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

Thomas J. Cahill, Alex R.B. Thomsen, Jeffrey T. Tarrasch, Bianca Plouffe, Anthony H. Nguyen, Fan Yang, Li Yin Huang, Alem W. Kahsai, Daniel L. Bassoni, Bryant J. Gavino, Jane E. Lamerdin, Sarah Triest, Arun K. Shukla, Benjamin Berger, John Little, Albert Antar, Adi Blanc, Chang Xiu Qu, Xin Chen, Kouki KawakamiAsuka Inoue, Junken Aoki, Jan Steyaert, Jin Peng Sun, Michel Bouvier, Georgios Skiniotis, Robert J. Lefkowitz

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)2562-2567
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number10
DOIs
StatePublished - Mar 7 2017

Keywords

  • Arrestin
  • Desensitization
  • Endocytosis
  • GPCR
  • Signaling

ASJC Scopus subject areas

  • General

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  • Cite this

    Cahill, T. J., Thomsen, A. R. B., Tarrasch, J. T., Plouffe, B., Nguyen, A. H., Yang, F., Huang, L. Y., Kahsai, A. W., Bassoni, D. L., Gavino, B. J., Lamerdin, J. E., Triest, S., Shukla, A. K., Berger, B., Little, J., Antar, A., Blanc, A., Qu, C. X., Chen, X., ... Lefkowitz, R. J. (2017). Distinct conformations of GPCR-β-arrestin complexes mediate desensitization, signaling, and endocytosis. Proceedings of the National Academy of Sciences of the United States of America, 114(10), 2562-2567. https://doi.org/10.1073/pnas.1701529114