Structural basis for the tethered peptide activation of adhesion GPCRs

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-Lai Zhang, Zhong-Liang Zhu, Yi Jiang, Lutao Du, Shi-Qing Feng, Torsten Schöneberg, Ines Liebscher (), H. Eric Xu () and Jin-Peng Sun ()
Additional contact information
Yu-Qi Ping: Shandong University
Peng Xiao: Shandong University
Fan Yang: Shandong University
Ru-Jia Zhao: Shandong University
Sheng-Chao Guo: Shandong University
Xu Yan: Shandong University
Xiang Wu: Shandong University
Chao Zhang: Shandong University
Yan Lu: Shandong University
Fenghui Zhao: Chinese Academy of Sciences
Fulai Zhou: Chinese Academy of Sciences
Yue-Tong Xi: Shandong University
Wanchao Yin: Chinese Academy of Sciences
Feng-Zhen Liu: Shandong University
Dong-Fang He: Shandong University
Dao-Lai Zhang: Binzhou Medical University
Zhong-Liang Zhu: University of Science and Technology of China
Yi Jiang: Chinese Academy of Sciences
Lutao Du: Shandong University
Shi-Qing Feng: Shandong University
Torsten Schöneberg: Rudolf Schönheimer Institute of Biochemistry
Ines Liebscher: Rudolf Schönheimer Institute of Biochemistry
H. Eric Xu: Chinese Academy of Sciences
Jin-Peng Sun: Shandong University

Nature, 2022, vol. 604, issue 7907, 763-770

Abstract: Abstract Adhesion G-protein-coupled receptors (aGPCRs) are important for organogenesis, neurodevelopment, reproduction and other processes1–6. Many aGPCRs are activated by a conserved internal (tethered) agonist sequence known as the Stachel sequence7–12. Here, we report the cryogenic electron microscopy (cryo-EM) structures of two aGPCRs in complex with Gs: GPR133 and GPR114. The structures indicate that the Stachel sequences of both receptors assume an α-helical–bulge–β-sheet structure and insert into a binding site formed by the transmembrane domain (TMD). A hydrophobic interaction motif (HIM) within the Stachel sequence mediates most of the intramolecular interactions with the TMD. Combined with the cryo-EM structures, biochemical characterization of the HIM motif provides insight into the cross-reactivity and selectivity of the Stachel sequences. Two interconnected mechanisms, the sensing of Stachel sequences by the conserved ‘toggle switch’ W6.53 and the constitution of a hydrogen-bond network formed by Q7.49/Y7.49 and the P6.47/V6.47φφG6.50 motif (φ indicates a hydrophobic residue), are important in Stachel sequence-mediated receptor activation and Gs coupling. Notably, this network stabilizes kink formation in TM helices 6 and 7 (TM6 and TM7, respectively). A common Gs-binding interface is observed between the two aGPCRs, and GPR114 has an extended TM7 that forms unique interactions with Gs. Our structures reveal the detailed mechanisms of aGPCR activation by Stachel sequences and their Gs coupling.

Date: 2022
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DOI: 10.1038/s41586-022-04619-y

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