TY - JOUR
T1 - Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation
AU - Brouwers, Bas
AU - Mendes de Oliveira, Edson
AU - Marti-Solano, Maria
AU - B.F. Monteiro, Fabiola
AU - Laurin, Suli-Anne
AU - M. Keogh, Julia
AU - Henning, Elana
AU - Bounds, Rebecca
AU - Daly, Carole A.
AU - Houston, Shane
AU - Ayinampudi, Vikram
AU - Wasiluk, Natalia
AU - Clarke, David
AU - Plouffe, Bianca
AU - Bouvier, Michel
AU - Babu, M Madan
AU - Farooqi, I. Sadaf
AU - Mokrosinski, Jacek
PY - 2021/3/23
Y1 - 2021/3/23
N2 - 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.
AB - 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.
U2 - 10.1016/j.celrep.2021.108862
DO - 10.1016/j.celrep.2021.108862
M3 - Article
VL - 34
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 12
M1 - 108862
ER -