Molecular Cell
Volume 81, Issue 22, 18 November 2021, Pages 4605-4621.e11
Journal home page for Molecular Cell

Article
Intrinsic bias at non-canonical, β-arrestin-coupled seven transmembrane receptors

https://doi.org/10.1016/j.molcel.2021.09.007Get rights and content
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open access

Highlights

  • D6R and C5aR2 couple to and signal through β-arrestins but not G proteins

  • D6R and C5aR2 exhibit distinct contribution of GRKs for β-arrestin recruitment

  • D6R and C5aR2 induce distinct β-arrestin conformations compared to GPCR counterparts

  • D6R and C5aR2 offer a novel experimental framework to study biased agonism

Summary

G-protein-coupled receptors (GPCRs), also known as seven transmembrane receptors (7TMRs), typically interact with two distinct signal-transducers, i.e., G proteins and β-arrestins (βarrs). Interestingly, there are some non-canonical 7TMRs that lack G protein coupling but interact with βarrs, although an understanding of their transducer coupling preference, downstream signaling, and structural mechanism remains elusive. Here, we characterize two such non-canonical 7TMRs, namely, the decoy D6 receptor (D6R) and the complement C5a receptor subtype 2 (C5aR2), in parallel with their canonical GPCR counterparts. We discover that D6R and C5aR2 efficiently couple to βarrs, exhibit distinct engagement of GPCR kinases (GRKs), and activate non-canonical downstream signaling pathways. We also observe that βarrs adopt distinct conformations for D6R and C5aR2, compared to their canonical GPCR counterparts, in response to common natural agonists. Our study establishes D6R and C5aR2 as βarr-coupled 7TMRs and provides key insights into their regulation and signaling with direct implication for biased agonism.

Keywords

GPCRs
biased agonism
arrestins
chemokine
complment cascade
biosensors
CRISPR-Cas9
COVID19
cancer
drug discovery

Data and code availability

  • The original raw data for immunoblots and confocal micrographs have been deposited in Mendeley Data (https://doi.org/10.17632/nzpd6k32gz.1).

  • Phosphoproteomics data are deposited in the ProteomeXchange repository (PXD027887) and has been made publicly available as of the date of publication.

  • This paper does not report any original code.

  • Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon reasonable request.

Cited by (0)

8

These authors contributed equally

9

Lead contact