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PMID: 27827372 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

Functional competence of a partially engaged GPCR-β-arrestin complex.

Nature communications ·Vol. 7 ·2016-00-09 ·Pages 13416

Kumari P, Srivastava A, Banerjee R, Ghosh E, Gupta P, Ranjan R, Chen X, Gupta B, Gupta C, Jaiman D, Shukla AK

Abstract

G Protein-coupled receptors (GPCRs) constitute the largest family of cell surface receptors and drug targets. GPCR signalling and desensitization is critically regulated by β-arrestins (βarr). GPCR-βarr interaction is biphasic where the phosphorylated carboxyl terminus of GPCRs docks to the N-domain of βarr first and then seven transmembrane core of the receptor engages with βarr. It is currently unknown whether fully engaged GPCR-βarr complex is essential for functional outcomes or partially engaged complex can also be functionally competent. Here we assemble partially and fully engaged complexes of a chimeric β2V2R with βarr1, and discover that the core interaction is dispensable for receptor endocytosis, ERK MAP kinase binding and activation. Furthermore, we observe that carvedilol, a βarr biased ligand, does not promote detectable engagement between βarr1 and the receptor core. These findings uncover a previously unknown aspect of GPCR-βarr interaction and provide novel insights into GPCR signalling and regulatory paradigms.

MeSH Terms
Carbazoles/pharmacology Carvedilol Endocytosis HEK293 Cells Humans Molecular Docking Simulation Phosphorylation Propanolamines/pharmacology Protein Binding/drug effects Receptors, G-Protein-Coupled/chemistry,metabolism Signal Transduction beta-Arrestins/chemistry,metabolism
Chemicals
Carbazoles Propanolamines Receptors, G-Protein-Coupled beta-Arrestins Carvedilol
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Kumari Punita
Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India.
Srivastava Ashish
Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India.
Banerjee Ramanuj
Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India.
Ghosh Eshan
Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India.
Gupta Pragya
Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India.
Ranjan Ravi
Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India.
Chen Xin
School of Pharmaceutical Engineering and Life Sciences, Changzhou University, Changzhou, Jiangsu 213164, China.
Gupta Bhagyashri
Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India.
Gupta Charu
Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India.
Jaiman Deepika
Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India.
Shukla Arun K
Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India.
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Article Info
Journal
Nature communications
Abbr.
Nat Commun
ISSN
2041-1723
DOI
10.1038/ncomms13416
Published
2016-00-09
Epub
2016-00-09
Pages
13416
Language
English
Region
England
NLM ID
101528555
PMCID
PMC5105198
Subset
IM
Grants
DBT-Wellcome Trust India Alliance · IA/I/14/1/501285 · India
External Links
PubMed source DOI: 10.1038/ncomms13416 PMC Full Text View journal details
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