Distinct conformations of GPCR-β-arrestin complexes mediate desensitization, signaling, and endocytosis.

TitleDistinct conformations of GPCR-β-arrestin complexes mediate desensitization, signaling, and endocytosis.
Publication TypeJournal Article
Year of Publication2017
AuthorsCahill, T. J., A. R. B. Thomsen, J. T. Tarrasch, B. Plouffe, A. H. Nguyen, F. Yang, L-Y. Huang, A. W. Kahsai, D. L. Bassoni, B. J. Gavino, J. E. Lamerdin, S. Triest, A. K. Shukla, B. Berger, J. Little, A. Antar, A. Blanc, C-X. Qu, X. Chen, K. Kawakami, A. Inoue, J. Aoki, J. Steyaert, J-P. Sun, M. Bouvier, G. Skiniotis, and R. J. Lefkowitz
JournalProc Natl Acad Sci U S A
Volume114
Issue10
Pagination2562-2567
Date Published2017 Mar 07
ISSN1091-6490
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.

DOI10.1073/pnas.1701529114
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID28223524
PubMed Central IDPMC5347553
Grant ListR01 DK090165 / DK / NIDDK NIH HHS / United States
F30 HL129803 / HL / NHLBI NIH HHS / United States
T32 HL007101 / HL / NHLBI NIH HHS / United States
R01 HL016037 / HL / NHLBI NIH HHS / United States
T32 GM007171 / GM / NIGMS NIH HHS / United States
R01 GM069905 / GM / NIGMS NIH HHS / United States
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