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Nat Commun. 2015 Sep 8;6:8202. doi: 10.1038/ncomms9202.

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

Author information

1
Laboratory of Quantum Biophysics and Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, 100101, China.
2
Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, 44 Wenhua Xi Road, Jinan, Shandong 250012, China.
3
Department of Physiology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
4
Department of Pharmacology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
5
Department of Biochemistry, University of Oxford, Oxford OX13QU, UK.
6
Hefei National Laboratory for Physical Science at Microscale and School of Life Science, University of Science and Technology of China, Hefei, Anhui 230027, China.
7
Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
8
Department of Medicine, School of Medicine, Duke University, Durham, North Carolina 27705, USA.

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 ((19)F-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 (19)F-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.

PMID:
26347956
PMCID:
PMC4569848
DOI:
10.1038/ncomms9202
[Indexed for MEDLINE]
Free PMC Article

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