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

Cell Rep. 2021 Mar 23;34(12):108862. 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.

Keywords: GPCRs; Gα(s); MC4R; MSH; melanocortin; obesity; therapy; weight loss; β-arrestin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Weight / genetics*
  • COS Cells
  • Cell Membrane / metabolism
  • Chlorocebus aethiops
  • Cyclic AMP / metabolism
  • Endocytosis*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • GTP-Binding Protein alpha Subunits, Gs
  • Genetic Variation*
  • HEK293 Cells
  • Humans
  • Models, Biological
  • Mutant Proteins / metabolism
  • Mutation / genetics
  • Phosphorylation
  • Protein Multimerization*
  • Receptor, Melanocortin, Type 4 / chemistry
  • Receptor, Melanocortin, Type 4 / genetics*
  • Signal Transduction
  • beta-Arrestins / metabolism

Substances

  • MC4R protein, human
  • Mutant Proteins
  • Receptor, Melanocortin, Type 4
  • beta-Arrestins
  • Cyclic AMP
  • Extracellular Signal-Regulated MAP Kinases
  • GTP-Binding Protein alpha Subunits, Gs