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.
Highlights
G protein-coupled receptors (GPCRs) have long been studied as monomeric units, but 43 accumulating evidence demonstrates that these receptors can form homo- and hetero44 oligomers with far-reaching functional implications
We explore the role of an intrinsically disordered region (IDR) of a model GPCR that could engage in diverse non-covalent interactions, such as electrostatic interactions, hydrogen bonds or hydrophobic interactions
This study focuses on the homooligomerization of the human adenosine A2A receptor (A2AR), a model GPCR, and seeks to address: (i) whether the C-terminus engages in A2AR oligomerization, and if so, (ii) whether the C-terminus forms multiple oligomeric interfaces
Summary
G protein-coupled receptors (GPCRs) have long been studied as monomeric units, but 43 accumulating evidence demonstrates that these receptors can form homo- and hetero oligomers with far-reaching functional implications. With the vast number of genes identified in the human genome(Takeda et al 2002), GPCRs are able to form a daunting number of combinations with unprecedented functional consequences. The existence of this intricate network of interactions among GPCRs presents major challenges and opportunities for the development of novel therapeutic approaches(Dorsam and Gutkind 2007; Farran 2017; Schonenbach, Hussain, and O’Malley 2015; Ferré et al 2014; Bräuner-Osborne, Wellendorph, and Jensen, n.d.; George, O’Dowd, and Lee 2002). It is crucial to identify the driving factors of GPCR oligomerization, such that this process can be more deliberately controlled to facilitate structure-function studies of GPCRs
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
