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Nat Commun. 2019 Mar 19;10(1):1261. doi: 10.1038/s41467-019-09204-y.

Distinct G protein-coupled receptor phosphorylation motifs modulate arrestin affinity and activation and global conformation.

Author information

1
Laboratory of Biomolecular Research, Paul Scherrer Institute, 5232, Villigen, Switzerland. damayer@ucsd.edu.
2
Department of Biology, ETH Zürich, 8093, Zürich, Switzerland. damayer@ucsd.edu.
3
Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, 92093-0636, California, USA. damayer@ucsd.edu.
4
Department of Biology, ETH Zürich, 8093, Zürich, Switzerland.
5
Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel.
6
Laboratory of Biomolecular Research, Paul Scherrer Institute, 5232, Villigen, Switzerland.
7
Fitzwilliam College, Cambridge, CB3 0DG, UK.
8
Institut für Medizinische Physik und Biophysik, Charité-Universitätsmedizin Berlin, Berlin, 10117, Germany.
9
University of Zurich, Zurich, 8057, Switzerland.
10
Condensed Matter Theory, Paul Scherrer Institute, 5232, Villigen, Switzerland.
11
Laboratory of Biomolecular Research, Paul Scherrer Institute, 5232, Villigen, Switzerland. dmitry.veprintsev@nottingham.ac.uk.
12
Department of Biology, ETH Zürich, 8093, Zürich, Switzerland. dmitry.veprintsev@nottingham.ac.uk.
13
Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands, NG7 2RD, UK. dmitry.veprintsev@nottingham.ac.uk.
14
Division of Physiology, Pharmacology & Neuroscience, School of Life Sciences, University of Nottingham, Nottingham, NG7 2UH, UK. dmitry.veprintsev@nottingham.ac.uk.

Abstract

Cellular functions of arrestins are determined in part by the pattern of phosphorylation on the G protein-coupled receptors (GPCRs) to which arrestins bind. Despite high-resolution structural data of arrestins bound to phosphorylated receptor C-termini, the functional role of each phosphorylation site remains obscure. Here, we employ a library of synthetic phosphopeptide analogues of the GPCR rhodopsin C-terminus and determine the ability of these peptides to bind and activate arrestins using a variety of biochemical and biophysical methods. We further characterize how these peptides modulate the conformation of arrestin-1 by nuclear magnetic resonance (NMR). Our results indicate different functional classes of phosphorylation sites: 'key sites' required for arrestin binding and activation, an 'inhibitory site' that abrogates arrestin binding, and 'modulator sites' that influence the global conformation of arrestin. These functional motifs allow a better understanding of how different GPCR phosphorylation patterns might control how arrestin functions in the cell.

PMID:
30890705
PMCID:
PMC6424980
DOI:
10.1038/s41467-019-09204-y
[Indexed for MEDLINE]
Free PMC Article

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