Dang Ting, Yu Jie, Cao Zhihe, Zhang Bingjie, Li Shanshan, Xin Ye, Yang Lingyun, Lou Ronghui, Zhuang Min, Shui Wenqing
iHuman Institute, ShanghaiTech University, Shanghai, China.
School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
Nat Chem Biol. 2025 Feb;21(2):256-267. doi: 10.1038/s41589-024-01714-1. Epub 2024 Sep 3.
The GLP-1 receptor, one of the most successful drug targets for the treatment of type 2 diabetes and obesity, is known to engage multiple intracellular signaling proteins. However, it remains less explored how the receptor interacts with proteins on the cell membrane. Here, we present a ligand-based proximity labeling approach to interrogate the native cell membrane interactome for the GLP-1 receptor after agonist simulation. Our study identified several unreported putative cell membrane interactors for the endogenous receptor in either a pancreatic β cell line or a neuronal cell line. We further uncovered new regulators of GLP-1 receptor-mediated signaling and insulinotropic responses in β cells. Additionally, we obtained a time-resolved cell membrane interactome map for the receptor in β cells. Therefore, our study provides a new approach that is generalizable to map endogenous cell membrane interactomes for G-protein-coupled receptors to decipher the molecular basis of their cell-type-specific functional regulation.
胰高血糖素样肽-1（GLP-1）受体是治疗2型糖尿病和肥胖症最成功的药物靶点之一，已知它能与多种细胞内信号蛋白相互作用。然而，该受体如何与细胞膜上的蛋白质相互作用仍有待深入研究。在此，我们提出一种基于配体的邻近标记方法，用于在激动剂模拟后探究GLP-1受体的天然细胞膜相互作用组。我们的研究在胰腺β细胞系或神经元细胞系中鉴定出了几种内源性受体未报道的假定细胞膜相互作用蛋白。我们进一步发现了β细胞中GLP-1受体介导的信号传导和促胰岛素反应的新调节因子。此外，我们获得了β细胞中该受体的时间分辨细胞膜相互作用组图谱。因此，我们的研究提供了一种可推广的新方法，用于绘制G蛋白偶联受体的内源性细胞膜相互作用组，以破译其细胞类型特异性功能调节的分子基础。
