Ghosh, Eshan ; Srivastava, Ashish ; Baidya, Mithu ; Kumari, Punita ; Dwivedi, Hemlata ; Nidhi, Kumari ; Ranjan, Ravi ; Dogra, Shalini ; Koide, Akiko ; Yadav, Prem N. ; Sidhu, Sachdev S. ; Koide, Shohei ; Shukla, Arun K. (2017) A synthetic intrabody-based selective and generic inhibitor of GPCR endocytosis Nature Nanotechnology, 12 (12). pp. 1190-1198. ISSN 1748-3387
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Official URL: http://doi.org/10.1038/nnano.2017.188
Related URL: http://dx.doi.org/10.1038/nnano.2017.188
Abstract
Beta-arrestins (βarrs) critically mediate desensitization, endocytosis and signalling of G protein-coupled receptors (GPCRs), and they scaffold a large number of interaction partners. However, allosteric modulation of their scaffolding abilities and direct targeting of their interaction interfaces to modulate GPCR functions selectively have not been fully explored yet. Here we identified a series of synthetic antibody fragments (Fabs) against different conformations of βarrs from phage display libraries. Several of these Fabs allosterically and selectively modulated the interaction of βarrs with clathrin and ERK MAP kinase. Interestingly, one of these Fabs selectively disrupted βarr-clathrin interaction, and when expressed as an intrabody, it robustly inhibited agonist-induced endocytosis of a broad set of GPCRs without affecting ERK MAP kinase activation. Our data therefore demonstrate the feasibility of selectively targeting βarr interactions using intrabodies and provide a novel framework for fine-tuning GPCR functions with potential therapeutic implications.
Item Type: | Article |
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Keywords: | GPCRs, β-arrestins, cellular signaling, endocytosis, ERK MAP kinase, Phage Display, synthetic antibody fragments, intrabodies |
ID Code: | 126437 |
Deposited On: | 13 Oct 2022 06:04 |
Last Modified: | 13 Oct 2022 06:04 |
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