Click here to close Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly. We suggest using a current version of Chrome, FireFox, or Safari.
XB-ART-61160
Cell 2024 Dec 31; doi: 10.1016/j.cell.2024.12.001.
Show Gene links Show Anatomy links

Evolutionary study and structural basis of proton sensing by Mus GPR4 and Xenopus GPR4.

Wen X , Shang P , Chen H , Guo L , Rong N , Jiang X , Li X , Liu J , Yang G , Zhang J , Zhu K , Meng Q , He X , Wang Z , Liu Z , Cheng H , Zheng Y , Zhang B , Pang J , Liu Z , Xiao P , Chen Y , Liu L , Luo F , Yu X , Yi F , Zhang P , Yang F , Deng C , Sun JP .


???displayArticle.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.

???displayArticle.pubmedLink??? 39753131
???displayArticle.link??? Cell