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.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710.|Department of Biochemistry, Duke University Medical Center, Durham, NC 27710.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Cahill
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710.
authors.forename: Alex R B
authors.initials: AR
authors.lastname: Thomsen
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109.|Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Tarrasch
authors.affiliation: Department of Biochemistry, Institute for Research in Immunology and Cancer, University of Montreal, Montreal, QC H3C 3J7, Canada.
authors.forename: Bianca
authors.initials: B
authors.lastname: Plouffe
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710.|Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710.
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Nguyen
authors.affiliation: Department of Molecular Biology and Biochemistry, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710.
authors.forename: Li-Yin
authors.initials: LY
authors.lastname: Huang
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710.
authors.forename: Alem W
authors.initials: AW
authors.lastname: Kahsai
authors.affiliation: DiscoverX Corporation, Fremont, CA 94538.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Bassoni
authors.affiliation: DiscoverX Corporation, Fremont, CA 94538.
authors.forename: Bryant J
authors.initials: BJ
authors.lastname: Gavino
authors.affiliation: DiscoverX Corporation, Fremont, CA 94538.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Lamerdin
authors.affiliation: Structural Biology Brussels, Vrije Universiteit Brussels, B-1050 Brussels, Belgium.|Structural Biology Research Center, Vlaams Instituut voor Biotechnologie, B-1050 Brussels, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Triest
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Shukla
authors.affiliation: Department of Biochemistry, Duke University Medical Center, Durham, NC 27710.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Berger
authors.affiliation: Department of Biochemistry, Duke University Medical Center, Durham, NC 27710.
authors.forename: John
authors.initials: J
authors.lastname: Little
authors.affiliation: Department of Biochemistry, Duke University Medical Center, Durham, NC 27710.
authors.forename: Albert
authors.initials: A
authors.lastname: Antar
authors.affiliation: Department of Biochemistry, Duke University Medical Center, Durham, NC 27710.
authors.forename: Adi
authors.initials: A
authors.lastname: Blanc
authors.affiliation: Department of Molecular Biology and Biochemistry, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Chang-Xiu
authors.initials: CX
authors.lastname: Qu
authors.affiliation: School of Pharmaceutical Engineering and Life Sciences, Changzhou University, Changzhou, Jiangsu 213164, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: Graduate School of Pharmaceutical Science, Tohoku University, Sendai, Miyagi 980-8578, Japan.
authors.forename: Kouki
authors.initials: K
authors.lastname: Kawakami
authors.affiliation: 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.
authors.forename: Asuka
authors.initials: A
authors.lastname: Inoue
authors.affiliation: 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.
authors.forename: Junken
authors.initials: J
authors.lastname: Aoki
authors.affiliation: Structural Biology Brussels, Vrije Universiteit Brussels, B-1050 Brussels, Belgium.|Structural Biology Research Center, Vlaams Instituut voor Biotechnologie, B-1050 Brussels, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Steyaert
authors.affiliation: Department of Molecular Biology and Biochemistry, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Jin-Peng
authors.initials: JP
authors.lastname: Sun
authors.affiliation: Department of Biochemistry, Institute for Research in Immunology and Cancer, University of Montreal, Montreal, QC H3C 3J7, Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Bouvier
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109.|Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Georgios
authors.initials: G
authors.lastname: Skiniotis
authors.affiliation: 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.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lefkowitz
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D004705:Endocytosis / Q000235:genetics*; D020555:GTP-Binding Protein Regulators / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D008968:Molecular Conformation; D046912:Multiprotein Complexes; D050505:Mutant Proteins / Q000737:chemistry* / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000235:genetics; D000071557:beta-Arrestins / Q000737:chemistry* / Q000235:genetics
chemical_list: D020555:GTP-Binding Protein Regulators; D046912:Multiprotein Complexes; D050505:Mutant Proteins; D043562:Receptors, G-Protein-Coupled; D000071557:beta-Arrestins
keywords: GPCR; arrestin; desensitization; endocytosis; signaling