Journal
CELL
Volume 185, Issue 10, Pages 1661-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2022.03.042
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Funding
- NIH [R21NS102694, R01MH054137, R01HL016037, R35 GM122491, R01 GM130142]
- Hope for Depression Research Foundation
- Brain and Behavior Research Foundation NARSAD Young Investigator Award
- National Institute on Drug Abuse - Intramural Research Program [Z1A DA000606]
- PhRMA Foundation
- Single-Molecule Imaging Center at St. Jude Children's Research Hospital
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Beta-arrestins are strongly autoinhibited in their basal state but can be activated by phosphorylated receptors and receptor agonism, releasing the beta-arrestin tail and allowing it to assume different conformations. The rate and efficiency of beta-arrestin activation depend on the phosphorylation pattern of the receptor and agonist-promoted receptor activation.
beta-arrestins bind G protein-coupled receptors to terminate G protein signaling and to facilitate other downstream signaling pathways. Using single-molecule fluorescence resonance energy transfer imaging, we show that beta-arrestin is strongly autoinhibited in its basal state. Its engagement with a phosphopeptide mimicking phosphorylated receptor tail efficiently releases the beta-arrestin tail from its N domain to assume distinct conformations. Unexpectedly, we find that beta-arrestin binding to phosphorylated receptor, with a phosphorylation barcode identical to the isolated phosphopeptide, is highly inefficient and that agonist-promoted receptor activation is required for beta-arrestin activation, consistent with the release of a sequestered receptor C tail. These findings, together with focused cellular investigations, reveal that agonism and receptor C-tail release are specific determinants of the rate and efficiency of beta-arrestin activation by phosphorylated receptor. We infer that receptor phosphorylation patterns, in combination with receptor agonism, synergistically establish the strength and specificity with which diverse, downstream beta-arrestin-mediated events are directed.
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