MRAP2 modifies the signaling and oligomerization state of the melanocortin-4 receptor

The melanocortin-4 receptor (MC4R) is a G protein-coupled receptor (GPCR) and a key regulator of appetite and metabolism. It can interact with the melanocortin-receptor accessory protein 2 (MRAP2), a single transmembrane helix protein known to interplay with several different GPCRs. However, the consequences of this interaction are not completely understood. Here we report that co-expression of MRAP2 has multiple effects on the MC4R: it enhances G protein-mediated signaling and simultaneously impairs β-arrestin2 recruitment and, consequently, internalization. In addition, co-expression of MRAP2 leads to an increased number of monomers of MC4R by disrupting receptor oligomers. A structural model of the active state MC4R–MRAP2 complex supports the experimentally observed monomerization. Taken together, our data indicate that MRAP2 is an accessory protein that interacts with and influences MC4R structure, biasing its signaling towards G protein-mediated effects.