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Monitoring GPCR-β-arrestin1/2 Interactions in Real Time Living Systems to Accelerate Drug Discovery
Published on: June 28, 2019
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GPCR binding and JNK3 activation by arrestin-3 have different structural requirements
Chen Zheng1, Liana D Weinstein1, Kevin K Nguyen1
1Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.
Biorxiv : the Preprint Server for Biology
|May 19, 2023
Summary
Arrestin-3 uniquely activates JNK3, a function independent of its binding to G protein-coupled receptors (GPCRs). This suggests arrestin-3
Area of Science:
- Molecular and Cellular Biology
- Biochemistry
- Pharmacology
Background:
- Arrestins are key regulators of G protein-coupled receptor (GPCR) signaling.
- Arrestin-3 is the sole subtype shown to activate JNK3.
- Specific lysine residues (Lys-295 in arrestin-3, Lys-294 in arrestin-2) are implicated in GPCR binding via phosphate interactions.
Approach:
- Investigated the distinct roles of arrestin-3 conformational states and Lys-295 in GPCR binding and JNK3 activation.
- Utilized various arrestin-3 mutants with altered GPCR binding affinities and Lys-295 charge properties.
- Assessed GPCR recruitment, subcellular localization, and JNK3 activation efficacy of these mutants.
Key Points:
- Mutants with enhanced GPCR binding exhibited reduced JNK3 activation, while a GPCR-non-binding mutant showed increased activity.
- Subcellular distribution did not correlate with GPCR recruitment or JNK3 activation.
- Lys-295 mutations differentially impacted receptor binding but had minimal effect on JNK3 activation.
Conclusions:
- GPCR binding and arrestin-3-mediated JNK3 activation possess distinct structural requirements.
- Arrestin-3's facilitation of JNK3 activation is likely a function independent of its GPCR-bound state.
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