Conformational dynamics of a G protein–coupled receptor helix 8 in lipid membranes

Muñoz-García, Juan C., Dijkman, Patricia M., Lavington, Steven, Suemy Kumagai, Patricia, Inacio dos Reis, Rosana, Yin, Daniel, Stansfeld, Phillip J., Costa-Filho, Antonio José and Watts, Anthony (2020) Conformational dynamics of a G protein–coupled receptor helix 8 in lipid membranes. Science Advances, 6 (33). ISSN 2375-2548

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Abstract

G protein–coupled receptors (GPCRs) are the largest and pharmaceutically most important class of membrane proteins encoded in the human genome, characterized by a seven-transmembrane helix architecture and a C-terminal amphipathic helix 8 (H8). In a minority of GPCR structures solved to date, H8 either is absent or adopts an unusual conformation. The controversial existence of H8 of the class A GPCR neurotensin receptor 1 (NTS1) has been examined here for the nonthermostabilized receptor in a functionally supporting membrane environment using electron paramagnetic resonance, molecular dynamics simulations, and circular dichroism. Lipid-protein interactions with phosphatidylserine and phosphatidylethanolamine lipids, in particular, stabilize the residues 374 to 390 of NTS1 into forming a helix. Furthermore, introduction of a helix-breaking proline residue in H8 elicited an increase in ß-arrestin–NTS1 interactions observed in pull-down assays, suggesting that the structure and/or dynamics of H8 might play an important role in GPCR signaling.

Item Type: Article
Faculty \ School: Faculty of Science > School of Pharmacy
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Depositing User: LivePure Connector
Date Deposited: 17 Aug 2020 23:55
Last Modified: 19 Sep 2020 23:44
URI: https://ueaeprints.uea.ac.uk/id/eprint/76463
DOI: 10.1126/sciadv.aav8207

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