%0 Journal Article
%T Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation.
%A Brouwers B
%A de Oliveira EM
%A Marti-Solano M
%A Monteiro FBF
%A Laurin SA
%A Keogh JM
%A Henning E
%A Bounds R
%A Daly CA
%A Houston S
%A Ayinampudi V
%A Wasiluk N
%A Clarke D
%A Plouffe B
%A Bouvier M
%A Babu MM
%A Farooqi IS
%A Mokrosiński J
%J Cell Rep
%V 34
%N 12
%D 03 2021 23
%M 33761344
暂无%R 10.1016/j.celrep.2021.108862
%X 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.