{Reference Type}: Journal Article
{Title}: Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation.
{Author}: Brouwers B;de Oliveira EM;Marti-Solano M;Monteiro FBF;Laurin SA;Keogh JM;Henning E;Bounds R;Daly CA;Houston S;Ayinampudi V;Wasiluk N;Clarke D;Plouffe B;Bouvier M;Babu MM;Farooqi IS;Mokrosiński J;
{Journal}: Cell Rep
{Volume}: 34
{Issue}: 12
{Year}: 03 2021 23
暂无{DOI}: 10.1016/j.celrep.2021.108862
{Abstract}: The Melanocortin-4 Receptor (MC4R) plays a pivotal role in energy homeostasis. We used human MC4R mutations associated with an increased or decreased risk of obesity to dissect mechanisms that regulate MC4R function. Most obesity-associated mutations impair trafficking to the plasma membrane (PM), whereas obesity-protecting mutations either accelerate recycling to the PM or decrease internalization, resulting in enhanced signaling. MC4R mutations that do not affect canonical Gαs protein-mediated signaling, previously considered to be non-pathogenic, nonetheless disrupt agonist-induced internalization, β-arrestin recruitment, and/or coupling to Gαs, 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.