Ligand-regulated Oligomerization of Beta(2)-adrenoceptors in a Model Lipid Bilayer

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2009 Sep 19

PMID 19763081

Citations 79

Authors

Juan Jose Fung

Xavier Deupi

Leonardo Pardo

Xiao Jie Yao

Gisselle A Velez-Ruiz

Brian T DeVree

Roger K Sunahara

Brian K Kobilka

Affiliations

Soon will be listed here.

Abstract

The beta(2)-adrenoceptor (beta(2)AR) was one of the first Family A G protein-coupled receptors (GPCRs) shown to form oligomers in cellular membranes, yet we still know little about the number and arrangement of protomers in oligomers, the influence of ligands on the organization or stability of oligomers, or the requirement for other proteins to promote oligomerization. We used fluorescence resonance energy transfer (FRET) to characterize the oligomerization of purified beta(2)AR site-specifically labelled at three different positions with fluorophores and reconstituted into a model lipid bilayer. Our results suggest that the beta(2)AR is predominantly tetrameric following reconstitution into phospholipid vesicles. Agonists and antagonists have little effect on the relative orientation of protomers in oligomeric complexes. In contrast, binding of inverse agonists leads to significant increases in FRET efficiencies for most labelling pairs, suggesting that this class of ligand promotes tighter packing of protomers and/or the formation of more complex oligomers by reducing conformational fluctuations in individual protomers. The results provide new structural insights into beta(2)AR oligomerization and suggest a possible mechanism for the functional effects of inverse agonists.

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