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Functional competence of a partially engaged GPCR–β-arrestin complex

G Protein-coupled receptors (GPCRs) constitute the largest family of cell surface receptors and drug targets. GPCR signalling and desensitization is critically regulated by β-arrestins (βarr). GPCR–βarr interaction is biphasic where the phosphorylated carboxyl terminus of GPCRs docks to the N-domain...

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Autores principales: Kumari, Punita, Srivastava, Ashish, Banerjee, Ramanuj, Ghosh, Eshan, Gupta, Pragya, Ranjan, Ravi, Chen, Xin, Gupta, Bhagyashri, Gupta, Charu, Jaiman, Deepika, Shukla, Arun K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5105198/
https://www.ncbi.nlm.nih.gov/pubmed/27827372
http://dx.doi.org/10.1038/ncomms13416
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author Kumari, Punita
Srivastava, Ashish
Banerjee, Ramanuj
Ghosh, Eshan
Gupta, Pragya
Ranjan, Ravi
Chen, Xin
Gupta, Bhagyashri
Gupta, Charu
Jaiman, Deepika
Shukla, Arun K.
author_facet Kumari, Punita
Srivastava, Ashish
Banerjee, Ramanuj
Ghosh, Eshan
Gupta, Pragya
Ranjan, Ravi
Chen, Xin
Gupta, Bhagyashri
Gupta, Charu
Jaiman, Deepika
Shukla, Arun K.
author_sort Kumari, Punita
collection PubMed
description G Protein-coupled receptors (GPCRs) constitute the largest family of cell surface receptors and drug targets. GPCR signalling and desensitization is critically regulated by β-arrestins (βarr). GPCR–βarr interaction is biphasic where the phosphorylated carboxyl terminus of GPCRs docks to the N-domain of βarr first and then seven transmembrane core of the receptor engages with βarr. It is currently unknown whether fully engaged GPCR–βarr complex is essential for functional outcomes or partially engaged complex can also be functionally competent. Here we assemble partially and fully engaged complexes of a chimeric β(2)V(2)R with βarr1, and discover that the core interaction is dispensable for receptor endocytosis, ERK MAP kinase binding and activation. Furthermore, we observe that carvedilol, a βarr biased ligand, does not promote detectable engagement between βarr1 and the receptor core. These findings uncover a previously unknown aspect of GPCR-βarr interaction and provide novel insights into GPCR signalling and regulatory paradigms.
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spelling pubmed-51051982016-11-18 Functional competence of a partially engaged GPCR–β-arrestin complex Kumari, Punita Srivastava, Ashish Banerjee, Ramanuj Ghosh, Eshan Gupta, Pragya Ranjan, Ravi Chen, Xin Gupta, Bhagyashri Gupta, Charu Jaiman, Deepika Shukla, Arun K. Nat Commun Article G Protein-coupled receptors (GPCRs) constitute the largest family of cell surface receptors and drug targets. GPCR signalling and desensitization is critically regulated by β-arrestins (βarr). GPCR–βarr interaction is biphasic where the phosphorylated carboxyl terminus of GPCRs docks to the N-domain of βarr first and then seven transmembrane core of the receptor engages with βarr. It is currently unknown whether fully engaged GPCR–βarr complex is essential for functional outcomes or partially engaged complex can also be functionally competent. Here we assemble partially and fully engaged complexes of a chimeric β(2)V(2)R with βarr1, and discover that the core interaction is dispensable for receptor endocytosis, ERK MAP kinase binding and activation. Furthermore, we observe that carvedilol, a βarr biased ligand, does not promote detectable engagement between βarr1 and the receptor core. These findings uncover a previously unknown aspect of GPCR-βarr interaction and provide novel insights into GPCR signalling and regulatory paradigms. Nature Publishing Group 2016-11-09 /pmc/articles/PMC5105198/ /pubmed/27827372 http://dx.doi.org/10.1038/ncomms13416 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Kumari, Punita
Srivastava, Ashish
Banerjee, Ramanuj
Ghosh, Eshan
Gupta, Pragya
Ranjan, Ravi
Chen, Xin
Gupta, Bhagyashri
Gupta, Charu
Jaiman, Deepika
Shukla, Arun K.
Functional competence of a partially engaged GPCR–β-arrestin complex
title Functional competence of a partially engaged GPCR–β-arrestin complex
title_full Functional competence of a partially engaged GPCR–β-arrestin complex
title_fullStr Functional competence of a partially engaged GPCR–β-arrestin complex
title_full_unstemmed Functional competence of a partially engaged GPCR–β-arrestin complex
title_short Functional competence of a partially engaged GPCR–β-arrestin complex
title_sort functional competence of a partially engaged gpcr–β-arrestin complex
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5105198/
https://www.ncbi.nlm.nih.gov/pubmed/27827372
http://dx.doi.org/10.1038/ncomms13416
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