Allosteric modulation of GPCR-induced β-arrestin trafficking and signaling by a synthetic intrabody

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• dc.contributor.author Baidya, Mithu
• dc.contributor.author Chaturvedi, Madhu
• dc.contributor.author Dwivedi, Hemlata
• dc.contributor.author Ranjan, Ashutosh
• dc.contributor.author Devost, Dominic
• dc.contributor.author Namkung, Yoon
• dc.contributor.author Stepniewski, Tomasz Maciej, 1988-
• dc.contributor.author Pandey, Shubhi
• dc.contributor.author Baruah, Minakshi
• dc.contributor.author Panigrahi, Bhanupriya
• dc.contributor.author Sarma, Parishmita
• dc.contributor.author Yadav, Manish K.
• dc.contributor.author Maharana, Jagannath
• dc.contributor.author Banerjee, Ramanuj
• dc.contributor.author Kawakami, Kouki
• dc.contributor.author Inoue, Asuka
• dc.contributor.author Selent, Jana
• dc.contributor.author Laporte, Stéphane A.
• dc.contributor.author Hébert, Terence E.
• dc.contributor.author Shukla, Arun K.
• dc.date.accessioned 2023-02-08T07:23:51Z
• dc.date.available 2023-02-08T07:23:51Z
• dc.date.issued 2022
• dc.description.abstract Agonist-induced phosphorylation of G protein-coupled receptors (GPCRs) is a primary determinant of β-arrestin (βarr) recruitment and trafficking. For several GPCRs such as the vasopressin receptor subtype 2 (V2R), agonist-stimulation first drives the translocation of βarrs to the plasma membrane, followed by endosomal trafficking, which is generally considered to be orchestrated by multiple phosphorylation sites. We have previously shown that mutation of a single phosphorylation site in the V2R (i.e., V2RT360A) results in near-complete loss of βarr translocation to endosomes despite robust recruitment to the plasma membrane, and compromised ERK1/2 activation. Here, we discover that a synthetic intrabody (Ib30), which selectively recognizes activated βarr1, efficiently rescues the endosomal trafficking of βarr1 and ERK1/2 activation for V2RT360A. Molecular dynamics simulations reveal that Ib30 enriches active-like βarr1 conformation with respect to the inter-domain rotation, and cellular assays demonstrate that it also enhances βarr1-β2-adaptin interaction. Our data provide an experimental framework to positively modulate the receptor-transducer-effector axis for GPCRs using intrabodies, which can be potentially integrated in the paradigm of GPCR-targeted drug discovery.
• dc.format.mimetype application/pdf
• dc.identifier.citation Baidya M, Chaturvedi M, Dwivedi-Agnihotri H, Ranjan A, Devost D, Namkung Y, Stepniewski TM, Pandey S, Baruah M, Panigrahi B, Sarma P, Yadav MK, Maharana J, Banerjee R, Kawakami K, Inoue A, Selent J, Laporte SA, Hébert TE, Shukla AK. Allosteric modulation of GPCR-induced β-arrestin trafficking and signaling by a synthetic intrabody. Nat Commun. 2022 Aug 8;13(1):4634. DOI: 10.1038/s41467-022-32386-x
• dc.identifier.doi http://dx.doi.org/10.1038/s41467-022-32386-x
• dc.identifier.issn 2041-1723
• dc.identifier.uri http://hdl.handle.net/10230/55671
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Nat Commun. 2022 Aug 8;13(1):4634
• dc.rights © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword G protein-coupled receptors
• dc.subject.keyword Hormone receptors
• dc.title Allosteric modulation of GPCR-induced β-arrestin trafficking and signaling by a synthetic intrabody
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion