@article{ab0426903bb24043b6dc0307eec2de56,
title = "Distinct conformations of GPCR-β-arrestin complexes mediate desensitization, signaling, and endocytosis",
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.",
keywords = "Arrestin, Desensitization, Endocytosis, GPCR, Signaling",
author = "Cahill, {Thomas J.} and Thomsen, {Alex R.B.} and Tarrasch, {Jeffrey T.} and Bianca Plouffe and Nguyen, {Anthony H.} and Fan Yang and Huang, {Li Yin} and Kahsai, {Alem W.} and Bassoni, {Daniel L.} and Gavino, {Bryant J.} and Lamerdin, {Jane E.} and Sarah Triest and Shukla, {Arun K.} and Benjamin Berger and John Little and Albert Antar and Adi Blanc and Qu, {Chang Xiu} and Xin Chen and Kouki Kawakami and Asuka Inoue and Junken Aoki and Jan Steyaert and Sun, {Jin Peng} and Michel Bouvier and Georgios Skiniotis and Lefkowitz, {Robert J.}",
note = "Funding Information: We thank L. Barak for generous gifts of plasmids encoding GFP-βarr1. We thank C.-R. Liang, L.-L. Gu, and J.-M. Shan for synthesizing BI-167107 compound. We thank C. Cahill, P. Achacoso, S. Johnson, C. Le Gouill, A. Laperri{\`e}re, M. Walters, M. DeLong, M. Plue, T. Milledge, D. Capel, and X. Jiang for support and discussion. This work received support from NIH Grants F30HL129803 (to T.J.C.), T32HL007101 (to A.W.K.), DK090165 (to G.S.), and HL16037 (to R.J.L.); the Danish Council for Independent Research and Lundbeck Foundation (A.R.B.T.); a Canadian Institutes of Health Research (CIHR) postdoctoral fellowship (to B.P.) and CIHR Grant MOP10501 (to M.B.); JST, PRESTO (to A.I.), and AMED-CREST (to J.A.); and a Howard Hughes Medical Institute (HHMI) Medical Research Fellowship (to A.H.N.). R.J.L. is an HHMI Investigator and a cofounder and shareholder of Trevena. M.B. holds a Canada Research Chair in Signal Transduction and Molecular Pharmacology. Publisher Copyright: {\textcopyright} 2017, National Academy of Sciences. All rights reserved.",
year = "2017",
month = mar,
day = "7",
doi = "10.1073/pnas.1701529114",
language = "English (US)",
volume = "114",
pages = "2562--2567",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "10",
}