Plasma membrane preassociation drives β-arrestin coupling to receptors and activation

Grimes, Jak; Köszegi, Zsombor; Lanoiselée, Yann; Miljuš, Tamara; O’Brien, Shannon; Stępniewski, Tomasz Maciej; Medel-Lacruz, Brian; Baidya, Mithu; Makarova, Maria; Mistry, Ravi; Goulding, Joëlle; Drube, Julia; Hoffmann, Carsten; Owen, Dylan M.; Shukla, Arun Kumar; Selent, Jana; Hill, Stephen J.; Calebiro, Davide

doi:10.1016/j.cell.2023.04.018

Cited by 28 publications

(12 citation statements)

References 95 publications

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“…LB is also observed for the L71C site in the finger loop and the F244C site in the C loop (Fig. 7c ), which is in good agreement with the MD results by Grimes et al 39 . The linewidths for both sites are smaller than the C-edge loops and no obvious chemical shift changes are observed, supporting transient membrane interaction.…”

Section: Resultssupporting

confidence: 91%

“…GPCR-βarr interactions occur at the plasma membrane, and the βarr C-edge loops are known to bind the lipid bilayer. A recent study by Grimes et al 39 shows that βarrs spontaneously pre-associate with the membrane, which facilitates their interactions with the receptor. As presented above, our NMR data indicates that V2Rpp-binding induces long-range allosteric effects and results in spectral changes in both C-edge loops, particularly at the L334C site (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Distinct activation mechanisms of β-arrestin-1 revealed by 19F NMR spectroscopy

Zhai,

Wang,

Chai

et al. 2023

Nat Commun

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Abstractβ-Arrestins (βarrs) are functionally versatile proteins that play critical roles in the G-protein-coupled receptor (GPCR) signaling pathways. While it is well established that the phosphorylated receptor tail plays a central role in βarr activation, emerging evidence highlights the contribution from membrane lipids. However, detailed molecular mechanisms of βarr activation by different binding partners remain elusive. In this work, we present a comprehensive study of the structural changes in critical regions of βarr1 during activation using 19F NMR spectroscopy. We show that phosphopeptides derived from different classes of GPCRs display different βarr1 activation abilities, whereas binding of the membrane phosphoinositide PIP2 stabilizes a distinct partially activated conformational state. Our results further unveil a sparsely-populated activation intermediate as well as complex cross-talks between different binding partners, implying a highly multifaceted conformational energy landscape of βarr1 that can be intricately modulated during signaling.

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Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Distinct activation mechanisms of β-arrestin-1 revealed by 19F NMR spectroscopy

Zhai,

Wang,

Chai

et al. 2023

Nat Commun

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“…Regarding the importance of steady-state PIP2 levels for receptor endocytosis, our results do not contradict the current consensus. The central role of PIP2 in GPCR-β-arrestin interactions has been confirmed recently in two elegant studies proposing that PIP2 binding may promote an “active-like” conformation for β-arrestins 31 or even drive their weak, spontaneous PM association, which then facilitates receptor-β-arrestin interactions 32 . In light of these findings, an overall reduction in steady-state PM PIP2 levels might slow the initiation of receptor endocytosis, which could explain the delayed kinetics of our endosomal receptor signals even when the end-point signal amplitude was not significantly reduced (e.g., Fig.…”

Section: Discussionmentioning

confidence: 90%

Effect of hormone-induced plasma membrane phosphatidylinositol 4,5-bisphosphate depletion on receptor endocytosis suggests the importance of local regulation in phosphoinositide signaling

Tóth,

Damouni

et al. 2024

Sci Rep

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Phosphatidylinositol 4,5-bisphosphate (PIP2) has been shown to be critical for the endocytosis of G protein-coupled receptors (GPCRs). We have previously demonstrated that depletion of PIP2 by chemically induced plasma membrane (PM) recruitment of a 5-phosphatase domain prevents the internalization of the β2 adrenergic receptor (β2AR) from the PM to early endosomes. In this study, we tested the effect of hormone-induced PM PIP2 depletion on β2AR internalization using type-1 angiotensin receptor (AT1R) or M3 muscarinic acetylcholine receptor (M3R). We followed the endocytic route of β2ARs in HEK 293T cells using bioluminescence resonance energy transfer between the receptor and endosome marker Rab5. To compare the effect of lipid depletion by different means, we created and tested an AT1R fusion protein that is capable of both recruitment-based and hormone-induced depletion methods. The rate of PM PIP2 depletion was measured using a biosensor based on the PH domain of phospholipase Cδ1. As expected, β2AR internalization was inhibited when PIP2 depletion was evoked by recruiting 5-phosphatase to PM-anchored AT1R. A similar inhibition occurred when wild-type AT1R was activated by adding angiotensin II. However, stimulation of the desensitization/internalization-impaired mutant AT1R (TSTS/4A) caused very little inhibition of β2AR internalization, despite the higher rate of measurable PIP2 depletion. Interestingly, inhibition of PIP2 resynthesis with the selective PI4KA inhibitor GSK-A1 had little effect on the change in PH-domain-measured PM PIP2 levels but did significantly decrease β2AR internalization upon either AT1R or M3R activation, indicating the importance of a locally synthetized phosphoinositide pool in the regulation of this process.

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“…[22] Even at the plasma membrane, there is heterogeneity in receptor expression, where hotspots for G protein:GPCR and β-arrestin:GPCR interactions can form in clathrincoated pits due to the regional composition promoting greater complex stabilization. [23,24] Signaling from such membrane microdomains also falls under the larger umbrella of location bias. Following activation, many GPCRs undergo receptor-mediated endocytosis which can serve as one mechanism to abrogate GPCR signaling by restricting the pool of ligand-accessible receptor or targeting the receptor for degradation.…”

Section: The Role Of β-Arrestins and G Proteins In Gpcr Signaling Fro...mentioning

confidence: 99%

Location bias: A “Hidden Variable” in GPCR pharmacology

Eiger,

Hicks,

Gardner

et al. 2023

BioEssays

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G protein‐coupled receptors (GPCRs) are the largest family of transmembrane receptors and primarily signal through two main effector proteins: G proteins and β‐arrestins. Many agonists of GPCRs promote “biased” responses, in which different cellular signaling pathways are activated with varying efficacies. The mechanisms underlying biased signaling have not been fully elucidated, with many potential “hidden variables” that regulate this behavior. One contributor is “location bias,” which refers to the generation of unique signaling cascades from a given GPCR depending upon the cellular location at which the receptor is signaling. Here, we review evidence that GPCRs are expressed at and traffic to various subcellular locations and discuss how location bias can impact the pharmacologic properties and characterization of GPCR agonists. We also evaluate how differences in subcellular environments can modulate GPCR signaling, highlight the physiological significance of subcellular GPCR signaling, and discuss the therapeutic potential of exploiting GPCR location bias.

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Plasma membrane preassociation drives β-arrestin coupling to receptors and activation

Cited by 28 publications

References 95 publications

Distinct activation mechanisms of β-arrestin-1 revealed by 19F NMR spectroscopy

Distinct activation mechanisms of β-arrestin-1 revealed by 19F NMR spectroscopy

Effect of hormone-induced plasma membrane phosphatidylinositol 4,5-bisphosphate depletion on receptor endocytosis suggests the importance of local regulation in phosphoinositide signaling

Location bias: A “Hidden Variable” in GPCR pharmacology

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