PXD027887

PXD027887 is an original dataset announced via ProteomeXchange.

Title	Intrinsic bias at non-canonical, β-arrestin-coupled seven transmembrane receptors
Description	G protein-coupled receptors (GPCRs) are typically characterized by their seven transmembrane (7TM) architecture, and interaction with two universal signal-transducers namely, the heterotrimeric G-proteins and β-arrestins (βarrs). Synthetic ligands and receptor mutants have been designed to elicit transducer-coupling preferences and distinct downstream signaling outcomes for many GPCRs. This raises the question if some naturally-occurring 7TMRs may selectively engage one of these two signal-transducers, even in response to their endogenous agonists. Although there are scattered hints in the literature that some 7TMRs lack G-protein coupling but interact with βarrs, an in-depth understanding of their transducer-coupling preference, GRK-engagement, downstream signaling and structural mechanism remains elusive. Here, we use an array of cellular, biochemical and structural approaches to comprehensively characterize two non-canonical 7TMRs namely, the human decoy D6 receptor (D6R) and the human complement C5a receptor (C5aR2), in parallel with their canonical GPCR counterparts, CCR2 and C5aR1, respectively. We discover that D6R and C5aR2 couple exclusively to βarrs, exhibit distinct GRK-preference, and activate non-canonical downstream signaling partners. We also observe that βarrs, in complex with these receptors, adopt distinct conformations compared to their canonical GPCR counterparts despite being activated by a common natural agonist. Our study therefore establishes D6R and C5aR2 as bona-fide arrestin-coupled receptors (ACRs), and provides important insights into their regulation by GRKs and downstream signaling with direct implications for biased agonism.
HostingRepository	PRIDE
AnnounceDate	2021-11-03
AnnouncementXML	Submission_2021-11-03_04:39:54.337.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	gagan jhingan
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2021-08-12 02:25:22	ID requested
⏵ 1	2021-11-03 04:39:55	announced

Pandey S, Kumari P, Baidya M, Kise R, Cao Y, Dwivedi-Agnihotri H, Banerjee R, Li XX, Cui CS, Lee JD, Kawakami K, Maharana J, Ranjan A, Chaturvedi M, Jhingan GD, Laporte SA, Woodruff TM, Inoue A, Shukla AK, -arrestin-coupled seven transmembrane receptors. Mol Cell, 81(22):4605-4621.e11(2021) [pubmed]

submitter keyword: GPCRs, biased signaling, β-arrestins, GPCR kinases, β-arrestin-coupled receptors, seven transmembrane receptors, Complement C5a

Dr. Arun K. Shukla
contact affiliation	Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India
contact email	arshukla@iitk.ac.in
lab head
gagan jhingan
contact affiliation	VProteomics
contact email	gaganjhingan@hotmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD027887
     1. Label: PRIDE project
     2. Name: Intrinsic bias at non-canonical, β-arrestin-coupled seven transmembrane receptors