MRAP2 modifies the signaling and oligomerization state of the melanocortin-4 receptor
- Iqra Sohail
- Suli-Anne Laurin
- Gunnar Kleinau
- Vidicha Chunilal
- Andrew Morton
- Alfonso Brenlla
- Zeynep Cansu Uretmen Kagiali
- Marie-José Blouin
- Javier A. Tello
- Annette G. Beck-Sickinger
- Martin J. Lohse
- Patrick Scheerer
- Michel Bouvier
- Peter McCormick
- Paolo Annibale
- Heike Biebermann
2025-09-25
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 – Gα s 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.