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MRAP2 modifies the signaling and oligomerization state of the melanocortin-4 receptor

Item Type:Article
Title:MRAP2 modifies the signaling and oligomerization state of the melanocortin-4 receptor
Creators Name:Sohail, Iqra, Laurin, Suli-Anne, Kleinau, Gunnar, Chunilal, Vidicha, Morton, Andrew, Brenlla, Alfonso, Uretmen Kagiali, Zeynep Cansu, Blouin, Marie-José, Tello, Javier A., Beck-Sickinger, Annette G., Lohse, Martin J., Scheerer, Patrick, Bouvier, Michel, McCormick, Peter, Annibale, Paolo and Biebermann, Heike
Abstract:The melanocortin-4 receptor is a G protein-coupled receptor and a key regulator of appetite and metabolism. It can interact with the melanocortin-receptor accessory protein 2, a single transmembrane helix protein known to interact with several different G protein-coupled receptors. However, the consequences of this interaction are not completely understood. Here we report that co-expression of melanocortin-receptor accessory protein 2 has multiple effects on the melanocortin-4 receptor: it enhances G protein-mediated signaling and simultaneously impairs β-arrestin2 recruitment and, consequently, internalization. In addition, co-expression of melanocortin-receptor accessory protein 2 leads to an increased number of monomers of melanocortin-4 receptor by disrupting receptor oligomers. A structural homology model of the active state melanocortin-4 receptor – melanocortin-receptor accessory protein 2 – Gαs complex suggests interaction sites that are relevant for receptor activation. Our data indicate that melanocortin-receptor accessory protein 2 is an accessory protein that interacts with and influences melanocortin-4 receptor structure, biasing its signaling towards G protein-mediated effects.
Keywords:Beta-Arrestin 2, HEK293 Cells, Membrane Proteins, Molecular Models, Protein Binding, Protein Multimerization, Signal Transducing Adaptor Proteins, Signal Transduction, Type 4 Melanocortin Receptor, Animals
Source:Nature Communications
ISSN:2041-1723
Publisher:Nature Publishing Group
Volume:16
Number:1
Page Range:8324
Date:25 September 2025
Official Publication:https://doi.org/10.1038/s41467-025-63988-w
PubMed:View item in PubMed
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