PT  - JOURNAL ARTICLE
AU  - Eshan Ghosh
AU  - Hemlata Dwivedi
AU  - Mithu Baidya
AU  - Ashish Srivastava
AU  - Punita Kumari
AU  - Tomek Stepniewski
AU  - Hee Ryung Kim
AU  - Mi-Hye Lee
AU  - Jaana van Gastel
AU  - Madhu Chaturvedi
AU  - Debarati Roy
AU  - Shubhi Pandey
AU  - Jagannath Maharana
AU  - Ramon Guixà-Gonzàlez
AU  - Louis M. Luttrell
AU  - Ka Young Chung
AU  - Somnath Dutta
AU  - Jana Selent
AU  - Arun K. Shukla
TI  - Conformational sensors and domain-swapping reveal structural and functional differences between β-arrestin isoforms
AID  - 10.1101/725622
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 725622
4099  - http://biorxiv.org/content/early/2019/08/05/725622.short
4100  - http://biorxiv.org/content/early/2019/08/05/725622.full
AB  - 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. 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 the 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.GPCRsG Protein-Coupled Receptors;βarrsβ-arrestins;Fabantigen binding fragment;ScFvsingle chain variable fragment;β2ARβ2 adrenergic receptor;V2Rvasopressin receptor subtype 2;V2RppV2R tail phosphopeptide;mBBrmonobromobimane;ERK MAP Kinaseextracellular signal regulated mitogen activated kinase;ELISAenzyme linked immunosorbent assay.