Conformational Sensors and Domain Swapping Reveal Structural and Functional Differences between β-Arrestin Isoforms
Summary: 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...
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Elsevier
2019-09-01
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Series: | Cell Reports |
Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124719311015 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Eshan Ghosh Hemlata Dwivedi Mithu Baidya Ashish Srivastava Punita Kumari Tomek Stepniewski Hee Ryung Kim Mi-Hye Lee Jaana van Gastel Madhu Chaturvedi Debarati Roy Shubhi Pandey Jagannath Maharana Ramon Guixà-González Louis M. Luttrell Ka Young Chung Somnath Dutta Jana Selent Arun K. Shukla |
spellingShingle |
Eshan Ghosh Hemlata Dwivedi Mithu Baidya Ashish Srivastava Punita Kumari Tomek Stepniewski Hee Ryung Kim Mi-Hye Lee Jaana van Gastel Madhu Chaturvedi Debarati Roy Shubhi Pandey Jagannath Maharana Ramon Guixà-González Louis M. Luttrell Ka Young Chung Somnath Dutta Jana Selent Arun K. Shukla Conformational Sensors and Domain Swapping Reveal Structural and Functional Differences between β-Arrestin Isoforms Cell Reports |
author_facet |
Eshan Ghosh Hemlata Dwivedi Mithu Baidya Ashish Srivastava Punita Kumari Tomek Stepniewski Hee Ryung Kim Mi-Hye Lee Jaana van Gastel Madhu Chaturvedi Debarati Roy Shubhi Pandey Jagannath Maharana Ramon Guixà-González Louis M. Luttrell Ka Young Chung Somnath Dutta Jana Selent Arun K. Shukla |
author_sort |
Eshan Ghosh |
title |
Conformational Sensors and Domain Swapping Reveal Structural and Functional Differences between β-Arrestin Isoforms |
title_short |
Conformational Sensors and Domain Swapping Reveal Structural and Functional Differences between β-Arrestin Isoforms |
title_full |
Conformational Sensors and Domain Swapping Reveal Structural and Functional Differences between β-Arrestin Isoforms |
title_fullStr |
Conformational Sensors and Domain Swapping Reveal Structural and Functional Differences between β-Arrestin Isoforms |
title_full_unstemmed |
Conformational Sensors and Domain Swapping Reveal Structural and Functional Differences between β-Arrestin Isoforms |
title_sort |
conformational sensors and domain swapping reveal structural and functional differences between β-arrestin isoforms |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2019-09-01 |
description |
Summary: 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. : Ghosh et al. discover structural differences between β-arrestin isoforms (β-arrestin 1 and 2), which are universal regulators of signaling and trafficking of G-protein-coupled receptors (GPCRs). These findings have direct implications for understanding the regulatory and signaling paradigms of GPCRs and designing novel therapeutics targeting this important class of receptors. Keywords: GPCRs, β-arrestins, cellular signaling, antibody fragments, biosensors, biased agonism, desensitization, negative staining, electron microscopy |
url |
http://www.sciencedirect.com/science/article/pii/S2211124719311015 |
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doaj-6c89aacecc9d4a92bef3658962de7d662020-11-25T01:36:40ZengElsevierCell Reports2211-12472019-09-01281332873299.e6Conformational Sensors and Domain Swapping Reveal Structural and Functional Differences between β-Arrestin IsoformsEshan Ghosh0Hemlata Dwivedi1Mithu Baidya2Ashish Srivastava3Punita Kumari4Tomek Stepniewski5Hee Ryung Kim6Mi-Hye Lee7Jaana van Gastel8Madhu Chaturvedi9Debarati Roy10Shubhi Pandey11Jagannath Maharana12Ramon Guixà-González13Louis M. Luttrell14Ka Young Chung15Somnath Dutta16Jana Selent17Arun K. Shukla18Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, IndiaDepartment of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, IndiaDepartment of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, IndiaDepartment of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, IndiaDepartment of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, IndiaResearch 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, SpainSchool of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon 16419, South KoreaDepartment of Medicine, Medical University of South Carolina, Charleston, SC 29425, USATranslational Neurobiology Group, Center of Molecular Neurology, VIB, Antwerp, Belgium; Receptor Biology Lab, Department of Biomedical Sciences, University of Antwerp, Antwerp, BelgiumDepartment of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, IndiaDepartment of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, IndiaDepartment of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, IndiaDepartment of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, IndiaLaboratory of Computational Medicine, Biostatistics Unit, Faculty of Medicine, Autonomous University of Barcelona, 08193 Bellaterra, SpainDepartment 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, USASchool of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon 16419, South KoreaMolecular Biophysics Unit, Indian Institute of Sciences, Bangalore, IndiaResearch 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, SpainDepartment of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India; Corresponding authorSummary: 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. : Ghosh et al. discover structural differences between β-arrestin isoforms (β-arrestin 1 and 2), which are universal regulators of signaling and trafficking of G-protein-coupled receptors (GPCRs). These findings have direct implications for understanding the regulatory and signaling paradigms of GPCRs and designing novel therapeutics targeting this important class of receptors. Keywords: GPCRs, β-arrestins, cellular signaling, antibody fragments, biosensors, biased agonism, desensitization, negative staining, electron microscopyhttp://www.sciencedirect.com/science/article/pii/S2211124719311015 |