Transient ligand contacts of the intrinsically disordered N-terminus of neuropeptide Y2 receptor regulate arrestin-3 recruitment

Anette Kaiser (), Juan C. Rojas Echeverri, Asat Baischew, Maik Pankonin, Karl D. Leitner, Claudio Iacobucci, Davide Sala, Christian Ihling, Ronny Müller, Rok Ferenc, Annette G. Beck-Sickinger, Peter Schmidt, Jens Meiler, Peter W. Hildebrand and Andrea Sinz ()
Additional contact information
Anette Kaiser: University of Leipzig Medical Center
Juan C. Rojas Echeverri: Martin Luther University Halle-Wittenberg
Asat Baischew: Martin Luther University Halle-Wittenberg
Maik Pankonin: Leipzig University
Karl D. Leitner: University of Leipzig Medical Center
Claudio Iacobucci: Martin Luther University Halle-Wittenberg
Davide Sala: Leipzig University
Christian Ihling: Martin Luther University Halle-Wittenberg
Ronny Müller: Leipzig University
Rok Ferenc: Leipzig University
Annette G. Beck-Sickinger: Leipzig University
Peter Schmidt: Leipzig University
Jens Meiler: Leipzig University
Peter W. Hildebrand: Leipzig University
Andrea Sinz: Martin Luther University Halle-Wittenberg

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Previous efforts in delineating molecular mechanisms of G protein-coupled receptor (GPCR) activation have focused on transmembrane regions and ligand-receptor contacts of the extracellular loops. The role of the highly flexible N-termini of rhodopsin-like GPCRs have not been well characterized to date. We hypothesize that transient contacts between the peptide ligand and the intrinsically disordered N-terminus (NT) of the neuropeptide Y (NPY) receptor Y2 (Y2R) will affect receptor signaling. We employ cross-linking mass spectrometry to capture ligand-receptor contacts including transient binding modes. A photo-reactive NPY analogue allows mapping the interaction between NPY and Y2R NT resulting in a total number of 40 cross-links. The cross-links provide distance constraints for deriving structural models of the interaction. Molecular dynamics simulations highlight the structural flexibility and rapid interconversion of ligand-receptor contacts. Mutagenesis of Y2R and functional characterization suggest that the cross-linking hotspots in the NT electrostatically control its conformational ensemble. The NT engages in transient contacts to the peptide and prolongs ligand residence time, which is required for efficient interaction of Y2R with arrestin-3, but not Gi. We delineate structure-function relationships for the intrinsically disordered Y2R NT and propose a functional role for transient binding modes involving the NT of a peptide-binding receptor.

Date: 2025
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DOI: 10.1038/s41467-025-64051-4

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