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 () and Renjie Chai ()
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Xiangyu Ma: Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University
Li-Nan Chen: Zhejiang University School of Medicine
Menghui Liao: Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University
Liyan Zhang: Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University
Kun Xi: Zhejiang University School of Medicine
Jiamin Guo: Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University
Cangsong Shen: Huazhong University of Science and Technology (HUST)
Dan-Dan Shen: Zhejiang University School of Medicine
Pengjun Cai: Shanghai Institute of Materia Media, Chinese Academy of Sciences
Qingya Shen: Zhejiang University
Jieyu Qi: Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University
Huibing Zhang: Zhejiang University School of Medicine
Shao-Kun Zang: Zhejiang University School of Medicine
Ying-Jun Dong: Zhejiang University School of Medicine
Luwei Miao: Zhejiang University School of Medicine
Jiao Qin: Zhejiang University School of Medicine
Su-Yu Ji: Zhejiang University School of Medicine
Yue Li: Shanghai Institute of Materia Media, Chinese Academy of Sciences
Jianfeng Liu: Huazhong University of Science and Technology (HUST)
Chunyou Mao: Sir Run Run Shaw Hospital, Zhejiang University School of Medicine
Yan Zhang: Zhejiang University School of Medicine
Renjie Chai: Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-54681-5

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