Ligand‐regulated oligomerization of β2‐adrenoceptors in a model lipid bilayer
Identifieur interne : 000562 ( Main/Exploration ); précédent : 000561; suivant : 000563Ligand‐regulated oligomerization of β2‐adrenoceptors in a model lipid bilayer
Auteurs : Juan José Fung [États-Unis] ; Xavier Deupi [Espagne] ; Leonardo Pardo [Espagne] ; Xiao Jie Yao [États-Unis] ; Gisselle A. Velez-Ruiz [États-Unis] ; Brian T. Devree [États-Unis] ; Roger K. Sunahara [États-Unis] ; Brian K. Kobilka [États-Unis]Source :
- The EMBO Journal [ 0261-4189 ] ; 2009-11-04.
English descriptors
- Teeft :
- Acad, Acceptor, Agonist, Agonist isoproterenol, Alprenolol, Average diameter, B2ar, B2ar monomers, B2ar oligomerization, B2ar oligomers, B2ar reconstituted, B2ars, Basal, Basal activity, Bilayer, Bilayers, Biol, Biol chem, Biology organization, Biology organization oligomers, Bioluminescence resonance energy transfer, Bouvier, Chem, Conformational changes, Crystal structure, Cysteine, Cytoplasmic, Dimer, Dimerization, Dopamine, Embo, Embo journal, Fung, Gpcr, Gpcrs, Gtpgs, Inactive state, Independent experiments, Inverse, Inverse agonist, Inverse agonists, Isoproterenol, Kobilka, Labelling, Ligand, Lipid, Lipid bilayer, Lipid bilayers, Lipid vesicles, Little effect, Mansoor, Model lipid bilayer, Molar ratio, Monomer, Monomeric, Monomeric b2ar, Monomeric rhodopsin, Mutant, Natl, Neutral antagonist, Oligomer, Oligomerization, Oligomers, Phospholipid, Phospholipid vesicles, Pngase, Proc, Proc natl acad, Protomers, Rasmussen, Receptor, Receptor oligomerization, Reconstituted, Reconstituted b2ar, Reconstituted receptor, Reconstitution, Relative orientation, Results show, Rhodopsin, Saturation, Saturation experiments, Supplementary data, Supplementary figure, Tetramer, Tetramers, Transmembrane, Uorescence, Uorophore, Uorophores, Vesicle.
Abstract
The β2‐adrenoceptor (β2AR) 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 β2AR site‐specifically labelled at three different positions with fluorophores and reconstituted into a model lipid bilayer. Our results suggest that the β2AR 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 β2AR oligomerization and suggest a possible mechanism for the functional effects of inverse agonists.
Url:
DOI: 10.1038/emboj.2009.267
Affiliations:
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Velez-Ruiz</name><affiliation wicri:level="1"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pharmacology, University of Michigan Medical School, MI, Ann Arbor</wicri:regionArea><wicri:noRegion>Ann Arbor</wicri:noRegion></affiliation></author><author><name sortKey="Devree, Brian T" sort="Devree, Brian T" uniqKey="Devree B" first="Brian T" last="Devree">Brian T. Devree</name><affiliation wicri:level="1"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pharmacology, University of Michigan Medical School, MI, Ann Arbor</wicri:regionArea><wicri:noRegion>Ann Arbor</wicri:noRegion></affiliation></author><author><name sortKey="Sunahara, Roger K" sort="Sunahara, Roger K" uniqKey="Sunahara R" first="Roger K" last="Sunahara">Roger K. 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We used fluorescence resonance energy transfer (FRET) to characterize the oligomerization of purified β2AR site‐specifically labelled at three different positions with fluorophores and reconstituted into a model lipid bilayer. Our results suggest that the β2AR 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 β2AR oligomerization and suggest a possible mechanism for the functional effects of inverse agonists.</div></front></TEI><affiliations><list><country><li>Espagne</li><li>États-Unis</li></country><region><li>Catalogne</li></region><settlement><li>Barcelone</li></settlement><orgName><li>Université autonome de Barcelone</li></orgName></list><tree><country name="États-Unis"><noRegion><name sortKey="Fung, Juan Jose" sort="Fung, Juan Jose" uniqKey="Fung J" first="Juan José" last="Fung">Juan José Fung</name></noRegion><name sortKey="Devree, Brian T" sort="Devree, Brian T" uniqKey="Devree B" first="Brian T" last="Devree">Brian T. Devree</name><name sortKey="Kobilka, Brian K" sort="Kobilka, Brian K" uniqKey="Kobilka B" first="Brian K" last="Kobilka">Brian K. Kobilka</name><name sortKey="Kobilka, Brian K" sort="Kobilka, Brian K" uniqKey="Kobilka B" first="Brian K" last="Kobilka">Brian K. Kobilka</name><name sortKey="Sunahara, Roger K" sort="Sunahara, Roger K" uniqKey="Sunahara R" first="Roger K" last="Sunahara">Roger K. Sunahara</name><name sortKey="Velez Uiz, Gisselle A" sort="Velez Uiz, Gisselle A" uniqKey="Velez Uiz G" first="Gisselle A" last="Velez-Ruiz">Gisselle A. Velez-Ruiz</name><name sortKey="Yao, Xiao Jie" sort="Yao, Xiao Jie" uniqKey="Yao X" first="Xiao Jie" last="Yao">Xiao Jie Yao</name></country><country name="Espagne"><region name="Catalogne"><name sortKey="Deupi, Xavier" sort="Deupi, Xavier" uniqKey="Deupi X" first="Xavier" last="Deupi">Xavier Deupi</name></region><name sortKey="Pardo, Leonardo" sort="Pardo, Leonardo" uniqKey="Pardo L" first="Leonardo" last="Pardo">Leonardo Pardo</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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