Structural determinants regulating cell surface targeting of melanocortin receptors

Abstract

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.

The Melanocortin System in Atlantic Salmon (Salmo salar L.) and Its Role in Appetite Control

“…The human N-glycosylated site (NxS/T) located in the N-terminus is also present in Atlantic salmon Mc4r paralogs. The glycosylated site and the disulfide bonds are important for the receptor structure folding, stability, and target trafficking (Chai et al, 2005;Tao, 2010;Rodrigues et al, 2013). Furthermore, the palmitoylation site at the Cys residue Cys318 of the C-terminus in human MC4R is also present in the Atlantic salmon Mc4ra1 and a2.…”

“…Further, the C-terminal palmitoylation site cysteine (Cys) residue Cys318 in human MC4R is conserved in the Atlantic salmon Mc4ra1 and a2. Importantly, motif DPxIY and C-terminal motif E(x) 7 LL for G Protein-Coupled Receptors (GPCRs) [reviewed in Rodrigues et al (2013)] are conserved in all salmon paralogs. There are two putative disulfide bonds in human MC4R, one between Cys271 (TMHVI) and Cys277 (ECL3) and another between Cys40 (Nterminus) and Cys271 (ECL3).…”

“…The N-terminal, extracellular loops (ECLs) 1-3, intracellular loops (ICLs) 1 to 3, and C-terminus (with helix VIII) are also shown. The N-terminal glycosylated amino acid residues and the important conserved motifs of GPCRs are marked in red (Rodrigues et al, 2013). C-terminal palmitoylation Cys is shown in yellow.…”

MC1R, the cAMP pathway, and the response to solar UV: extending the horizon beyond pigmentation

“…MC1R is synthesized in the rough ER where several quality control systems check for completion of post‐translational processing and determine the intracellular retention of missfolded or missprocessed mutants. As opposed to other MCRs, particularly MC2R, MC1R does not require the interaction with specific accessory proteins for efficient anterograde transport (Rodrigues et al., ). Within the ER, newly synthesized MC1R molecules undergo dimerization, and maybe even formation of higher order oligomers.…”

“…Interestingly, the il2 of MC1R is particularly well conserved among vertebrate species and also shows a striking degree of homology between the five MCR subtypes. Thus, the MCRs might share common mechanisms of regulation of plasma membrane expression (Rodrigues et al., ). Of note, this discussion is based on data obtained for the MC1R‐001 splice variant.…”