University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
MRC Laboratory of Molecular Biology, Cambridge, UK.
Cell Rep. 2021 Mar 23;34(12):108862. doi: 10.1016/j.celrep.2021.108862.
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 Gα protein-mediated signaling, previously considered to be non-pathogenic, nonetheless disrupt agonist-induced internalization, β-arrestin recruitment, and/or coupling to Gα, 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.
黑皮质素 4 受体（MC4R）在能量平衡中起着关键作用。我们利用与肥胖风险增加或降低相关的人类 MC4R 突变来剖析调节 MC4R 功能的机制。大多数与肥胖相关的突变会损害向质膜（PM）的运输，而肥胖保护突变要么加速向 PM 的回收，要么减少内化，从而增强信号转导。先前被认为非致病性的不影响经典 Gα 蛋白介导信号转导的 MC4R 突变，尽管不影响激动剂诱导的内化、β-arrestin 募集和/或与 Gα 的偶联，但它们破坏了配体可及的位点，这些位点与 MC4R 与效应器的偶联以及 MC4R 同源二聚化有关，这被多种肥胖相关突变所破坏。人类遗传研究表明，内吞作用、细胞内运输和同源二聚化调节 MC4R 的功能，达到了与生理相关的水平，支持开发 MC4R 的伴侣蛋白、激动剂和别构调节剂，用于减肥治疗。
