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

Mithu Baidya, Madhu Chaturvedi, Hemlata Dwivedi-Agnihotri, Ashutosh Ranjan, Dominic Devost, Yoon Namkung, Tomasz Maciej Stepniewski, Shubhi Pandey, Minakshi Baruah, Bhanupriya Panigrahi, Parishmita Sarma, Manish K. Yadav, Jagannath Maharana, Ramanuj Banerjee, Kouki Kawakami, Asuka Inoue, Jana Selent, Stéphane A. Laporte, Terence E. Hébert and Arun K. Shukla ()
Additional contact information
Mithu Baidya: Indian Institute of Technology
Madhu Chaturvedi: Indian Institute of Technology
Hemlata Dwivedi-Agnihotri: Indian Institute of Technology
Ashutosh Ranjan: Indian Institute of Technology
Dominic Devost: McGill University
Yoon Namkung: McGill University
Tomasz Maciej Stepniewski: Department of Experimental and Health Sciences of Pompeu Fabra University (UPF)-Hospital del Mar Medical Research Institute (IMIM)
Shubhi Pandey: Indian Institute of Technology
Minakshi Baruah: Indian Institute of Technology
Bhanupriya Panigrahi: Indian Institute of Technology
Parishmita Sarma: Indian Institute of Technology
Manish K. Yadav: Indian Institute of Technology
Jagannath Maharana: Indian Institute of Technology
Ramanuj Banerjee: Indian Institute of Technology
Kouki Kawakami: Tohoku University
Asuka Inoue: Tohoku University
Jana Selent: Department of Experimental and Health Sciences of Pompeu Fabra University (UPF)-Hospital del Mar Medical Research Institute (IMIM)
Stéphane A. Laporte: McGill University
Terence E. Hébert: McGill University
Arun K. Shukla: Indian Institute of Technology

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32386-x

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