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

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 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.

SUBMITTER: Pandey S

PROVIDER: S-EPMC7612807 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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

Pandey Shubhi S Kumari Punita P Baidya Mithu M Kise Ryoji R Cao Yubo Y Dwivedi-Agnihotri Hemlata H Banerjee Ramanuj R Li Xaria X XX Cui Cedric S CS Lee John D JD Kawakami Kouki K Maharana Jagannath J Ranjan Ashutosh A Chaturvedi Madhu M Jhingan Gagan Deep GD Laporte Stéphane A SA Woodruff Trent M TM Inoue Asuka A Shukla Arun K AK

Molecular cell 20210927 22

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 rec ...[more]

PMID: 34582793

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Dataset Information

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

Publications

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

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