TY  - JOUR
AU  - Navarro, Gemma
AU  - Cordomí, Arnau
AU  - Zelman-Femiak, Monika
AU  - Brugarolas, Marc
AU  - Moreno, Estefania
AU  - Aguinaga, David
AU  - Perez-Benito, Laura
AU  - Cortés, Antoni
AU  - Casadó, Vicent
AU  - Mallol, Josefa
AU  - Canela, Enric I
AU  - Lluís, Carme
AU  - Pardo, Leonardo
AU  - García-Sáez, Ana J
AU  - McCormick, Peter J
AU  - Franco, Rafael
TI  - Quaternary structure of a G-protein-coupled receptor heterotetramer in complex with Gi and Gs.
JO  - BMC biology
VL  - 14
IS  - 1
SN  - 1741-7007
CY  - Berlin
PB  - Springer
M1  - DKFZ-2017-05308
SP  - 26
PY  - 2016
AB  - 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.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.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.
KW  - Receptors, Purinergic P1 (NLM Chemicals)
KW  - Heterotrimeric GTP-Binding Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:27048449
C2  - pmc:PMC4822319
DO  - DOI:10.1186/s12915-016-0247-4
UR  - https://inrepo02.dkfz.de/record/130228
ER  -