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09:03
Parallel Interrogation of β-Arrestin2 Recruitment for Ligand Screening on a GPCR-Wide Scale using PRESTO-Tango Assay
Published on: March 10, 2020
Distinct loops in arrestin differentially regulate ligand binding within the GPCR opsin.
Martha E Sommer1, Klaus Peter Hofmann, Martin Heck
1Institut für Medizinische Physik und Biophysik (CC2), Charité - Universitätsmedizin Berlin, Charitéplatz 1, D-10117 Berlin, Germany. martha.sommer@charite.de
Nature Communications
|August 9, 2012
Summary
Rod arrestin selectively binds phosphorylated opsin, sequestering toxic all-trans-retinal in half the receptors. This asymmetric binding allows rhodopsin regeneration in the remaining receptors, protecting rod cells in bright light.
Area of Science:
- Biochemistry
- Molecular Biology
- Vision Science
Background:
- G-protein-coupled receptors (GPCRs) are crucial cell signaling proteins.
- Arrestin binding is a universal mechanism for GPCR regulation.
- Rod opsin, a GPCR, plays a key role in visual signal transduction.
Purpose of the Study:
- To investigate the mechanism of rod arrestin binding to phosphorylated opsin.
- To elucidate how arrestin binding affects ligand uptake and rhodopsin regeneration.
- To understand the role of arrestin's distinct domains in receptor interaction.
Main Methods:
- Utilized environmentally sensitive fluorophores attached to arrestin.
- Studied arrestin binding to phosphorylated opsin in native membranes.
- Analyzed the effects of arrestin binding on all-trans-retinal and 11-cis-retinal binding.
Main Results:
- Rod arrestin induced all-trans-retinal uptake in only half of the phosphorylated opsin population.
- Agonist uptake blocked subsequent 11-cis-retinal binding (regeneration) in occupied receptors.
- The other half of aporeceptors remained available for regeneration.
- Arrestin's N-domain (loop V-VI) conformational changes correlate with agonist entry.
- Arrestin's C-domain (loop XVIII-XIX) engages the aporeceptor prior to agonist binding.
Conclusions:
- A model is proposed where distinct arrestin domains bind to separate aporeceptor sites.
- Asymmetric ligand binding by aporeceptors results from differential domain engagement.
- This mechanism protects rod cells by sequestering toxic all-trans-retinal while permitting regeneration.
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