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

Autor:	Cahill TJ 3rd; Department of Medicine, Duke University Medical Center, Durham, NC 27710.; Department of Biochemistry, Duke University Medical Center, Durham, NC 27710., Thomsen AR; Department of Medicine, Duke University Medical Center, Durham, NC 27710., Tarrasch JT; Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109.; Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109., Plouffe B; Department of Biochemistry, Institute for Research in Immunology and Cancer, University of Montreal, Montreal, QC H3C 3J7, Canada., Nguyen AH; Department of Medicine, Duke University Medical Center, Durham, NC 27710.; Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710., Yang F; Department of Molecular Biology and Biochemistry, Shandong University School of Medicine, Jinan, Shandong 250012, China., Huang LY; Department of Medicine, Duke University Medical Center, Durham, NC 27710., Kahsai AW; Department of Medicine, Duke University Medical Center, Durham, NC 27710., Bassoni DL; DiscoverX Corporation, Fremont, CA 94538., Gavino BJ; DiscoverX Corporation, Fremont, CA 94538., Lamerdin JE; DiscoverX Corporation, Fremont, CA 94538., Triest S; Structural Biology Brussels, Vrije Universiteit Brussels, B-1050 Brussels, Belgium.; Structural Biology Research Center, Vlaams Instituut voor Biotechnologie, B-1050 Brussels, Belgium., Shukla AK; Department of Medicine, Duke University Medical Center, Durham, NC 27710., Berger B; Department of Biochemistry, Duke University Medical Center, Durham, NC 27710., Little J 4th; Department of Biochemistry, Duke University Medical Center, Durham, NC 27710., Antar A; Department of Biochemistry, Duke University Medical Center, Durham, NC 27710., Blanc A; Department of Biochemistry, Duke University Medical Center, Durham, NC 27710., Qu CX; Department of Molecular Biology and Biochemistry, Shandong University School of Medicine, Jinan, Shandong 250012, China., Chen X; School of Pharmaceutical Engineering and Life Sciences, Changzhou University, Changzhou, Jiangsu 213164, China., Kawakami K; Graduate School of Pharmaceutical Science, Tohoku University, Sendai, Miyagi 980-8578, Japan., Inoue A; Graduate School of Pharmaceutical Science, Tohoku University, Sendai, Miyagi 980-8578, Japan.; Japan Science and Technology Agency (JST), Precursory Research for Embryonic Science and Technology (PRESTO), Kawaguchi, Saitama 332-0012, Japan., Aoki J; Graduate School of Pharmaceutical Science, Tohoku University, Sendai, Miyagi 980-8578, Japan.; Core Research for Evolutionary Science and Technology (AMED-CREST), Japan Agency for Medical Research and Development, Chiyoda-ku, Tokyo 100-0004, Japan., Steyaert J; Structural Biology Brussels, Vrije Universiteit Brussels, B-1050 Brussels, Belgium.; Structural Biology Research Center, Vlaams Instituut voor Biotechnologie, B-1050 Brussels, Belgium., Sun JP; Department of Molecular Biology and Biochemistry, Shandong University School of Medicine, Jinan, Shandong 250012, China., Bouvier M; Department of Biochemistry, Institute for Research in Immunology and Cancer, University of Montreal, Montreal, QC H3C 3J7, Canada., Skiniotis G; Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109.; Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109., Lefkowitz RJ; Department of Medicine, Duke University Medical Center, Durham, NC 27710; lefko001@receptor-biol.duke.edu.; Department of Biochemistry, Duke University Medical Center, Durham, NC 27710.; Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2017 Mar 07; Vol. 114 (10), pp. 2562-2567. Date of Electronic Publication: 2017 Feb 21.
DOI:	10.1073/pnas.1701529114
Abstrakt:	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.
Databáze:	MEDLINE
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