Dynamic tuneable G protein-coupled receptor monomer-dimer populations

Patricia M. Dijkman; Oliver K. Castell; Alan Goddard; Juan C. Munoz-Garcia; Chris de Graaf; Mark I. Wallace; Anthony Watts

doi:10.1038/s41467-018-03727-6

Dynamic tuneable G protein-coupled receptor monomer-dimer populations

Patricia M. Dijkman, Oliver K. Castell, Alan Goddard, Juan C. Munoz-Garcia, Chris de Graaf, Mark I. Wallace, Anthony Watts

College of Health and Life Sciences

Research output: Contribution to journal › Article › peer-review

Abstract

G protein-coupled receptors (GPCRs) are the largest class of membrane receptors, playing a key role in the regulation of processes as varied as neurotransmission and immune response. Evidence for GPCR oligomerisation has been accumulating that challenges the idea that GPCRs function solely as monomeric receptors; however, GPCR oligomerisation remains controversial primarily due to the difficulties in comparing evidence from very different types of structural and dynamic data. Using a combination of single-molecule and ensemble FRET, double electron–electron resonance spectroscopy, and simulations, we show that dimerisation of the GPCR neurotensin receptor 1 is regulated by receptor density and is dynamically tuneable over the physiological range. We propose a “rolling dimer” interface model in which multiple dimer conformations co-exist and interconvert. These findings unite previous seemingly conflicting observations, provide a compelling mechanism for regulating receptor signalling, and act as a guide for future physiological studies.

Original language	English
Article number	1710
Journal	Nature Communications
Volume	9
DOIs	https://doi.org/10.1038/s41467-018-03727-6
Publication status	Published - 27 Apr 2018

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This article is licensed under a Creative Commons
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© The Author(s) 2018

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Dynamic tuneable G protein-coupled receptor monomer-dimer populations
This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/. © The Author(s) 2018
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Cite this

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abstract = "G protein-coupled receptors (GPCRs) are the largest class of membrane receptors, playing a key role in the regulation of processes as varied as neurotransmission and immune response. Evidence for GPCR oligomerisation has been accumulating that challenges the idea that GPCRs function solely as monomeric receptors; however, GPCR oligomerisation remains controversial primarily due to the difficulties in comparing evidence from very different types of structural and dynamic data. Using a combination of single-molecule and ensemble FRET, double electron–electron resonance spectroscopy, and simulations, we show that dimerisation of the GPCR neurotensin receptor 1 is regulated by receptor density and is dynamically tuneable over the physiological range. We propose a “rolling dimer” interface model in which multiple dimer conformations co-exist and interconvert. These findings unite previous seemingly conflicting observations, provide a compelling mechanism for regulating receptor signalling, and act as a guide for future physiological studies.",

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Dynamic tuneable G protein-coupled receptor monomer-dimer populations

Abstract

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