山东大学孙金鹏等研究人员合作揭示小鼠GPR4和非洲爪蟾GPR4的质子感应的演化研究与结构基础。相关论文于2025年1月2日在线发表在《细胞》杂志上。
研究人员观察到不同物种中，G蛋白偶联受体4（GPR4）活性的最佳pH与血液pH范围之间存在正相关关系。通过在不同pH条件下解析非洲爪蟾（Xenopus tropicalis）GPR4（xtGPR4）和小鼠（Mus musculus）GPR4（mmGPR4）的7-冷冻电子显微镜（cryo-EM）结构，研究人员发现，HECL2-45.47和H7.36的质子化促进了极性网络的建立，并加强了细胞外环2（ECL2）与7跨膜域（7TM）之间的紧密关联，同时也揭示了一条保守的传播通路。
这些都是不同物种中质子化引发GPR4激活的共同机制。此外，特定的细胞外HECL2-45.41的质子化有助于xtGPR4较为酸性的最佳pH范围。总体而言，该研究从结构、功能和演化的角度揭示了GPR4质子感应的共同机制和差异机制。
据了解，动物通过演化出质子感应膜受体，如GPR4，来监测与其生理相关的pH变化，并产生适应性反应。然而，GPR4对质子感应的演化轨迹和结构机制仍未得到解决。
附：英文原文
Title: Evolutionary study and structural basis of proton sensing by Mus GPR4 and Xenopus GPR4
Author: Xin Wen, Pan Shang, Haidi Chen, Lulu Guo, Naikang Rong, Xiaoyu Jiang, Xuan Li, Junyan Liu, Gongming Yang, Jiacheng Zhang, Kongkai Zhu, Qingbiao Meng, Xuefei He, Zhihai Wang, Zili Liu, Haoran Cheng, Yilin Zheng, Bifei Zhang, Jiaojiao Pang, Zhaoqian Liu, Peng Xiao, Yuguo Chen, Lunxu Liu, Fengming Luo, Xiao Yu, Fan Yi, Pengju Zhang, Fan Yang, Cheng Deng, Jin-Peng Sun
Issue&Volume: 2025-01-02
Abstract: Animals have evolved pH-sensing membrane receptors, such as G-protein-coupled receptor 4 (GPR4), to monitor pH changes related to their physiology and generate adaptive reactions. However, the evolutionary trajectory and structural mechanism of proton sensing by GPR4 remain unresolved. Here, we observed a positive correlation between the optimal pH of GPR4 activity and the blood pH range across different species. By solving 7-cryoelectron microscopy (cryo-EM) structures of Xenopus tropicalis GPR4 (xtGPR4) and Mus musculus GPR4 (mmGPR4) under varying pH conditions, we identified that protonation of HECL2-45.47 and H7.36 enabled polar network establishment and tighter association between the extracellular loop 2 (ECL2) and 7 transmembrane (7TM) domain, as well as a conserved propagating path, which are common mechanisms underlying protonation-induced GPR4 activation across different species. Moreover, protonation of distinct extracellular HECL2-45.41 contributed to the more acidic optimal pH range of xtGPR4. Overall, our study revealed common and distinct mechanisms of proton sensing by GPR4, from a structural, functional, and evolutionary perspective.
DOI: 10.1016/j.cell.2024.12.001
Source: https://www.cell.com/cell/abstract/S0092-8674(24)01380-1