title: A ligand-mimetic model for constitutive activation of the melanocortin-1 receptor.
abstract: Dark coat color in the mouse and fox results from constitutively activated melanocortin-1 receptors. Receptor mutations in the mouse (E92K, L98P), cow (L99P), fox (C125R), and sheep (D119N) cluster near the membrane/extracellular junctions of the second and third transmembrane domains, an acidic domain that is the likely site of electrostatic interaction with an arginine residue in the ligand, alpha-MSH. For transmembrane residues E92, D119, and C125, conversion to a basic residue is required for constitutive activation. Unlike constitutively activating mutations in many G protein-coupled receptors that increase agonist efficacy and affinity, these MC1-R mutations have the opposite effect. Therefore, these mutations do not activate the receptor by directly disrupting intramolecular constraints on formation of the active high-affinity state, R*, but do so indirectly by mimicking ligand binding.
authors.affiliation: Vollum Institute, Oregon Health Sciences University, Portland 97201, USA.
authors.forename: D
authors.initials: D
authors.lastname: Lu
authors.forename: D I
authors.initials: DI
authors.lastname: Vage
authors.forename: R D
authors.initials: RD
authors.lastname: Cone
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001224:Aspartic Acid / Q000235:genetics; D002417:Cattle; D017124:Conserved Sequence; D005589:Foxes; D005799:Genes, Dominant; D018698:Glutamic Acid / Q000235:genetics; D006200:Hair Color / Q000235:genetics; D006639:Histidine / Q000235:genetics; D008024:Ligands; D008239:Lysine / Q000235:genetics; D051379:Mice; D008957:Models, Genetic; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011392:Proline / Q000235:genetics; D018043:Receptors, Corticotropin / Q000235:genetics* / Q000378:metabolism*; D044101:Receptors, Melanocortin; D012756:Sheep
chemical_list: D008024:Ligands; D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin; D001224:Aspartic Acid; D018698:Glutamic Acid; D006639:Histidine; D011392:Proline; D008239:Lysine