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

Publication ,  Journal Article
Cahill, TJ; Thomsen, ARB; Tarrasch, JT; Plouffe, B; Nguyen, AH; Yang, F; Huang, L-Y; Kahsai, AW; Bassoni, DL; Gavino, BJ; Lamerdin, JE ...
Published in: Proc Natl Acad Sci U S A
March 7, 2017

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.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

March 7, 2017

Volume

114

Issue

10

Start / End Page

2562 / 2567

Location

United States

Related Subject Headings

  • beta-Arrestins
  • Receptors, G-Protein-Coupled
  • Mutant Proteins
  • Multiprotein Complexes
  • Molecular Conformation
  • Humans
  • HEK293 Cells
  • GTP-Binding Protein Regulators
  • Endocytosis
  • Amino Acid Sequence
 

Citation

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Cahill, T. J., Thomsen, A. R. B., Tarrasch, J. T., Plouffe, B., Nguyen, A. H., Yang, F., … Lefkowitz, R. J. (2017). Distinct conformations of GPCR-β-arrestin complexes mediate desensitization, signaling, and endocytosis. Proc Natl Acad Sci U S A, 114(10), 2562–2567. https://doi.org/10.1073/pnas.1701529114
Cahill, Thomas J., Alex R. B. Thomsen, Jeffrey T. Tarrasch, Bianca Plouffe, Anthony H. Nguyen, Fan Yang, Li-Yin Huang, et al. “Distinct conformations of GPCR-β-arrestin complexes mediate desensitization, signaling, and endocytosis.Proc Natl Acad Sci U S A 114, no. 10 (March 7, 2017): 2562–67. https://doi.org/10.1073/pnas.1701529114.
Cahill TJ, Thomsen ARB, Tarrasch JT, Plouffe B, Nguyen AH, Yang F, et al. Distinct conformations of GPCR-β-arrestin complexes mediate desensitization, signaling, and endocytosis. Proc Natl Acad Sci U S A. 2017 Mar 7;114(10):2562–7.
Cahill, Thomas J., et al. “Distinct conformations of GPCR-β-arrestin complexes mediate desensitization, signaling, and endocytosis.Proc Natl Acad Sci U S A, vol. 114, no. 10, Mar. 2017, pp. 2562–67. Pubmed, doi:10.1073/pnas.1701529114.
Cahill TJ, Thomsen ARB, Tarrasch JT, Plouffe B, Nguyen AH, Yang F, Huang L-Y, Kahsai AW, Bassoni DL, Gavino BJ, Lamerdin JE, Triest S, Shukla AK, Berger B, Little J, Antar A, Blanc A, Qu C-X, Chen X, Kawakami K, Inoue A, Aoki J, Steyaert J, Sun J-P, Bouvier M, Skiniotis G, Lefkowitz RJ. Distinct conformations of GPCR-β-arrestin complexes mediate desensitization, signaling, and endocytosis. Proc Natl Acad Sci U S A. 2017 Mar 7;114(10):2562–2567.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

March 7, 2017

Volume

114

Issue

10

Start / End Page

2562 / 2567

Location

United States

Related Subject Headings

  • beta-Arrestins
  • Receptors, G-Protein-Coupled
  • Mutant Proteins
  • Multiprotein Complexes
  • Molecular Conformation
  • Humans
  • HEK293 Cells
  • GTP-Binding Protein Regulators
  • Endocytosis
  • Amino Acid Sequence