Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation
Bas Brouwers, Edson Mendes de Oliveira, Maria Martí-Solano, Fabíola Branco Filippin-Monteiro, Suli‐Anne Laurin, Julia M. Keogh, Elana Henning, Rebecca Bounds, Carole Daly, Shane Houston, V. Ayinampudi, Natalia Wasiluk, David T. Clarke, Bianca Plouffe, Michel Bouvier, M. Madan Babu, I. Sadaf Farooqi, Jacek Mokrosiński
Abstract
, establishing their causal role in severe obesity. Structural mapping reveals ligand-accessible sites by which MC4R couples to effectors and residues involved in the homodimerization of MC4R, which is disrupted by multiple obesity-associated mutations. Human genetic studies reveal that endocytosis, intracellular trafficking, and homodimerization regulate MC4R function to a level that is physiologically relevant, supporting the development of chaperones, agonists, and allosteric modulators of MC4R for weight loss therapy.