Author:
Cahill Thomas J.,Thomsen Alex R. B.,Tarrasch Jeffrey T.,Plouffe Bianca,Nguyen Anthony H.,Yang Fan,Huang Li-Yin,Kahsai Alem W.,Bassoni Daniel L.,Gavino Bryant J.,Lamerdin Jane E.,Triest Sarah,Shukla Arun K.,Berger Benjamin,Little John,Antar Albert,Blanc Adi,Qu Chang-Xiu,Chen Xin,Kawakami Kouki,Inoue Asuka,Aoki Junken,Steyaert Jan,Sun Jin-Peng,Bouvier Michel,Skiniotis Georgios,Lefkowitz Robert J.
Abstract
β-Arrestins (βarrs) interact with G protein-coupled receptors (GPCRs) to desensitize G protein signaling, to initiate signaling on their own, and to mediate receptor endocytosis. Prior structural studies have revealed two unique conformations of GPCR–βarr complexes: the “tail” conformation, with βarr primarily coupled to the phosphorylated GPCR C-terminal tail, and the “core” conformation, where, in addition to the phosphorylated C-terminal tail, βarr is further engaged with the receptor transmembrane core. However, the relationship of these distinct conformations to the various functions of βarrs is unknown. Here, we created a mutant form of βarr lacking the “finger-loop” region, which is unable to form the core conformation but retains the ability to form the tail conformation. We find that the tail conformation preserves the ability to mediate receptor internalization and βarr signaling but not desensitization of G protein signaling. Thus, the two GPCR–βarr conformations can carry out distinct functions.
Funder
HHS | NIH | National Heart, Lung, and Blood Institute
Howard Hughes Medical Institute
HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases
Det Frie Forskningsråd
Lundbeckfonden
Gouvernement du Canada | Canadian Institutes of Health Research
Publisher
Proceedings of the National Academy of Sciences