PXD063931-1

PXD063931 is an original dataset announced via ProteomeXchange.

Title	GLP-1R and GIPR heterodimerization and expression determine downstream signaling and metabolic phenotypes
Description	Advancements in unimolecular drugs co-targeting the glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) have demonstrated remarkable clinical efficacy in treating type 2 diabetes (T2D) and obesity. However, the paradoxical ability of both GIPR agonism and antagonism to complement GLP-1R agonism underscores the need to elucidate molecular mechanisms underlying incretin receptor pharmacology and crosstalk. Here, we show that GLP-1 promotes heterodimerization via interactions between TM4 of GLP-1R and TM1/2 of GIPR. Phosphoproteomics profiling and molecular dynamics simulations reveal that dimerizing and non-dimerizing GLP-1R agonists differentially engage with GLP-1R and elicit distinct regulation of downstream signaling networks in human islets. Co-expression of GLP-1R and GIPR amplifies GIPR-mediated signaling in a β-arrestin-dependent manner, while GLP-1R-mediated signaling is suppressed by GIPR expression. Additionally, upregulation or downregulation of GIPR expression was associated with adiposity and diabetic traits, respectively. Collectively, these findings uncover mechanisms underlying the interplay between GLP-1R and GIPR and highlight heterodimerization as an innovative strategy for incretin-based therapies and personalized treatment.
HostingRepository	PRIDE
AnnounceDate	2026-05-13
AnnouncementXML	Submission_2026-05-13_10:16:44.482.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Pierre Sabatier
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	phosphorylated residue; acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Astral

Revision	Datetime	Status	ChangeLog Entry
0	2025-05-14 11:07:36	ID requested
⏵ 1	2026-05-13 10:16:44	announced

Dataset with its publication pending

submitter keyword: pancreatic islets, phosphoproteomics,GLP-1R

Jesper Olsen
contact affiliation	Novo Nordisk Foundation Center for Protein Research, University of Copenhagen
contact email	jesper.olsen@cpr.ku.dk
lab head
Pierre Sabatier
contact affiliation	Department of Surgical Sciences, Uppsala University. Novo Nordisk Foundation Center for Protein Research, University of Copenhagen.
contact email	pierre63.sabatier@gmail.com
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/05/PXD063931

PRIDE project URI

• PRIDE
  1. PXD063931
     1. Label: PRIDE project
     2. Name: GLP-1R and GIPR heterodimerization and expression determine downstream signaling and metabolic phenotypes