Molecular insights into the atypical activation mechanism of GPR156 in maintaining auditory function

Ma, X.; Chen, L.-N.; Liao, M.; Zhang, L.; Xi, K.; Guo, J.; Shen, C.; Cai, P.; Shen, Q.; Qi, J.; Zhang, H.; Zang, S.-K.; Dong, Y.-J.; Miao, L.; Qin, J.; Ji, S.-Y.; Li, Y.; Liu, J.; Mao, C.; Zhang, Y.; Chai, R.

doi:10.1101/2024.03.07.581839

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bioRxiv · 10.1101/2024.03.07.581839

Molecular insights into the atypical activation mechanism of GPR156 in maintaining auditory function

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Abstract

The class C orphan GPCR GPR156, which lacks the typical extracellular region, plays a pivotal role in auditory function through Gi2/3. Here, we demonstrate that GPR156 with high constitutive activity is essential for maintaining auditory function, and we further present two cryo-EM structures of human GPR156. The GPR156 dimer in both the apo state and Gi3 protein-coupled state adopt a TM5/6-TM5/6 interface, indicating the high constitutive activity of GPR156 in the apo state. The C-terminus 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. These observations explain how GPCR activity is maintained through dimerization and provide a mechanistic insight into the sustained role of GPR156 in maintaining auditory function.

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Ma, X., Chen, L.-N., Liao, M., Zhang, L., Xi, K., Guo, J., Shen, C., Cai, P., Shen, Q., Qi, J., Zhang, H., Zang, S.-K., Dong, Y.-J., Miao, L., Qin, J., Ji, S.-Y., Li, Y., Liu, J., Mao, C., Zhang, Y., Chai, R.. 2024-03-08. Molecular insights into the atypical activation mechanism of GPR156 in maintaining auditory function. https://doi.org/10.1101/2024.03.07.581839

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