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

Punita Kumari, Ashish Srivastava, Ramanuj Banerjee, Eshan Ghosh, Pragya Gupta, Ravi Ranjan, Xin Chen, Bhagyashri Gupta, Charu Gupta, Deepika Jaiman and Arun K. Shukla ()
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Punita Kumari: Indian Institute of Technology
Ashish Srivastava: Indian Institute of Technology
Ramanuj Banerjee: Indian Institute of Technology
Eshan Ghosh: Indian Institute of Technology
Pragya Gupta: Indian Institute of Technology
Ravi Ranjan: Indian Institute of Technology
Xin Chen: School of Pharmaceutical Engineering and Life Sciences, Changzhou University
Bhagyashri Gupta: Indian Institute of Technology
Charu Gupta: Indian Institute of Technology
Deepika Jaiman: Indian Institute of Technology
Arun K. Shukla: Indian Institute of Technology

Nature Communications, 2016, vol. 7, issue 1, 1-16

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13416

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