Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation
| Autor: | M. Madan Babu, Elana Henning, Maria Marti-Solano, Bianca Plouffe, Carole A. Daly, Julia M. Keogh, Michel Bouvier, Bas Brouwers, Rebecca Bounds, Jacek Mokrosinski, Fabiola B.F. Monteiro, I. Sadaf Farooqi, Suli-Anne Laurin, Vikram Ayinampudi, David Clarke, Natalia Wasiluk, Edson Mendes de Oliveira, Shane Houston |
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| Přispěvatelé: | Farooqi, Ismaa [0000-0001-7609-3504], Apollo - University of Cambridge Repository |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
obesity MC4R Energy homeostasis Gα(s) 0302 clinical medicine Chlorocebus aethiops Cyclic AMP GTP-Binding Protein alpha Subunits Gs Phosphorylation Internalization Extracellular Signal-Regulated MAP Kinases lcsh:QH301-705.5 beta-Arrestins media_common Chemistry Effector 16. Peace & justice Endocytosis Cell biology COS Cells Receptor Melanocortin Type 4 Signal Transduction Gs alpha subunit media_common.quotation_subject Allosteric regulation Biology Affect (psychology) Models Biological General Biochemistry Genetics and Molecular Biology Article GPCRs 03 medical and health sciences SDG 3 - Good Health and Well-being Animals Humans melanocortin MSH G protein-coupled receptor therapy β-arrestin Gαs Body Weight Cell Membrane Genetic Variation 030104 developmental biology HEK293 Cells lcsh:Biology (General) Mutation Mutant Proteins weight loss Protein Multimerization 030217 neurology & neurosurgery Function (biology) |
| Zdroj: | Cell Reports Brouwers, B, Mendes de Oliveira, E, Marti-Solano, M, B.F. Monteiro, F, Laurin, S-A, M. Keogh, J, Henning, E, Bounds, R, Daly, C A, Houston, S, Ayinampudi, V, Wasiluk, N, Clarke, D, Plouffe, B, Bouvier, M, Babu, M M, Farooqi, I S & Mokrosinski, J 2021, ' Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation ', Cell Reports, vol. 34, no. 12, 108862 . https://doi.org/10.1016/j.celrep.2021.108862 Cell Reports, Vol 34, Iss 12, Pp 108862-(2021) |
| ISSN: | 2211-1247 |
| DOI: | 10.1016/j.celrep.2021.108862 |
| Popis: | Summary 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. Graphical abstract Highlights • 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. |
| Databáze: | OpenAIRE |
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