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

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, fo...

ver descrição completa

Detalhes bibliográficos
Autores: Baidya, Mithu, Chaturvedi, Madhu, Dwivedi, Hemlata, Ranjan, Ashutosh, Devost, Dominic, Namkung, Yoon, Stepniewski, Tomasz Maciej, 1988-, Pandey, Shubhi, Baruah, Minakshi, Panigrahi, Bhanupriya, Sarma, Parishmita, Yadav, Manish K., Maharana, Jagannath, Banerjee, Ramanuj, Kawakami, Kouki, Inoue, Asuka, Selent, Jana, Laporte, Stéphane A., Hébert, Terence E., Shukla, Arun K.
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Recursos:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10230/55671
Acesso em linha:http://hdl.handle.net/10230/55671
http://dx.doi.org/10.1038/s41467-022-32386-x
Access Level:acceso abierto
Palavra-chave:G protein-coupled receptors
Hormone receptors
Descrição
Resumo: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.

Registos relacionados