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 Üretmen Kagıalı, Marie‐José Blouin, Javier A. Tello, Annette G. Beck‐Sickinger, Martin J. Lohse, Patrick Scheerer, Michel Bouvier, Peter J. McCormick, Paolo Annibale, Heike Biebermann
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 – 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.