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      A monomeric G protein-coupled receptor isolated in a high-density lipoprotein particle efficiently activates its G protein.

      Proceedings of the National Academy of Sciences of the United States of America

      Animals, Cattle, Fluorescence Resonance Energy Transfer, GTP-Binding Proteins, metabolism, Humans, Lipoproteins, HDL, chemistry, ultrastructure, Microscopy, Electron, Transmission, Models, Molecular, Protein Binding, Protein Structure, Quaternary, Receptors, Adrenergic, beta-2, isolation & purification

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          Abstract

          G protein-coupled receptors (GPCRs) respond to a diverse array of ligands, mediating cellular responses to hormones and neurotransmitters, as well as the senses of smell and taste. The structures of the GPCR rhodopsin and several G proteins have been determined by x-ray crystallography, yet the organization of the signaling complex between GPCRs and G proteins is poorly understood. The observations that some GPCRs are obligate heterodimers, and that many GPCRs form both homo- and heterodimers, has led to speculation that GPCR dimers may be required for efficient activation of G proteins. However, technical limitations have precluded a definitive analysis of G protein coupling to monomeric GPCRs in a biochemically defined and membrane-bound system. Here we demonstrate that a prototypical GPCR, the beta2-adrenergic receptor (beta2AR), can be incorporated into a reconstituted high-density lipoprotein (rHDL) phospholipid bilayer particle together with the stimulatory heterotrimeric G protein, Gs. Single-molecule fluorescence imaging and FRET analysis demonstrate that a single beta2AR is incorporated per rHDL particle. The monomeric beta2AR efficiently activates Gs and displays GTP-sensitive allosteric ligand-binding properties. These data suggest that a monomeric receptor in a lipid bilayer is the minimal functional unit necessary for signaling, and that the cooperativity of agonist binding is due to G protein association with a receptor monomer and not receptor oligomerization.

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          Author and article information

          Journal
          17452637
          10.1073/pnas.0611448104
          1863461

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