A highly conserved δ-opioid receptor region determines RGS4 interaction

The FEBS Journal
Christos KaroussiotisZafiroula Georgoussi

Abstract

The δ-opioid receptor (δ-OR) couples to Gi/Go proteins to modulate a variety of responses in the nervous system. Τhe Regulator of G protein Signaling 4 (RGS4) was previously shown to directly interact within the C-terminal region of δ-OR using its N-terminal domain to negatively modulate opioid receptor signaling. Herein, using molecular dynamics simulations and in vitro pull down experiments we delimit this interaction to twelve helix 8 residues of δ-ΟR and to the first seventeen N-terminal residues (NT) of RGS4. Monitoring the complex arrangement and stabilization between RGS4 and δ-OR by molecular dynamics simulations combined with mutagenesis studies we defined that two critical interactions are formed: one between Phe329 of helix8 of δ-ΟR and Pro9 of the NT of RGS4 and the other a salt bridge between Glu323 of δ-ΟR and Lys17 of RGS4. Our observations allow drafting for the first time a structural model of a ternary complex including the δ-opioid receptor, a G protein and a RGS protein. Furthermore, the high degree of conservation among opioid receptors of the RGS4-binding region, points to a conserved interaction mode between opioid receptors and this important regulatory protein. This article is protected by copyright. Al...Continue Reading

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Citations

Aug 23, 2020·International Journal of Molecular Sciences·Mariona Torrens-FontanalsJana Selent
Mar 12, 2021·Cellular and Molecular Neurobiology·Laura J Gledhill, Anna-Marie Babey
Sep 25, 2021·Journal of Neuroscience Research·Jade DegrandmaisonLouis Gendron

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