{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMRAP2 is an accessory protein that modulates the trafficking and signaling of several G protein–coupled receptors—most notably members of the melanocortin receptor (MCR) family. In vitro studies have demonstrated that MRAP2 interacts with all five MCRs, promoting functional expression of the ACTH receptor (MC2R) while concurrently dampening the ligand responsiveness of MC1R, MC3R, MC4R, and MC5R. In polarized cells, for instance, proper delivery of MC3R to the apical membrane has been shown to involve MRAP2, highlighting its important role in receptor localization and function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its mechanistic role at the cellular level, MRAP2 is emerging as a key regulator of energy homeostasis and body weight. Mouse models harboring whole‐body or brain‐specific deletions of Mrap2 develop severe obesity early in life, implicating impaired receptor modulation—particularly at the melanocortin‐4 receptor (MC4R)—as one underlying mechanism. In humans, rare genetic variants and copy number changes affecting MRAP2 have been linked to early‐onset obesity, hyperphagia, and metabolic disturbances such as hyperglycemia and hypertension, emphasizing the protein’s significance in metabolic regulation and its contribution to monogenic forms of obesity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to modulating melanocortin receptors, MRAP2 regulates other G protein–coupled receptors that are central to feeding behavior and energy expenditure. It has been shown to inhibit the trafficking and signaling of prokineticin receptor 1 (PKR1) and the orexin receptor 1 (OX1R), both of which are expressed in the brain regions governing appetite. Moreover, MRAP2 biases the signaling of the ghrelin receptor (GHSR1a) by suppressing its constitutive activity, enhancing G protein–dependent signaling, and limiting β‐arrestin recruitment. Intriguingly, altered MRAP2 expression has now also been observed in the endometrium—suggesting potential roles in reproductive physiology and even embryo implantation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the mechanistic level, MRAP2 is distinguished by its unusual dual membrane topology. It assembles as an anti‐parallel homodimer and is capable of forming higher–order oligomers through interactions mediated by its transmembrane domain. These unique structural features underpin its capacity to differentially modulate receptor signaling across diverse physiological systems, thereby providing insights into its versatile roles in metabolic and potentially reproductive processes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Li F Chan, Tom R Webb, Teng-Teng Chung, et al. 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