Tethered agonist exposure in intact adhesion/class B2 GPCRs through intrinsic structural flexibility of the GAIN domain
Tethered agonist exposure in intact adhesion/class B2 GPCRs through intrinsic structural flexibility of the GAIN domain
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DOI：
10.1016/j.molcel.2020.12.042
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发表时间：
2021-03-04
期刊：
影响因子：
16
通讯作者：
Langenhan, Tobias
中科院分区：
文献类型：
--
作者：
Beliu, Gerti;Altrichter, Steffen;Langenhan, Tobias
粘附G蛋白偶联受体（aGPCR）/B2家族GPCR在器官发育和运作过程中执行关键任务，其遗传病变与人类疾病（包括癌症）相关。异常的结构aGPCR特征是隐藏在GPCR自蛋白水解诱导（GAIN）结构域内的拴系激动剂（TA）的存在及其非共价异聚体两亚基布局。TA如何在维持这种微妙的受体结构的同时准备激活，这是涉及或排除aGPCR异二聚体分离的相互冲突的信号传导范式的核心。我们在5种哺乳动物aGPCR同源物（ADGRB 3、ADGRE 2、ADGRE 5、ADGRG 1和ADGRL 1）中研究了这一问题，并证明细胞表面存在完整的aGPCR异源二聚体，核心TA区域在切割的GAIN结构域中变得暴露，并且GAIN结构域内的运动调节拴系激动剂暴露的水平，从而可能控制aGPCR活性。总的来说，这些发现描绘了完整aGPCR的TA依赖性信号传导的统一机制。
Adhesion G protein-coupled receptors (aGPCRs)/family B2 GPCRs execute critical tasks during development and the operation of organs, and their genetic lesions are associated with human disorders, including cancers. Exceptional structural aGPCR features are the presence of a tethered agonist (TA) concealed within a GPCR autoproteolysis-inducing (GAIN) domain and their non-covalent heteromeric two-subunit layout. How the TA is poised for activation while maintaining this delicate receptor architecture is central to conflicting signaling paradigms that either involve or exclude aGPCR heterodimer separation. We investigated this matter in five mammalian aGPCR homologs (ADGRB3, ADGRE2, ADGRE5, ADGRG1, and ADGRL1) and demonstrate that intact aGPCR heterodimers exist at the cell surface, that the core TA region becomes unmasked in the cleaved GAIN domain, and that intra-GAIN domain movements regulate the level of tethered agonist exposure, thereby likely controlling aGPCR activity. Collectively, these findings delineate a unifying mechanism for TA-dependent signaling of intact aGPCRs.