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, Dan Dan 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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number10601
JournalNature Communications
Volume15
Issue number1
DOIs
Publication statusPublished - Dec 2024

Fingerprint

Dive into the research topics of 'Molecular insights into the activation mechanism of GPR156 in maintaining auditory function'. Together they form a unique fingerprint.

Cite this