Differential Requirement of the Extracellular Domain in Activation of Class B G Protein-coupled Receptors

• DOI: 10.1074/jbc.m116.726620
• Publication Date: 2016-05-14T00:17:50Z
• Authors: Li-Hua Zhao; Yanting Yin; Dehua Yang; Bo Liu; Li Hou; Xiaoxi Wang; Kuntal Pal; Yi Jiang; Yang Feng; Xiaoqing Cai; Antao Dai; Mingyao Liu; Ming-Wei Wang; Karsten Melcher; H.Eric Xu
• Keywords: Rhodopsin-like receptors; Parathyroid hormone receptor

G protein-coupled receptors (GPCRs) from the secretin-like (class B) family are key players in hormonal homeostasis and important drug targets for treatment of metabolic disorders neuronal diseases. They consist a large N-terminal extracellular domain (ECD) transmembrane (TMD) with GPCR signature seven helices. Class B GPCRs activated by peptide hormones their C termini bound to receptor ECD N TMD. It is thought that functions as an affinity trap bind localize hormone receptor. This turn would allow terminus insert into TMD induce conformational changes activate downstream signaling. In contrast this prevailing model, we demonstrate human class vary widely requirement activation. one group, represented corticotrophin-releasing factor 1 (CRF1R), parathyroid (PTH1R), pituitary adenylate cyclase activating polypeptide type (PAC1R), high binding can be bypassed induced proximity mass action effects, whereas other glucagon (GCGR) glucagon-like peptide-1 (GLP-1R), required signaling even when covalently linked Furthermore, activation GLP-1R small molecules interact intracellular side dependent on presence its ECD, suggesting direct role