G蛋白偶联受体
兴奋剂
受体
细胞生物学
G蛋白
信号转导
逮捕
化学
生物
生物化学
作者
Andrew N. Dates,Daniel T.D. Jones,Jeffrey S. Smith,Meredith A. Skiba,Maria F. Rich,Maggie M. Burruss,Andrew C. Kruse,Stephen C. Blacklow
标识
DOI:10.1016/j.chembiol.2024.03.004
摘要
Summary
Adhesion G protein-coupled receptor (aGPCR) signaling influences development and homeostasis in a wide range of tissues. In the current model for aGPCR signaling, ligand binding liberates a conserved sequence that acts as an intramolecular, tethered agonist (TA), yet this model has not been evaluated systematically for all aGPCRs. Here, we assessed the TA-dependent activities of all 33 aGPCRs in a suite of transcriptional reporter, G protein activation, and β-arrestin recruitment assays using a new fusion protein platform. Strikingly, only ∼50% of aGPCRs exhibited robust TA-dependent activation, and unlike other GPCR families, aGPCRs showed a notable preference for G12/13 signaling. AlphaFold2 predictions assessing TA engagement in the predicted intramolecular binding pocket aligned with the TA dependence of the cellular responses. This dataset provides a comprehensive resource to inform the investigation of all human aGPCRs and for targeting aGPCRs therapeutically.
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