 Tethered peptide activation mechanism of the adhesion GPCRs ADGRG2 and ADGRG4Peng 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,
Yan Lu,
Shao-Long Li,
Jun-Yan He,
Chuanxin Wang,
Lei Zhang (),
Liangliang Kong (),
Jin-Peng Sun () and
Xiao Yu ()
Nature, 2022, vol. 604, issue 7907, 771-778 Abstract: Abstract Adhesion G protein-coupled receptors (aGPCRs) constitute an evolutionarily ancient family of receptors that often undergo autoproteolysis to produce α and β subunits1–3. A tethered agonism mediated by the ‘Stachel sequence’ of the β subunit has been proposed to have central roles in aGPCR activation4–6. Here we present three cryo-electron microscopy structures of aGPCRs coupled to the Gs heterotrimer. Two of these aGPCRs are activated by tethered Stachel sequences—the ADGRG2-β–Gs complex and the ADGRG4-β–Gs complex (in which β indicates the β subunit of the aGPCR)—and the other is the full-length ADGRG2 in complex with the exogenous ADGRG2 Stachel-sequence-derived peptide agonist IP15 (ADGRG2(FL)–IP15–Gs). The Stachel sequences of both ADGRG2-β and ADGRG4-β assume a U shape and insert deeply into the seven-transmembrane bundles. Constituting the FXφφφXφ motif (in which φ represents a hydrophobic residue), five residues of ADGRG2-β or ADGRG4-β extend like fingers to mediate binding to the seven-transmembrane domain and activation of the receptor. The structure of the ADGRG2(FL)–IP15–Gs complex reveals the structural basis for the improved binding affinity of IP15 compared with VPM–p15 and indicates that rational design of peptidic agonists could be achieved by exploiting aGPCR-β structures. By converting the ‘finger residues’ to acidic residues, we develop a method to generate peptidic antagonists towards several aGPCRs. Collectively, our study provides structural and biochemical insights into the tethered activation mechanism of aGPCRs. Date: 2022 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:604:y:2022:i:7907:d:10.1038_s41586-022-04590-8 Ordering information: This journal article can be ordered from DOI: 10.1038/s41586-022-04590-8 Access Statistics for this article Nature is currently edited by Magdalena Skipper More articles in Nature from Nature |
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