A LIGAND-MIMETIC MODEL FOR CONSTITUTIVE ACTIVATION OF THE MELANOCORTIN-1 RECEPTOR

Dark coat color in the mouse and fox results from constitutively activ ated melanocortin-1 receptors. Receptor mutations in the mouse (E92K, L98P), cow (L99P), fox (C125R), and sheep (D119N) cluster near the mem brane/extracellular junctions of the second and third transmembrane do mains, an acidic domain that is the likely site of electrostatic inter action with an arginine residue in the ligand, alpha-MSH. For transmem brane residues E92, D119, and C125, conversion to a basic residue is r equired for constitutive activation. Unlike constitutively activating mutations in many G protein-coupled receptors that increase agonist ef ficacy and affinity, these MC1-R mutations have the opposite effect. T herefore, these mutations do not activate the receptor by directly dis rupting intramolecular constraints on formation of the active high-aff inity state, R, but do so indirectly by mimicking ligand binding.