Oligomerization of the Human Adenosine A_2AReceptor 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 GPCR oligomerization remain relatively unexplored. In this study, 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 the homo-oligomerization of the receptor. The formation of A2AR oligomers declines progressively and systematically with the shortening of the C-terminus. Multiple interaction sites and types are responsible for A2AR oligomerization, including disulfide linkages, hydrogen bonds, electrostatic interactions, and hydrophobic interactions. These interactions are enhanced by depletion interactions along the C-terminus, forming 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 guidance for structure-function studies of A2AR and other GPCRs.

Modulation of adenosine A2a receptor oligomerization by receptor activation and PIP2 interactions

“…Such lipid interactions could be important in determining GPCR oligomerization, e.g., in functionally important nanodomains ( Calebiro and Sungkaworn, 2018 ) with a high local concentration of PIP 2 ( van den Bogaart et al., 2011 ). It is also possible that the intrinsically disordered C termini of GPCRs ( Nguyen et al, 2020 ) may play a role in interactions with anionic lipids, such as PIP 2 , especially as they contain multiple basic residues ( Tovo-Rodrigues et al., 2014 ).…”