Unknown

Dataset Information

0

Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation.


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.

SUBMITTER: Brouwers B 

PROVIDER: S-EPMC7994375 | biostudies-literature |

REPOSITORIES: biostudies-literature

Similar Datasets

| S-EPMC4847754 | biostudies-literature
| S-EPMC3408882 | biostudies-literature
| S-EPMC6893576 | biostudies-literature
| S-EPMC9818419 | biostudies-literature
| S-EPMC2897609 | biostudies-literature
| S-EPMC6409670 | biostudies-literature
| S-EPMC4390356 | biostudies-literature
| S-EPMC4244031 | biostudies-literature
| S-EPMC3624906 | biostudies-literature
| S-EPMC3262050 | biostudies-literature