Oligomerization of the Human Adenosine A_2AReceptor is Driven by the Intrinsically Disordered C-terminus

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 A_2Areceptor (A_2AR), a model GPCR that forms oligomers bothin vitroandin vivo. Combining experimental and computational approaches, we discover that the intrinsically disordered C-terminus of A_2AR drives the homo-oligomerization of the receptor. The formation of A_2AR oligomers declines progressively and systematically with the shortening of the C-terminus. Multiple interaction sites and types are responsible for A_2AR 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 A_2AR 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 A_2AR and other GPCRs.