MRAP2 modifies the signaling and oligomerization state of the melanocortin-4 receptor
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<sub>s</sub> 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.
Authors
- Heike Biebermann (ORCID: https://orcid.org/0000-0002-2024-7778)
- Gunnar Kleinau (ORCID: https://orcid.org/0000-0003-2131-671X)
- Paolo Annibale (ORCID: https://orcid.org/0000-0003-3208-5347)
- Javier A. Tello (ORCID: https://orcid.org/0000-0001-6637-2155)
- Vidicha Chunilal (ORCID: https://orcid.org/0000-0003-2881-2900)
- Iqra Sohail
- Zeynep Cansu Üretmen Kagıalı (ORCID: https://orcid.org/0000-0003-0007-5814)
- Alfonso Brenlla
- Suli‐Anne Laurin (ORCID: https://orcid.org/0000-0001-6713-4503)
- Peter J. McCormick (ORCID: https://orcid.org/0000-0002-2225-5181)
- Andrew Morton (ORCID: https://orcid.org/0000-0002-8180-542X)
- Patrick Scheerer (ORCID: https://orcid.org/0000-0001-5028-2075)
- Annette G. Beck‐Sickinger (ORCID: https://orcid.org/0000-0003-4560-8020)
- Martin J. Lohse (ORCID: https://orcid.org/0000-0002-0599-3510)
- Michel Bouvier (ORCID: https://orcid.org/0000-0003-1128-0100)
- Marie‐José Blouin
Institutions
- University of Liverpool (GB)
- Queen Mary University of London (GB)
- University of St Andrews (GB)
- Max Delbrück Center (DE)
- Humboldt-Universität zu Berlin (DE)
- Institute for Research in Immunology and Cancer (CA)
- William Harvey Research Institute (GB)
- Urologische Klinik München (DE)
- Université de Montréal (CA)
- Leipzig University (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-09-25
- DOI
- https://doi.org/10.1038/s41467-025-63988-w
- Citations
- 3
- Primary Topic
- Regulation of Appetite and Obesity
- Type
- article
- Field-Weighted Citation Impact
- 2.74
Funders
- Deutsche Forschungsgemeinschaft