{"title":"粘附 G 蛋白偶联受体中系留激动剂信号的异质性","authors":"","doi":"10.1016/j.chembiol.2024.03.004","DOIUrl":null,"url":null,"abstract":"<div><p><span><span><span>Adhesion G protein-coupled receptor (aGPCR) signaling influences development and homeostasis<span> in a wide range of tissues. In the current model for aGPCR signaling, ligand binding liberates a </span></span>conserved sequence<span> 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 </span></span>fusion protein platform. Strikingly, only ∼50% of aGPCRs exhibited robust TA-dependent activation, and unlike other GPCR families, aGPCRs showed a notable preference for G</span><sub>12/13</sub> 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.</p></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"31 8","pages":"Pages 1542-1553.e4"},"PeriodicalIF":6.6000,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Heterogeneity of tethered agonist signaling in adhesion G protein-coupled receptors\",\"authors\":\"\",\"doi\":\"10.1016/j.chembiol.2024.03.004\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p><span><span><span>Adhesion G protein-coupled receptor (aGPCR) signaling influences development and homeostasis<span> in a wide range of tissues. In the current model for aGPCR signaling, ligand binding liberates a </span></span>conserved sequence<span> 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 </span></span>fusion protein platform. Strikingly, only ∼50% of aGPCRs exhibited robust TA-dependent activation, and unlike other GPCR families, aGPCRs showed a notable preference for G</span><sub>12/13</sub> 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.</p></div>\",\"PeriodicalId\":265,\"journal\":{\"name\":\"Cell Chemical Biology\",\"volume\":\"31 8\",\"pages\":\"Pages 1542-1553.e4\"},\"PeriodicalIF\":6.6000,\"publicationDate\":\"2024-08-15\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell Chemical Biology\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S245194562400120X\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Chemical Biology","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S245194562400120X","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
粘附 G 蛋白偶联受体(aGPCR)信号传导影响着多种组织的发育和稳态。在目前的 aGPCR 信号传导模型中,配体结合会释放出一个保守序列,该序列可充当分子内的系链激动剂(TA),但这一模型尚未针对所有 aGPCR 进行过系统评估。在这里,我们利用一个新的融合蛋白平台,在一系列转录报告、G 蛋白激活和 β - 逮捕素招募试验中评估了所有 33 个 aGPCR 的 TA 依赖性活性。令人吃惊的是,只有 50% 的 aGPCR 表现出强大的 TA 依赖性激活,而且与其他 GPCR 家族不同,aGPCR 对 G12/13 信号转导表现出明显的偏好。AlphaFold2 预测评估了 TA 在预测的分子内结合口袋中的参与情况,这与细胞反应的 TA 依赖性相一致。该数据集提供了一个全面的资源,为研究所有人类 aGPCRs 和治疗 aGPCRs 提供了信息。
Heterogeneity of tethered agonist signaling in adhesion G protein-coupled receptors
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.
Cell Chemical BiologyBiochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
14.70
自引率
2.30%
发文量
143
期刊介绍:
Cell Chemical Biology, a Cell Press journal established in 1994 as Chemistry & Biology, focuses on publishing crucial advances in chemical biology research with broad appeal to our diverse community, spanning basic scientists to clinicians. Pioneering investigations at the chemistry-biology interface, the journal fosters collaboration between these disciplines. We encourage submissions providing significant conceptual advancements of broad interest across chemical, biological, clinical, and related fields. Particularly sought are articles utilizing chemical tools to perturb, visualize, and measure biological systems, offering unique insights into molecular mechanisms, disease biology, and therapeutics.