Structural determinants regulating cell surface targeting of melanocortin receptors

Melanocortin receptors (MCRs) belong to the G-protein-coupled receptor family of transmembrane proteins. They recognize specific ligands named melanocortins that are mainly produced in the pituitary and hypothalamus. Newly synthesized MCRs at the endoplasmic reticulum are subjected to quality control mechanisms that screen for the correct structure, folding or processing, essential for their proper cell surface expression. Some motifs, located at the N- or C-terminus or even on transmembrane and in loop regions, have been implicated in these biological processes. This article reviews these specific domains and the role of accessory proteins and post-translation modifications in MCRs' targeting to cell surface. Additionally, promising approaches involving pharmacological stabilization of misfolded and misrouted mutant MCRs, which improve their forward transport, are reported. Understanding the MCRs' structural determinants fundamental for their proper cell surface integration is essential for correcting abnormalities found in some diseases.