Biphasic activation of β-arrestin 1 upon interaction with a GPCR revealed by methyl-TROSY NMR

Yutaro Shiraishi, Yutaka Kofuku, Takumi Ueda, Shubhi Pandey, Hemlata Dwivedi-Agnihotri, Arun K. Shukla and Ichio Shimada ()
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Yutaro Shiraishi: Laboratory for Dynamic Structure of Biomolecules, RIKEN Center for Biosystems Dynamics Research (BDR)
Yutaka Kofuku: Graduate School of Pharmaceutical Sciences, The University of Tokyo
Takumi Ueda: Graduate School of Pharmaceutical Sciences, The University of Tokyo
Shubhi Pandey: Indian Institute of Technology
Hemlata Dwivedi-Agnihotri: Indian Institute of Technology
Arun K. Shukla: Indian Institute of Technology
Ichio Shimada: Laboratory for Dynamic Structure of Biomolecules, RIKEN Center for Biosystems Dynamics Research (BDR)

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: Abstract β-arrestins (βarrs) play multifaceted roles in the function of G protein-coupled receptors (GPCRs). βarrs typically interact with phosphorylated C-terminal tail (C tail) and transmembrane core (TM core) of GPCRs. However, the effects of the C tail- and TM core-mediated interactions on the conformational activation of βarrs have remained elusive. Here, we show the conformational changes for βarr activation upon the C tail- and TM core-mediated interactions with a prototypical GPCR by nuclear magnetic resonance (NMR) spectroscopy. Our NMR analyses demonstrated that while the C tail-mediated interaction alone induces partial activation, in which βarr exists in equilibrium between basal and activated conformations, the TM core- and the C tail-mediated interactions together completely shift the equilibrium toward the activated conformation. The conformation-selective antibody, Fab30, promotes partially activated βarr into the activated-like conformation. This plasticity of βarr conformation in complex with GPCRs engaged in different binding modes may explain the multifunctionality of βarrs.

Date: 2021
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DOI: 10.1038/s41467-021-27482-3

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