstract

Adhesion G Protein Coupled Receptors (aGPCRs) have evolved an activation mechanism to translate extracellular force into liberation of a tethered agonist (TA) to effect cell signalling. We report here that ADGRF1 can signal through all major G protein classes and identify the structural basis for a previously reported Gαq preference by cryo-EM. Our structure shows that Gαq preference in ADGRF1 may derive from tighter packing at the conserved F569 of the TA, altering contacts between TM helix I and VII, with a concurrent rearrangement of TM helix VII and helix VIII at the site of Gα recruitment. Mutational studies of the interface and of contact residues within the 7TM domain identify residues critical for signalling, and suggest that Gαs signalling is more sensitive to mutation of TA or binding site residues than Gαq. Our work advances the detailed molecular understanding of aGPCR TA activation, identifying features that potentially explain preferential signal modulation.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38083-7
    DOI: 10.1038/s41467-023-38083-7
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    1. Manuel Grundmann & Nicole Merten & Davide Malfacini & Asuka Inoue & Philip Preis & Katharina Simon & Nelly Rüttiger & Nicole Ziegler & Tobias Benkel & Nina Katharina Schmitt & Satoru Ishida & Ines Mül, 2018. "Lack of beta-arrestin signaling in the absence of active G proteins," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
    2. Yu-Qi Ping & Peng Xiao & Fan Yang & Ru-Jia Zhao & Sheng-Chao Guo & Xu Yan & Xiang Wu & Chao Zhang & Yan Lu & Fenghui Zhao & Fulai Zhou & Yue-Tong Xi & Wanchao Yin & Feng-Zhen Liu & Dong-Fang He & Dao-, 2022. "Structural basis for the tethered peptide activation of adhesion GPCRs," Nature, Nature, vol. 604(7907), pages 763-770, April.
    3. 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.
    4. 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.
    5. Peng Xiao & Shengchao Guo & Xin Wen & Qing-Tao He & Hui Lin & Shen-Ming Huang & Lu Gou & Chao Zhang & Zhao Yang & Ya-Ni Zhong & Chuan-Cheng Yang & Yu Li & Zheng Gong & Xiao-Na Tao & Zhi-Shuai Yang & Y, 2022. "Tethered peptide activation mechanism of the adhesion GPCRs ADGRG2 and ADGRG4," Nature, Nature, vol. 604(7907), pages 771-778, April.
    6. Ji-Won Lee & Bill X. Huang & HeungSun Kwon & Md Abdur Rashid & Giorgi Kharebava & Abhishek Desai & Samarjit Patnaik & Juan Marugan & Hee-Yong Kim, 2016. "Orphan GPR110 (ADGRF1) targeted by N-docosahexaenoylethanolamine in development of neurons and cognitive function," Nature Communications, Nature, vol. 7(1), pages 1-16, December.
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