Structural basis of adhesion GPCR GPR110 activation by stalk peptide and G-proteins coupling

Xinyan Zhu, Yu Qian, Xiaowan Li, Zhenmei Xu, Ruixue Xia, Na Wang, Jiale Liang, Han Yin, Anqi Zhang, Changyou Guo, Guangfu Wang and Yuanzheng He ()
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Xinyan Zhu: Laboratory of Receptor Structure and Signaling, HIT Center for Life Sciences, Harbin Institute of Technology
Yu Qian: Laboratory of Receptor Structure and Signaling, HIT Center for Life Sciences, Harbin Institute of Technology
Xiaowan Li: Laboratory of Neuroscience, HIT Center for Life Sciences, Harbin Institute of Technology
Zhenmei Xu: Laboratory of Receptor Structure and Signaling, HIT Center for Life Sciences, Harbin Institute of Technology
Ruixue Xia: Laboratory of Receptor Structure and Signaling, HIT Center for Life Sciences, Harbin Institute of Technology
Na Wang: Laboratory of Receptor Structure and Signaling, HIT Center for Life Sciences, Harbin Institute of Technology
Jiale Liang: Laboratory of Receptor Structure and Signaling, HIT Center for Life Sciences, Harbin Institute of Technology
Han Yin: Laboratory of Receptor Structure and Signaling, HIT Center for Life Sciences, Harbin Institute of Technology
Anqi Zhang: HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology
Changyou Guo: HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology
Guangfu Wang: Laboratory of Neuroscience, HIT Center for Life Sciences, Harbin Institute of Technology
Yuanzheng He: Laboratory of Receptor Structure and Signaling, HIT Center for Life Sciences, Harbin Institute of Technology

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract Adhesion G protein-coupled receptors (aGPCRs) are keys of many physiological events and attractive targets for various diseases. aGPCRs are also known to be capable of self-activation via an autoproteolysis process that removes the inhibitory GAIN domain on the extracellular side of receptor and releases a stalk peptide to bind and activate the transmembrane side of receptor. However, the detailed mechanism of aGPCR activation remains elusive. Here, we report the cryo-electron microscopy structures of GPR110 (ADGRF1), a member of aGPCR, in complex with Gq, Gs, Gi, G12 and G13. The structures reveal distinctive ligand engaging model and activation conformations of GPR110. The structures also unveil the rarely explored GPCR/G12 and GPCR/G13 engagements. A comparison of Gq, Gs, Gi, G12 and G13 engagements with GPR110 reveals details of G-protein engagement, including a dividing point at the far end of the alpha helix 5 (αH5) of Gα subunit that separates Gq/Gs engagements from Gi/G12/G13 engagements. This is also where Gq/Gs bind the receptor through both hydrophobic and polar interaction, while Gi/G12/G13 engage receptor mainly through hydrophobic interaction. We further provide physiological evidence of GPR110 activation via stalk peptide. Taken together, our study fills the missing information of GPCR/G-protein engagement and provides a framework for understanding aGPCR activation and GPR110 signaling.

Date: 2022
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DOI: 10.1038/s41467-022-33173-4

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