Differential Requirement of the Extracellular Domain in Activation of Class B G Protein-coupled Receptors
Differential Requirement of the Extracellular Domain in Activation of Class B G Protein-coupled Receptors
复制标题
B 类 G 蛋白偶联受体激活中胞外结构域的差异要求
DOI：
10.1074/jbc.m116.726620
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发表时间：
2016-07-15
影响因子：
4.8
通讯作者：
Xu, H. Eric
中科院分区：
文献类型：
--
作者：
Zhao, Li-Hua;Yin, Yanting;Xu, H. Eric
来自促分泌素样（B类）家族的G蛋白偶联受体（GPCR）是激素稳态的关键参与者，并且是治疗代谢紊乱和神经元疾病的重要药物靶标。它们由一个大的N-末端胞外结构域（ECD）和一个跨膜结构域（TMD）组成，具有七个跨膜螺旋的GPCR特征。GPCR类被肽激素激活，其C末端与受体ECD结合，其N末端与TMD结合。据认为，ECD起到亲和陷阱的作用，以将激素结合并定位于受体。这反过来将允许激素N末端插入TMD并诱导TMD的构象变化以激活下游信号传导。与此流行的模型相反，我们证明了人类B类GPCR在其对ECD的激活需求方面差异很大。在以促肾上腺皮质激素释放因子受体1（CRF 1 R）、甲状旁腺激素受体（PTH 1 R）和垂体腺苷酸环化酶激活多肽1型受体（PAC 1 R）为代表的一组中，高亲和力激素结合的ECD要求可以通过诱导的邻近效应和质量作用效应绕过，而在另一组中，以胰高血糖素受体（GCGR）和胰高血糖素样肽-1受体（GLP-1 R）为代表，即使当激素与TMD共价连接时，LCD也是信号传导所需的。此外，与受体胞内侧相互作用的小分子对GLP-1 R的活化依赖于其LCD的存在，表明ECD在GLP-1 R活化中的直接作用。
G protein-coupled receptors (GPCRs) from the secretin-like (class B) family are key players in hormonal homeostasis and are important drug targets for the treatment of metabolic disorders and neuronal diseases. They consist of a large N-terminal extra cellular domain (ECD) and a transmembrane domain (TMD) with the GPCR signature of seven transmembrane helices. Class GPCRs are activated by peptide hormones with their C termini bound to the receptor ECD and their N termini bound to the TMD. It is thought that the ECD functions as an affinity trap to bind and localize the hormone to the receptor. This in turn would allow the hormone N terminus to insert into the TMD and induce conformational changes of the TMD to activate downstream signaling. In contrast to this prevailing model, we demonstrate that human class B GPCRs vary widely in their requirement of the ECD for activation. In one group, represented by corticotrophin-releasing factor receptor 1 (CRF1R), parathyroid hormone receptor (PTH1R), and pituitary adenylate cyclase activating polypeptide type 1 receptor (PAC1R), the ECD requirement for high affinity hormone binding can be bypassed by induced proximity and mass action effects, whereas in the other group, represented by glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R), the LCD is required for signaling even when the hormone is covalently linked to the TMD. Furthermore, the activation of GLP-1R by small molecules that interact with the intracellular side of the receptor is dependent on the presence of its LCD, suggesting a direct role of the ECD in GLP-1R activation.