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

Bas Brouwers, Edson Mendes de Oliveira, Maria Marti-Solano, Fabiola B.F. Monteiro, Suli-Anne Laurin, Julia M. Keogh, Elana Henning, Rebecca Bounds, Carole A. Daly, Shane Houston, Vikram Ayinampudi, Natalia Wasiluk, David Clarke, Bianca Plouffe, Michel Bouvier, M Madan Babu, I. Sadaf Farooqi*, Jacek Mokrosinski

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Downloads (Pure)

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.
Original languageEnglish
Article number108862
Number of pages21
JournalCell Reports
Volume34
Issue number12
DOIs
Publication statusPublished - 23 Mar 2021

Fingerprint Dive into the research topics of 'Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation'. Together they form a unique fingerprint.

Cite this