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

Abstract

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 beta-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.