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

• Published in: Nature communications Vol. 13; no. 1; p. 5513
• Main Authors: Zhu, Xinyan, Qian, Yu, Li, Xiaowan, Xu, Zhenmei, Xia, Ruixue, Wang, Na, Liang, Jiale, Yin, Han, Zhang, Anqi, Guo, Changyou, Wang, Guangfu, He, Yuanzheng
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.09.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 101/28; 631/535/1258/1259; 631/80/86/2363; 82/80; Adhesion; Coupling; Electron microscopy; G protein-coupled receptors; Humanities and Social Sciences; Hydrophobicity; multidisciplinary; Peptides; Physiology; Proteins; Receptors; Science; Science (multidisciplinary); Selectivity
• DOI: 10.1038/s41467-022-33173-4
• ISSN: 2041-1723

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 G q , G s , G i , G 12 and G 13. The structures reveal distinctive ligand engaging model and activation conformations of GPR110. The structures also unveil the rarely explored GPCR/G 12 and GPCR/G 13 engagements. A comparison of G q , G s , G i , G 12 and G 13 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 G q /G s engagements from G i /G 12 /G 13 engagements. This is also where G q /G s bind the receptor through both hydrophobic and polar interaction, while G i /G 12 /G 13 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. aGPCRs play key roles in multiple physiological processes. Here the authors report cryo-EM structures of GPR110 in complexes with G q , G s , G i , G 12 and G 13 protein to reveal a detailed mechanism of aGPCR activation via the tethered stalk peptide and principles of G-protein coupling and selectivity on GPR110.