PXD061422

PXD061422 is an original dataset announced via ProteomeXchange.

Title	Post-translational modifications orchestrate the intrinsic signaling bias of orphan receptor GPR52
Description	Despite recent advances in GPCR structure and pharmacology, the regulation of GPCR activation, signaling, and functioning by diverse post-translational modifications (PTMs) has been largely unexplored. Furthermore, for a special category of self-activating orphan GPCRs, it is completely unknown whether and how specific PTMs control their unique signaling profiles and cellular functions. In this study of GPR52, an orphan GPCR with exceedingly high constitutive G protein signaling activity and emerging as a neurotherapeutic target, we discovered its disproportionately low arrestin recruitment activity. Through profiling the N-glycosylation and phosphorylation patterns of the receptor and clarifying their roles in G protein versus arrestin coupling, we found these two types of PTMs in specific motifs differentially shape the intrinsic signaling bias of GPR52. While N-terminal N-glycosylation promotes constitutive Gs signaling possibly through favoring the self-activating conformation, phosphorylation in helix 8, to our great surprise, suppresses arrestin recruitment and thus attenuates receptor internalization. In addition, we uncovered the counteracting roles of N-glycosylation and phosphorylation in modulating GPR52-dependent accumulation of the huntingtin protein (HTT) in brain striatal cells. Thus, our study provides novel insights into the regulation of intrinsic signaling bias and cellular function of an orphan GPCR via distinct PTMs in different motifs.
HostingRepository	iProX
AnnounceDate	2025-03-03
AnnouncementXML	Submission_2025-03-03_19:25:24.661.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Shanshan Li
SpeciesList	scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	deaminated residue; phosphorylated residue
Instrument	timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2025-03-03 19:25:09	ID requested
⏵ 1	2025-03-03 19:25:25	announced

Dataset with its publication pending

submitter keyword: GPR52, N-glycosylation, Phosphorylation, Constitutive activity

Wenqing Shui
contact affiliation	iHuman Institute, ShanghaiTech University
contact email	shuiwq@shanghaitech.edu.cn
lab head
Shanshan Li
contact affiliation	iHuman Institute, ShanghaiTech University
contact email	lishsh@shanghaitech.edu.cn
dataset submitter

iProX dataset URI