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| 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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