Intrinsic bias at non-canonical, ß-arrestin-coupled seven transmembrane receptors.
Mol Cell
; 81(22): 4605-4621.e11, 2021 11 18.
Article
in English
| MEDLINE | ID: covidwho-1440263
ABSTRACT
G-protein-coupled receptors (GPCRs), also known as seven transmembrane receptors (7TMRs), typically interact with two distinct signal-transducers, i.e., G proteins and ß-arrestins (ßarrs). Interestingly, there are some non-canonical 7TMRs that lack G protein coupling but interact with ßarrs, 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 ßarrs, exhibit distinct engagement of GPCR kinases (GRKs), and activate non-canonical downstream signaling pathways. We also observe that ßarrs 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 ßarr-coupled 7TMRs and provides key insights into their regulation and signaling with direct implication for biased agonism.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Protein Conformation
/
Signal Transduction
/
Cell Membrane
/
Beta-Arrestins
Limits:
Animals
/
Humans
Language:
English
Journal:
Mol Cell
Journal subject:
Molecular Biology
Year:
2021
Document Type:
Article
Affiliation country:
J.molcel.2021.09.007
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