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Structural Insights into β-arrestin/CB1 Receptor Interaction: NMR and CD Studies on Model Peptides

Activation of the cannabinoid CB1 receptor induces different cellular signaling cascades through coupling to different effector proteins (G-proteins and β-arrestins), triggering numerous therapeutic effects. Conformational changes and rearrangements at the intracellular domain of this GPCR receptor...

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Detalles Bibliográficos
Autores principales: Morales, Paula, Bruix, Marta, Jiménez, M. Angeles
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662265/
https://www.ncbi.nlm.nih.gov/pubmed/33143110
http://dx.doi.org/10.3390/ijms21218111
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author Morales, Paula
Bruix, Marta
Jiménez, M. Angeles
author_facet Morales, Paula
Bruix, Marta
Jiménez, M. Angeles
author_sort Morales, Paula
collection PubMed
description Activation of the cannabinoid CB1 receptor induces different cellular signaling cascades through coupling to different effector proteins (G-proteins and β-arrestins), triggering numerous therapeutic effects. Conformational changes and rearrangements at the intracellular domain of this GPCR receptor that accompany ligand binding dictate the signaling pathways. The GPCR-binding interface for G proteins has been extensively studied, whereas β-arrestin/GPCR complexes are still poorly understood. To gain knowledge in this direction, we designed peptides that mimic the motifs involved in the putative interacting region: β-arrestin1 finger loop and the transmembrane helix 7-helix 8 (TMH7-H8) elbow located at the intracellular side of the CB1 receptor. According to circular dichroism and NMR data, these peptides form a native-like, helical conformation and interact with each other in aqueous solution, in the presence of trifluoroethanol, and using zwitterionic detergent micelles as membrane mimics. These results increase our understanding of the binding mode of β-arrestin and CB1 receptor and validate minimalist approaches to structurally comprehend complex protein systems.
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spelling pubmed-76622652020-11-14 Structural Insights into β-arrestin/CB1 Receptor Interaction: NMR and CD Studies on Model Peptides Morales, Paula Bruix, Marta Jiménez, M. Angeles Int J Mol Sci Article Activation of the cannabinoid CB1 receptor induces different cellular signaling cascades through coupling to different effector proteins (G-proteins and β-arrestins), triggering numerous therapeutic effects. Conformational changes and rearrangements at the intracellular domain of this GPCR receptor that accompany ligand binding dictate the signaling pathways. The GPCR-binding interface for G proteins has been extensively studied, whereas β-arrestin/GPCR complexes are still poorly understood. To gain knowledge in this direction, we designed peptides that mimic the motifs involved in the putative interacting region: β-arrestin1 finger loop and the transmembrane helix 7-helix 8 (TMH7-H8) elbow located at the intracellular side of the CB1 receptor. According to circular dichroism and NMR data, these peptides form a native-like, helical conformation and interact with each other in aqueous solution, in the presence of trifluoroethanol, and using zwitterionic detergent micelles as membrane mimics. These results increase our understanding of the binding mode of β-arrestin and CB1 receptor and validate minimalist approaches to structurally comprehend complex protein systems. MDPI 2020-10-30 /pmc/articles/PMC7662265/ /pubmed/33143110 http://dx.doi.org/10.3390/ijms21218111 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Morales, Paula
Bruix, Marta
Jiménez, M. Angeles
Structural Insights into β-arrestin/CB1 Receptor Interaction: NMR and CD Studies on Model Peptides
title Structural Insights into β-arrestin/CB1 Receptor Interaction: NMR and CD Studies on Model Peptides
title_full Structural Insights into β-arrestin/CB1 Receptor Interaction: NMR and CD Studies on Model Peptides
title_fullStr Structural Insights into β-arrestin/CB1 Receptor Interaction: NMR and CD Studies on Model Peptides
title_full_unstemmed Structural Insights into β-arrestin/CB1 Receptor Interaction: NMR and CD Studies on Model Peptides
title_short Structural Insights into β-arrestin/CB1 Receptor Interaction: NMR and CD Studies on Model Peptides
title_sort structural insights into β-arrestin/cb1 receptor interaction: nmr and cd studies on model peptides
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662265/
https://www.ncbi.nlm.nih.gov/pubmed/33143110
http://dx.doi.org/10.3390/ijms21218111
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