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...

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Autores: Dwivedi, Hemlata, Chaturvedi, Madhu, Baidya, Mithu, Stepniewski, Tomasz Maciej, 1988-, Pandey, Shubhi, Maharana, Jagannath, Srivastava, Ashish, Caengprasath, Natarin, Hanyaloglu, Aylin C., Selent, Jana, Shukla, Arun K.
Tipo de documento: artigo
Estado:Versão publicada
Data de publicação:2020
País:España
Recursos:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositório:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10230/45391
Acesso em linha:http://hdl.handle.net/10230/45391
http://dx.doi.org/10.1126/sciadv.abb8368
Access Level:Acceso aberto
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spelling Distinct phosphorylation sites in a prototypical GPCR differently orchestrate β-arrestin interaction, trafficking, and signalingDwivedi, HemlataChaturvedi, MadhuBaidya, MithuStepniewski, Tomasz Maciej, 1988-Pandey, ShubhiMaharana, JagannathSrivastava, AshishCaengprasath, NatarinHanyaloglu, Aylin C.Selent, JanaShukla, Arun K.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 (V2R), positioned either individually or in clusters, differentially contribute to βarr recruitment, trafficking, and ERK1/2 activation. Even a single phosphorylation site in V2R, 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 (AAAS)202020202020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/45391http://dx.doi.org/10.1126/sciadv.abb8368reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésSci Adv. 2020; 6(37):eabb8368Copyright © 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/info:eu-repo/semantics/openAccessoai:recercat.cat:10230/453912026-05-29T05:05:01Z
dc.title.none.fl_str_mv 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
spellingShingle Distinct phosphorylation sites in a prototypical GPCR differently orchestrate β-arrestin interaction, trafficking, and signaling
Dwivedi, Hemlata
title_short 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_sort Distinct phosphorylation sites in a prototypical GPCR differently orchestrate β-arrestin interaction, trafficking, and signaling
dc.creator.none.fl_str_mv Dwivedi, Hemlata
Chaturvedi, Madhu
Baidya, Mithu
Stepniewski, Tomasz Maciej, 1988-
Pandey, Shubhi
Maharana, Jagannath
Srivastava, Ashish
Caengprasath, Natarin
Hanyaloglu, Aylin C.
Selent, Jana
Shukla, Arun K.
author Dwivedi, Hemlata
author_facet Dwivedi, Hemlata
Chaturvedi, Madhu
Baidya, Mithu
Stepniewski, Tomasz Maciej, 1988-
Pandey, Shubhi
Maharana, Jagannath
Srivastava, Ashish
Caengprasath, Natarin
Hanyaloglu, Aylin C.
Selent, Jana
Shukla, Arun K.
author_role author
author2 Chaturvedi, Madhu
Baidya, Mithu
Stepniewski, Tomasz Maciej, 1988-
Pandey, Shubhi
Maharana, Jagannath
Srivastava, Ashish
Caengprasath, Natarin
Hanyaloglu, Aylin C.
Selent, Jana
Shukla, Arun K.
author2_role author
author
author
author
author
author
author
author
author
author
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 (V2R), positioned either individually or in clusters, differentially contribute to βarr recruitment, trafficking, and ERK1/2 activation. Even a single phosphorylation site in V2R, 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.
publishDate 2020
dc.date.none.fl_str_mv 2020
2020
2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/45391
http://dx.doi.org/10.1126/sciadv.abb8368
url http://hdl.handle.net/10230/45391
http://dx.doi.org/10.1126/sciadv.abb8368
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Sci Adv. 2020; 6(37):eabb8368
dc.rights.none.fl_str_mv https://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Association for the Advancement of Science (AAAS)
publisher.none.fl_str_mv American Association for the Advancement of Science (AAAS)
dc.source.none.fl_str_mv reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
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