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Quaternary structure of a G-protein-coupled receptor heterotetramer in complex with G proteins

Navarro, G, Cordomi, A, Zelman-Femiak, M, Brugarolas, M, Moreno, E, Aguinaga, D, Pérez-Benito, L, Cortes, A, Casadó, V, Mallol, J, Isidre Canela, E, Lluis, C, Pardo, L, García-Sáez, AJ, McCormick, P and Franco, R (2016) Quaternary structure of a G-protein-coupled receptor heterotetramer in complex with G proteins BMC Biology, 14 (26).

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Abstract

Background: G-protein-coupled receptors (GPCRs), in the form of monomers or homodimers that bind heterotrimeric G proteins, are fundamental in the transfer of extracellular stimuli to intracellular signaling pathways. Different GPCRs may also interact to form heteromers that are novel signaling units. Despite the exponential growth in the number of solved GPCR crystal structures, the structural properties of heteromers remain unknown. Results: We used single-particle tracking experiments in cells expressing functional adenosine A1-A2A receptors fused to fluorescent proteins to show the loss of Brownian movement of the A1 receptor in the presence of the A2A receptor, and a preponderance of cell surface 2:2 receptor heteromers (dimer of dimers). Using computer modeling, aided by bioluminescence resonance energy transfer assays to monitor receptor homomerization and heteromerization and G-protein coupling, we predict the interacting interfaces and propose a quaternary structure of the GPCR tetramer in complex with two G proteins. Conclusions: The combination of results points to a molecular architecture formed by a rhombus-shaped heterotetramer, which is bound to two different interacting heterotrimeric G proteins (Gi and Gs). These novel results constitute an important advance in understanding the molecular intricacies involved in GPCR function

Item Type: Article
Subjects : Veterinary Medicine
Authors :
NameEmailORCID
Navarro, GUNSPECIFIEDUNSPECIFIED
Cordomi, AUNSPECIFIEDUNSPECIFIED
Zelman-Femiak, MUNSPECIFIEDUNSPECIFIED
Brugarolas, MUNSPECIFIEDUNSPECIFIED
Moreno, EUNSPECIFIEDUNSPECIFIED
Aguinaga, DUNSPECIFIEDUNSPECIFIED
Pérez-Benito, LUNSPECIFIEDUNSPECIFIED
Cortes, AUNSPECIFIEDUNSPECIFIED
Casadó, VUNSPECIFIEDUNSPECIFIED
Mallol, JUNSPECIFIEDUNSPECIFIED
Isidre Canela, EUNSPECIFIEDUNSPECIFIED
Lluis, CUNSPECIFIEDUNSPECIFIED
Pardo, LUNSPECIFIEDUNSPECIFIED
García-Sáez, AJUNSPECIFIEDUNSPECIFIED
McCormick, Pp.mccormick@surrey.ac.ukUNSPECIFIED
Franco, RUNSPECIFIEDUNSPECIFIED
Date : 2016
Identification Number : https://doi.org/10.1186/s12915-016-0247-4
Copyright Disclaimer : © 2016 Navarro et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Uncontrolled Keywords : GPCR, Heterotetramer, Heterotrimeric G protein, Single-particle tracking, BRET, Molecular modeling
Depositing User : Symplectic Elements
Date Deposited : 17 May 2017 10:46
Last Modified : 18 May 2017 12:43
URI: http://epubs.surrey.ac.uk/id/eprint/829144

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