Conformational sensors and domain swapping reveal structural and functional differences between β-arrestin isoforms

Ghosh, Eshan; Dwivedi, Hemlata; Baidya, Mithu; Srivastava, Ashish; Kumari, Punita; Stepniewski, Tomek; Kim, Hee Ryung; Lee, Mi-Hye; van Gastel, Jaana; Chaturvedi, Madhu; Roy, Debarati; Pandey, Shubhi; Maharana, Jagannath; Guixà González, Ramon, 1978-; Luttrell, Louis M.; Chung, Ka Young; Dutta, Somnath; Selent, Jana; Shukla, Arun K.

Conformational sensors and domain swapping reveal structural and functional differences between β-arrestin isoforms

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dc.contributor.author Ghosh, Eshan
dc.contributor.author Dwivedi, Hemlata
dc.contributor.author Baidya, Mithu
dc.contributor.author Srivastava, Ashish
dc.contributor.author Kumari, Punita
dc.contributor.author Stepniewski, Tomek
dc.contributor.author Kim, Hee Ryung
dc.contributor.author Lee, Mi-Hye
dc.contributor.author van Gastel, Jaana
dc.contributor.author Chaturvedi, Madhu
dc.contributor.author Roy, Debarati
dc.contributor.author Pandey, Shubhi
dc.contributor.author Maharana, Jagannath
dc.contributor.author Guixà González, Ramon, 1978-
dc.contributor.author Luttrell, Louis M.
dc.contributor.author Chung, Ka Young
dc.contributor.author Dutta, Somnath
dc.contributor.author Selent, Jana
dc.contributor.author Shukla, Arun K.
dc.date.accessioned 2019-10-04T11:04:09Z
dc.date.available 2019-10-04T11:04:09Z
dc.date.issued 2019
dc.description.abstract Desensitization, signaling, and trafficking of G-protein-coupled receptors (GPCRs) are critically regulated by multifunctional adaptor proteins, β-arrestins (βarrs). The two isoforms of βarrs (βarr1 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 βarr isoforms is still lacking. By using a set of complementary approaches, including antibody-fragment-based conformational sensors, we discover structural differences between βarr1 and 2 upon their interaction with activated and phosphorylated receptors. Interestingly, domain-swapped chimeras of βarrs display robust complementation in functional assays, thereby linking the structural differences between receptor-bound βarr1 and 2 with their divergent functional outcomes. Our findings reveal important insights into the ability of βarr isoforms to drive distinct functional outcomes and underscore the importance of integrating this aspect in the current framework of biased agonism.
dc.format.mimetype application/pdf
dc.identifier.citation Ghosh E, Dwivedi H, Baidya M, Srivastava A, Kumari P, Stepniewski T et al. Conformational sensors and domain swapping reveal structural and functional differences between β-arrestin isoforms. Cell Rep. 2019;28(13):3287-99. DOI: 10.1016/j.celrep.2019.08.053
dc.identifier.doi http://dx.doi.org/10.1016/j.celrep.2019.08.053
dc.identifier.issn 2211-1247
dc.identifier.uri http://hdl.handle.net/10230/42388
dc.language.iso eng
dc.publisher Elsevier
dc.relation.ispartof Cell Reports. 2019;28(13):3287-99
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject.keyword GPCRs
dc.subject.keyword Antibody fragments
dc.subject.keyword Biased agonism
dc.subject.keyword Biosensors
dc.subject.keyword Cellular signaling
dc.subject.keyword Desensitization
dc.subject.keyword Electron microscopy
dc.subject.keyword Negative staining
dc.subject.keyword β-arrestins
dc.title Conformational sensors and domain swapping reveal structural and functional differences between β-arrestin isoforms
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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