Marsango, S., Caltabiano, G., Pou, C., Varela Liste, M. J. and Milligan, G. (2015) Analysis of human dopamine D3 receptor quaternary structure. Journal of Biological Chemistry, 290, pp. 15146-15162. (doi: 10.1074/jbc.M114.630681) (PMID:25931118) (PMCID:PMC4463457)
|
Text
106039.pdf - Published Version Available under License Creative Commons Attribution. 3MB |
Abstract
The dopamine D3 receptor is a class A, rhodopsinlike 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 modelling, 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 to published crystal structures of dimeric β1-adrenoceptor, 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-adrenoceptor-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.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Caltabiano, Dr Gianluigi and Milligan, Professor Graeme and Pou, Dr Chantevy and Marsango, Dr Sara |
| Authors: | Marsango, S., Caltabiano, G., Pou, C., Varela Liste, M. J., and Milligan, G. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences College of Medical Veterinary and Life Sciences > School of Molecular Biosciences |
| Journal Name: | Journal of Biological Chemistry |
| Publisher: | American Society for Biochemistry and Molecular Biology, Inc. |
| ISSN: | 0021-9258 |
| ISSN (Online): | 1083-351X |
| Copyright Holders: | Copyright © 2015 American Society for Biochemistry and Molecular Biology, Inc. |
| First Published: | First published in Journal of Biological Chemistry 290;15146-15162 |
| Publisher Policy: | Reproduced under a Creative Commons License |
University Staff: Request a correction | Enlighten Editors: Update this record
Altmetric
Altmetric