Cell reports (Cambridge), 2021-03, Vol.34 (12), p.108862-108862, Article 108862
2021
Details
- Autor(en) / Beteiligte
- Titel
- Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation
- Ist Teil von
- Cell reports (Cambridge), 2021-03, Vol.34 (12), p.108862-108862, Article 108862
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2021
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- 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. [Display omitted] •Obesity-associated MC4R mutations that do not reduce cAMP disrupt other processes•MC4R mutations impact receptor homodimerization, endocytosis, and trafficking•Obesity-protecting mutations increase plasma membrane MC4Rs and enhance signaling•Multiple mechanisms regulate melanocortin tone to a physiologically relevant level Using mutations in the human Melanocortin-4 Receptor (MC4R), Brouwers et al. identify receptor trafficking and endocytosis, coupling to Gαs/β-arrestins, and homodimerization as mechanisms involved in the regulation of body weight that may be targeted for weight loss therapy.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2211-1247eISSN: 2211-1247DOI: 10.1016/j.celrep.2021.108862Titel-ID: cdi_doaj_primary_oai_doaj_org_article_47adf08d015c4c769ac1331dc6211c1b
- Format
- –
- Schlagworte
- Animals, beta-Arrestins - metabolism, Body Weight - genetics, Cell Membrane - metabolism, Chlorocebus aethiops, COS Cells, Cyclic AMP - metabolism, Endocytosis, Extracellular Signal-Regulated MAP Kinases - metabolism, Genetic Variation, GPCRs, GTP-Binding Protein alpha Subunits, Gs, Gαs, HEK293 Cells, Humans, MC4R, melanocortin, Models, Biological, MSH, Mutant Proteins - metabolism, Mutation - genetics, obesity, Phosphorylation, Protein Multimerization, Receptor, Melanocortin, Type 4 - chemistry, Receptor, Melanocortin, Type 4 - genetics, Signal Transduction, therapy, weight loss, β-arrestin