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Discrete GPCR-triggered endocytic modes enable β-arrestins to flexibly regulate cell signaling
Benjamin Barsi-Rhyne1,2, Aashish Manglik3,4,5, Mark von Zastrow1,2,5,6
1Tetrad Graduate Program, University of California, San Francisco, San Francisco, United States.
Elife
|October 17, 2022
Summary
Researchers discovered a second way beta-arrestins (β-arrestins) trigger receptor endocytosis, involving the C-lobe base, not just the C-terminus. This dual mechanism allows for diverse cell signaling control.
Area of Science:
- Cellular signaling and protein-protein interactions
- Molecular mechanisms of receptor trafficking and desensitization
- G-protein-coupled receptor (GPCR) regulation
Background:
- Beta-arrestins (β-arrestins) are key regulators of G-protein-coupled receptor (GPCR) signaling, mediating receptor desensitization and endocytosis.
- Previously, only one mode of β-arrestin activation for endocytosis was known, involving the C-terminus (CT) displacement.
- GPCR-mediated β-arrestin activity is ligand-dependent and influences downstream signaling and trafficking.
Purpose of the Study:
- To investigate alternative mechanisms of GPCR-mediated β-arrestin endocytic activity.
- To identify novel modes of β-arrestin activation beyond C-terminus (CT) displacement.
- To understand how different activation modes influence GPCR signaling and trafficking.
Main Methods:
- Biochemical assays to analyze β-arrestin conformation and interactions.
- Investigating receptor-specific binding kinetics of β-arrestins to GPCRs.
- Assessing the impact of distinct β-arrestin activation modes on downstream signaling.
Main Results:
- A second mode of β-arrestin endocytic activity was identified, dependent on the C-lobe base (CLB) and independent of CT displacement.
- GPCRs were classified based on β-arrestin binding kinetics ('class A' for transient, 'class B' for stable).
- Class A GPCRs primarily trigger the CLB-dependent mode, while Class B GPCRs engage both CLB and CT modes.
- The CLB-dependent mode promotes rapid signal desensitization, whereas the CT-dependent mode supports prolonged signaling.
Conclusions:
- β-arrestin-mediated endocytosis is regulated by at least two distinct modes, involving the C-terminus (CT) and C-lobe base (CLB).
- Receptor binding properties dictate which β-arrestin activation mode is engaged, leading to differential signaling outcomes.
- This discovery provides a revised framework for understanding β-arrestin function in fine-tuning GPCR signaling and trafficking.
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