Web of Science: 22 cites, Scopus: 22 cites, Google Scholar: cites,
Analysis of Human Dopamine D Receptor Quaternary Structure
Marsango, Sara (University of Glasgow)
Caltabiano, Gianluigi 1978- (Universitat Autònoma de Barcelona. Laboratori de Medicina Computacional)
Pou, Chantevy (University of Glasgow)
Varela Liste, María José (University of Glasgow)
Milligan, Graeme (University of Glasgow)

Data: 2015
Resum: Background: The dopamine D receptor can form dimers/oligomers, but the molecular basis for this is poorly defined. Results: Molecular modeling, mutagenesis, and analysis of inactive state receptor crystal structures allowed assessment of models of receptor organization. Conclusion: The dopamine D receptor can assume different dimeric and a rhombic tetrameric arrangements. Significance: These findings provide understanding of the molecular basis of D receptor quaternary structure. The dopamine D receptor is a class A, rhodopsin-like G protein-coupled receptor that can form dimers and/or higher order oligomers. However, the molecular basis for production of these complexes is not well defined. Using combinations of molecular modeling, site-directed mutagenesis, and homogenous time-resolved FRET, the interfaces that allow dopamine D receptor monomers to interact were defined and used to describe likely quaternary arrangements of the receptor. These were then compared with published crystal structures of dimeric β-adrenoreceptor, μ-opioid, and CXCR4 receptors. The data indicate important contributions of residues from within each of transmembrane domains I, II, IV, V, VI, and VII as well as the intracellular helix VIII in the formation of D-D receptor interfaces within homo-oligomers and are consistent with the D receptor adopting a β-adrenoreceptor-like quaternary arrangement. Specifically, results suggest that D protomers can interact with each other via at least two distinct interfaces: the first one comprising residues from transmembrane domains I and II along with those from helix VIII and a second one involving transmembrane domains IV and V. Moreover, rather than existing only as distinct dimeric species, the results are consistent with the D receptor also assuming a quaternary structure in which two transmembrane domain I-II-helix VIII dimers interact to form a "rhombic" tetramer via an interface involving residues from transmembrane domains VI and VII. In addition, the results also provide insights into the potential contribution of molecules of cholesterol to the overall organization and potential stability of the D receptor and possibly other GPCR quaternary structures.
Drets: Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. Creative Commons
Llengua: Anglès
Document: Article ; recerca ; Versió publicada
Matèria: G protein-coupled receptor ; Dopamine receptor ; GPCR quaternary structure ; Fluorescence resonance energy transfer ; Homodimer
Publicat a: Journal of biological chemistry, Vol. 290 (april 2015) , p. 15146-15162, ISSN 1083-351X

DOI: 10.1074/jbc.M114.630681
PMID: 25931118

17 p, 2.9 MB

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 Registre creat el 2018-01-31, darrera modificació el 2022-11-22

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