Conformational Sensors and Domain Swapping Reveal Structural and Functional Differences between beta-Arrestin Isoforms

Ghosh, Eshan and Dwivedi, Hemlata and Baidya, Mithu and Srivastava, Ashish and Kumari, Punita and Stepniewski, Tomek and Kim, Hee Ryung and Lee, Mi-Hye and van Gastel, Jaana and Chaturvedi, Madhu and Roy, Debarati and Pandey, Shubhi and Maharana, Jagannath and Guixa-Gonzalez, Ramon and Luttrell, Louis M and Chung, Ka Young and Dutta, Somnath and Selent, Jana and Shukla, Arun K (2019) Conformational Sensors and Domain Swapping Reveal Structural and Functional Differences between beta-Arrestin Isoforms. In: CELL REPORTS, 28 (13). 3287+.

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Abstract

Desensitization, signaling, and trafficking of G-protein-coupled receptors (GPCRs) are critically regulated by multifunctional adaptor proteins, beta-arrestins (beta arrs). The two isoforms of beta arrs (beta arr1 and 2) share a high degree of sequence and structural similarity; still, however, they often mediate distinct functional outcomes in the context of GPCR signaling and regulation. A mechanistic basis for such a functional divergence of beta arr isoforms is still lacking. By using a set of complementary approaches, including antibody-fragment-based conformational sensors, we discover structural differences between beta arr1 and 2 upon their interaction with activated and phosphorylated receptors. Interestingly, domain-swapped chimeras of beta arrs display robust complementation in functional assays, thereby linking the structural differences between receptor-bound beta arr1 and 2 with their divergent functional outcomes. Our findings reveal important insights into the ability of beta arr isoforms to drive distinct functional outcomes and underscore the importance of integrating this aspect in the current framework of biased agonism.

Item Type:	Journal Article
Publication:	CELL REPORTS
Publisher:	CELL PRESS
Additional Information:	copyright for this article belongs to CELL PRESS
Department/Centre:	Division of Biological Sciences > Molecular Biophysics Unit
Date Deposited:	23 Oct 2019 06:14
Last Modified:	23 Oct 2019 06:14
URI:	http://eprints.iisc.ac.in/id/eprint/63771

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