Phospho-selective mechanisms of arrestin conformations and functions revealed by unnatural amino acid incorporation and 19F-NMR

Fan Yang, Xiao Yu, Chuan Liu, Chang-Xiu Qu, Zheng Gong, Hong-Da Liu, Fa-Hui Li, Hong-Mei Wang, Dong-Fang He, Fan Yi, Song Chen, Chang-Lin Tian, Kun-Hong Xiao, Jiang-Yun Wang () and Jin-Peng Sun ()
Additional contact information
Fan Yang: Laboratory of Quantum Biophysics and Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences
Xiao Yu: Shandong University School of Medicine
Chuan Liu: Shandong University School of Medicine
Chang-Xiu Qu: Shandong University School of Medicine
Zheng Gong: Shandong University School of Medicine
Hong-Da Liu: Shandong University School of Medicine
Fa-Hui Li: Laboratory of Quantum Biophysics and Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences
Hong-Mei Wang: Shandong University School of Medicine
Dong-Fang He: Shandong University School of Medicine
Fan Yi: Shandong University School of Medicine
Chang-Lin Tian: Hefei National Laboratory for Physical Science at Microscale and School of Life Science, University of Science and Technology of China
Kun-Hong Xiao: School of Medicine, University of Pittsburgh
Jiang-Yun Wang: Laboratory of Quantum Biophysics and Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences
Jin-Peng Sun: Shandong University School of Medicine

Nature Communications, 2015, vol. 6, issue 1, 1-15

Abstract: Abstract Specific arrestin conformations are coupled to distinct downstream effectors, which underlie the functions of many G-protein-coupled receptors (GPCRs). Here, using unnatural amino acid incorporation and fluorine-19 nuclear magnetic resonance (19F-NMR) spectroscopy, we demonstrate that distinct receptor phospho-barcodes are translated to specific β-arrestin-1 conformations and direct selective signalling. With its phosphate-binding concave surface, β-arrestin-1 ‘reads’ the message in the receptor phospho-C-tails and distinct phospho-interaction patterns are revealed by 19F-NMR. Whereas all functional phosphopeptides interact with a common phosphate binding site and induce the movements of finger and middle loops, different phospho-interaction patterns induce distinct structural states of β-arrestin-1 that are coupled to distinct arrestin functions. Only clathrin recognizes and stabilizes GRK2-specific β-arrestin-1 conformations. The identified receptor-phospho-selective mechanism for arrestin conformation and the spacing of the multiple phosphate-binding sites in the arrestin enable arrestin to recognize plethora phosphorylation states of numerous GPCRs, contributing to the functional diversity of receptors.

Date: 2015
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DOI: 10.1038/ncomms9202

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