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Nat Nanotechnol. 2017 Dec;12(12):1190-1198. doi: 10.1038/nnano.2017.188. Epub 2017 Oct 2.

A synthetic intrabody-based selective and generic inhibitor of GPCR endocytosis.

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Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India.
CSIR-Central Drug Research Institute, Lucknow 226031, India.
Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York 10016, USA.
Department of Medicine, New York University School of Medicine, New York 10016, USA.
Department of Molecular Genetics, University of Toronto, Ontario MSS1A8, Canada.
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York 10016, USA.


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.

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