Functional competence of a partially engaged GPCR-β-arrestin complex.
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.
Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India.
Punita
P
Kumari
Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India.
Ashish
A
Srivastava
Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India.
Ramanuj
R
Banerjee
Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India.
Eshan
E
Ghosh
Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India.
Pragya
P
Gupta
Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India.
Ravi
R
Ranjan
School of Pharmaceutical Engineering and Life Sciences, Changzhou University, Changzhou, Jiangsu 213164, China.
Xin
X
Chen
Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India.
Bhagyashri
B
Gupta
Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India.
Charu
C
Gupta
Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India.
Deepika
D
Jaiman
Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India.
Arun K
AK
Shukla
D002227:Carbazoles / Q000494:pharmacology; D000077261:Carvedilol; D004705:Endocytosis; D057809:HEK293 Cells; D006801:Humans; D062105:Molecular Docking Simulation; D010766:Phosphorylation; D011412:Propanolamines / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D000071557:beta-Arrestins / Q000737:chemistry / Q000378:metabolism*
D002227:Carbazoles; D011412:Propanolamines; D043562:Receptors, G-Protein-Coupled; D000071557:beta-Arrestins; D000077261:Carvedilol