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

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

Journal: Cell reports 2020;28(13):3287-3299.e6

PMID: 31553900

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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.

Address: Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India.; Research Programme on Biomedical Informatics (GRIB), Department of Experimental and Health Sciences of Pompeu Fabra University (UPF)-Hospital del Mar Medical Research Institute (IMIM), 08003 Barcelona, Spain.; School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon 16419, South Korea.; Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.; Translational Neurobiology Group, Center of Molecular Neurology, VIB, Antwerp, Belgium; Receptor Biology Lab, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.; Laboratory of Computational Medicine, Biostatistics Unit, Faculty of Medicine, Autonomous University of Barcelona, 08193 Bellaterra, Spain.; Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA; Research Service of the Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29401, USA.; Molecular Biophysics Unit, Indian Institute of Sciences, Bangalore, India.; Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India. Electronic address: [email protected].

DOI: 10.1016/j.celrep.2019.08.053

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MeSH Terms: HEK293 Cells, Humans, Molecular Dynamics Simulation, Protein Domains, Protein Isoforms, Sequence Homology, Amino Acid, Signal Transduction, beta-Arrestins