Homo-oligomerization of the human adenosine A2a receptor is driven by the intrinsically disordered C-terminus
Abstract
G protein-coupled receptors (GPCRs) have long been shown to exist as oligomers with functional properties distinct from those of the monomeric counterparts, but the driving factors of oligomerization remain relatively unexplored. Herein, we focus on the human adenosine A2A receptor (A2AR), a model GPCR that forms oligomers both in vitro and in vivo. Combining experimental and computational approaches, we discover that the intrinsically disordered C-terminus of A2AR drives receptor homo-oligomerization. The formation of A2AR oligomers declines progressively with the shortening of the C-terminus. Multiple interaction types are responsible for A2AR oligomerization, including disulfide linkages, hydrogen bonds, electrostatic interactions, and hydrophobic interactions. These interactions are enhanced by depletion interactions, giving rise to a tunable network of bonds that allow A2AR oligomers to adopt multiple interfaces. This study uncovers the disordered C-terminus as a prominent driving factor for the oligomerization of a GPCR, offering important insight into the effect of C-terminus modification on receptor oligomerization of A2AR and other GPCRs reconstituted in vitro for biophysical studies.
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All data generated or analysed during this study are included in the manuscript and supporting files.
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Funding
National Institute of General Medical Sciences (R35GM136411)
- Khanh Dinh Quoc Nguyen
- Michael Vigers
- Susanna Seppälä
- Nicole Star Schonenbach
- Michelle Ann O'Malley
- Songi Han
National Institute of Mental Health (Small Business Innovation Research Award,1R43MH119906-01)
- Khanh Dinh Quoc Nguyen
- Jennifer Paige Hoover
- Michelle Ann O'Malley
- Songi Han
National Science Foundation (MCB-1714888)
- Eric Sefah
- Blake Mertz
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2021, Nguyen et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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