Analysis of human dopamine D3 receptor quaternary structure

Sara Marsango, Gianluigi Caltabiano, Chantevy Pou, María José Varela Liste, Graeme Milligan

Research output: Contribution to journalArticleResearchpeer-review

20 Citations (Scopus)

Abstract

© 2015 by The American Society for Biochemistry and Molecular Biology, Inc. The dopamine D3 receptor is a class A, rhodopsin-like G proteincoupled 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 D3 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 dimericβ1-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 D3-D3 receptor interfaces within homo-oligomers and are consistent with the D3 receptor adopting a β1-adrenoreceptor-like quaternary arrangement. Specifically, results suggest that D3 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 D3 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 D3 receptor and possibly other GPCR quaternary structures.
Original languageEnglish
Pages (from-to)15146-15162
JournalJournal of Biological Chemistry
Volume290
Issue number24
DOIs
Publication statusPublished - 12 Jun 2015

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