Homo-oligomerization of the human adenosine A2A receptor is driven by the intrinsically disordered C-terminus

eLife

Blake Mertz¹  Eric Sefah¹  Michael Vigers²  Nicole Star Schonenbach²  Susanna Seppälä²  Michelle Ann O'Malley²  Jennifer Paige Hoover³  Khanh Dinh Quoc Nguyen³  Songi Han⁴ 

[1] C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, United States;Department of Chemical Engineering, University of California, Santa Barbara, Santa Barbara, United States;Department of Chemistry and Biochemistry, University of California, Santa Barbara, Santa Barbara, United States;Department of Chemistry and Biochemistry, University of California, Santa Barbara, Santa Barbara, United States;Department of Chemical Engineering, University of California, Santa Barbara, Santa Barbara, United States;

关键词: c-terminus;    oligomerization;    gpcrs;    adenosine a2a receptor;    depletion interactions;    intrinsically disordered regions;    E. coli;    S. cerevisiae;   

DOI  :  10.7554/eLife.66662

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY