Molecular insights into the activation mechanism of GPR156 in maintaining auditory function
Xiangyu Ma, Li-Nan Chen, Menghui Liao, Liyan Zhang, Kun Xi, Jiamin Guo, Cangsong Shen, Dandan Shen, Pengjun Cai, Qingya Shen, Jieyu Qi, Huibing Zhang, Shao‐Kun Zang, Ying-Jun Dong, Luwei Miao, Jiao Qin, Su‐Yu Ji, Yue Li, Jianfeng Liu, Chunyou Mao, Yan Zhang, Renjie Chai
Abstract
The class C orphan G-protein-coupled receptor (GPCR) GPR156, which lacks the large extracellular region, plays a pivotal role in auditory function through Gi2/3. Here, we firstly demonstrate that GPR156 with high constitutive activity is essential for maintaining auditory function, and further reveal the structural basis of the sustained role of GPR156. We present the cryo-EM structures of human apo GPR156 and the GPR156–Gi3 complex, unveiling a small extracellular region formed by extracellular loop 2 (ECL2) and the N-terminus. The GPR156 dimer in both apo state and Gi3 protein-coupled state adopt a transmembrane (TM)5/6-TM5/6 interface, indicating the high constitutive activity of GPR156 in the apo state. Furthermore, C-terminus in G-bound subunit of GPR156 plays a dual role in promoting G protein binding within G-bound subunit while preventing the G-free subunit from binding to additional G protein. Together, these results explain how GPR156 constitutive activity is maintained through dimerization and provide a mechanistic insight into the sustained role of GPR156 in maintaining auditory function. GPR156 has been identified as a regulator in auditory hair cells. Here, authors present the cryo-EM structures of human apo GPR156 and the GPR156–Gi3 complex to reveal the activation mechanism of GPR156 in maintaining auditory function.