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

Daniel Mayer, Fred F. Damberger, Mamidi Samarasimhareddy, Miki Feldmueller, Ziva Vuckovic, Tilman Flock, Brian Bauer, Eshita Mutt, Franziska Zosel, Frédéric H.T. Allain, Jörg Standfuss, Gebhard F.X. Schertler, Xavier Deupi, Martha E. Sommer, Mattan Hurevich, Assaf Friedler, Dmitry B. Veprintsev

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75 Citations (Scopus)


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.

Original languageEnglish
Article number1261
Number of pages14
JournalNature Communications
Issue number1
Publication statusPublished - 1 Dec 2019
Externally publishedYes

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