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Distinct phosphorylation sites in a prototypical GPCR differently orchestrate β-arrestin interaction, trafficking, and signaling
Agonist-induced phosphorylation of G protein–coupled receptors (GPCRs) is a key determinant for their interaction with β-arrestins (βarrs) and subsequent functional responses. Therefore, it is important to decipher the contribution and interplay of different receptor phosphorylation sites in governi...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486103/ https://www.ncbi.nlm.nih.gov/pubmed/32917711 http://dx.doi.org/10.1126/sciadv.abb8368 |
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author | Dwivedi-Agnihotri, Hemlata Chaturvedi, Madhu Baidya, Mithu Stepniewski, Tomasz Maciej Pandey, Shubhi Maharana, Jagannath Srivastava, Ashish Caengprasath, Natarin Hanyaloglu, Aylin C. Selent, Jana Shukla, Arun K. |
author_facet | Dwivedi-Agnihotri, Hemlata Chaturvedi, Madhu Baidya, Mithu Stepniewski, Tomasz Maciej Pandey, Shubhi Maharana, Jagannath Srivastava, Ashish Caengprasath, Natarin Hanyaloglu, Aylin C. Selent, Jana Shukla, Arun K. |
author_sort | Dwivedi-Agnihotri, Hemlata |
collection | PubMed |
description | Agonist-induced phosphorylation of G protein–coupled receptors (GPCRs) is a key determinant for their interaction with β-arrestins (βarrs) and subsequent functional responses. Therefore, it is important to decipher the contribution and interplay of different receptor phosphorylation sites in governing βarr interaction and functional outcomes. Here, we find that several phosphorylation sites in the human vasopressin receptor (V(2)R), positioned either individually or in clusters, differentially contribute to βarr recruitment, trafficking, and ERK1/2 activation. Even a single phosphorylation site in V(2)R, suitably positioned to cross-talk with a key residue in βarrs, has a decisive contribution in βarr recruitment, and its mutation results in strong G-protein bias. Molecular dynamics simulation provides mechanistic insights into the pivotal role of this key phosphorylation site in governing the stability of βarr interaction and regulating the interdomain rotation in βarrs. Our findings uncover important structural aspects to better understand the framework of GPCR-βarr interaction and biased signaling. |
format | Online Article Text |
id | pubmed-7486103 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-74861032020-09-17 Distinct phosphorylation sites in a prototypical GPCR differently orchestrate β-arrestin interaction, trafficking, and signaling Dwivedi-Agnihotri, Hemlata Chaturvedi, Madhu Baidya, Mithu Stepniewski, Tomasz Maciej Pandey, Shubhi Maharana, Jagannath Srivastava, Ashish Caengprasath, Natarin Hanyaloglu, Aylin C. Selent, Jana Shukla, Arun K. Sci Adv Research Articles Agonist-induced phosphorylation of G protein–coupled receptors (GPCRs) is a key determinant for their interaction with β-arrestins (βarrs) and subsequent functional responses. Therefore, it is important to decipher the contribution and interplay of different receptor phosphorylation sites in governing βarr interaction and functional outcomes. Here, we find that several phosphorylation sites in the human vasopressin receptor (V(2)R), positioned either individually or in clusters, differentially contribute to βarr recruitment, trafficking, and ERK1/2 activation. Even a single phosphorylation site in V(2)R, suitably positioned to cross-talk with a key residue in βarrs, has a decisive contribution in βarr recruitment, and its mutation results in strong G-protein bias. Molecular dynamics simulation provides mechanistic insights into the pivotal role of this key phosphorylation site in governing the stability of βarr interaction and regulating the interdomain rotation in βarrs. Our findings uncover important structural aspects to better understand the framework of GPCR-βarr interaction and biased signaling. American Association for the Advancement of Science 2020-09-11 /pmc/articles/PMC7486103/ /pubmed/32917711 http://dx.doi.org/10.1126/sciadv.abb8368 Text en Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/ https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution license (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Articles Dwivedi-Agnihotri, Hemlata Chaturvedi, Madhu Baidya, Mithu Stepniewski, Tomasz Maciej Pandey, Shubhi Maharana, Jagannath Srivastava, Ashish Caengprasath, Natarin Hanyaloglu, Aylin C. Selent, Jana Shukla, Arun K. Distinct phosphorylation sites in a prototypical GPCR differently orchestrate β-arrestin interaction, trafficking, and signaling |
title | Distinct phosphorylation sites in a prototypical GPCR differently orchestrate β-arrestin interaction, trafficking, and signaling |
title_full | Distinct phosphorylation sites in a prototypical GPCR differently orchestrate β-arrestin interaction, trafficking, and signaling |
title_fullStr | Distinct phosphorylation sites in a prototypical GPCR differently orchestrate β-arrestin interaction, trafficking, and signaling |
title_full_unstemmed | Distinct phosphorylation sites in a prototypical GPCR differently orchestrate β-arrestin interaction, trafficking, and signaling |
title_short | Distinct phosphorylation sites in a prototypical GPCR differently orchestrate β-arrestin interaction, trafficking, and signaling |
title_sort | distinct phosphorylation sites in a prototypical gpcr differently orchestrate β-arrestin interaction, trafficking, and signaling |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486103/ https://www.ncbi.nlm.nih.gov/pubmed/32917711 http://dx.doi.org/10.1126/sciadv.abb8368 |
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