DeSiphering receptor core-induced and ligand-dependent conformational changes in arrestin via genetic encoded trimethylsilyl 1H-NMR probe

Qi Liu, Qing-tao He, Xiaoxuan Lyu, Fan Yang, Zhong-liang Zhu, Peng Xiao, Zhao Yang, Feng Zhang, Zhao-ya Yang, Xiao-yan Wang, Peng Sun, Qian-wen Wang, Chang-xiu Qu, Zheng Gong, Jing-yu Lin, Zhen Xu, Shao-le Song, Shen-ming Huang, Sheng-chao Guo, Ming-jie Han, Kong-kai Zhu, Xin Chen, Alem W. Kahsai, Kun-Hong Xiao, Wei Kong, Fa-hui Li, Ke Ruan, Zi-jian Li, Xiao Yu, Xiao-gang Niu, Chang-wen Jin, Jiangyun Wang () and Jin-peng Sun ()
Additional contact information
Qi Liu: Chinese Academy of Sciences
Qing-tao He: Chinese Academy of Sciences
Xiaoxuan Lyu: Chinese Academy of Sciences
Fan Yang: Shandong University
Zhong-liang Zhu: University of Science and Technology of China
Peng Xiao: Shandong University
Zhao Yang: Shandong University
Feng Zhang: Chinese Academy of Sciences
Zhao-ya Yang: Chinese Academy of Sciences
Xiao-yan Wang: Chinese Academy of Sciences
Peng Sun: Chinese Academy of Sciences
Qian-wen Wang: Chinese Academy of Sciences
Chang-xiu Qu: Shandong University
Zheng Gong: Shandong University
Jing-yu Lin: Shandong University
Zhen Xu: Chinese Academy of Sciences
Shao-le Song: Chinese Academy of Sciences
Shen-ming Huang: Peking University
Sheng-chao Guo: Shandong University
Ming-jie Han: Chinese Academy of Sciences
Kong-kai Zhu: University of Jinan
Xin Chen: Changzhou University
Alem W. Kahsai: Duke University, School of Medicine
Kun-Hong Xiao: University of Pittsburgh
Wei Kong: Peking University
Fa-hui Li: Chinese Academy of Sciences
Ke Ruan: University of Science and Technology of China
Zi-jian Li: Peking University
Xiao Yu: Shandong University
Xiao-gang Niu: Peking University
Chang-wen Jin: Peking University
Jiangyun Wang: Chinese Academy of Sciences
Jin-peng Sun: Shandong University

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: Abstract Characterization of the dynamic conformational changes in membrane protein signaling complexes by nuclear magnetic resonance (NMR) spectroscopy remains challenging. Here we report the site-specific incorporation of 4-trimethylsilyl phenylalanine (TMSiPhe) into proteins, through genetic code expansion. Crystallographic analysis revealed structural changes that reshaped the TMSiPhe-specific amino-acyl tRNA synthetase active site to selectively accommodate the trimethylsilyl (TMSi) group. The unique up-field 1H-NMR chemical shift and the highly efficient incorporation of TMSiPhe enabled the characterization of multiple conformational states of a phospho-β2 adrenergic receptor/β-arrestin-1(β-arr1) membrane protein signaling complex, using only 5 μM protein and 20 min of spectrum accumulation time. We further showed that extracellular ligands induced conformational changes located in the polar core or ERK interaction site of β-arr1 via direct receptor transmembrane core interactions. These observations provided direct delineation and key mechanism insights that multiple receptor ligands were able to induce distinct functionally relevant conformational changes of arrestin.

Date: 2020
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DOI: 10.1038/s41467-020-18433-5

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