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 () and Heike Biebermann ()
Additional contact information
Iqra Sohail: Max-Delbrück-Center for Molecular Medicine-Berlin
Suli-Anne Laurin: Université de Montréal
Gunnar Kleinau: Group Structural Biology of Cellular Signaling
Vidicha Chunilal: William Harvey Research Institute Queen Mary University of London
Andrew Morton: University of St Andrews
Alfonso Brenlla: University of St Andrews
Zeynep Cansu Uretmen Kagiali: Institute for Experimental Paediatric Endocrinology
Marie-José Blouin: Université de Montréal
Javier A. Tello: University of St Andrews
Annette G. Beck-Sickinger: University of Leipzig
Martin J. Lohse: Max-Delbrück-Center for Molecular Medicine-Berlin
Patrick Scheerer: Group Structural Biology of Cellular Signaling
Michel Bouvier: Université de Montréal
Peter McCormick: University of Liverpool
Paolo Annibale: Max-Delbrück-Center for Molecular Medicine-Berlin
Heike Biebermann: Institute for Experimental Paediatric Endocrinology

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-63988-w

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