The melanocortin receptor accessory protein 2 (MRAP2) plays a pivotal role in the regulation of several G- protein coupled receptors (GPCR) that are essential for energy balance and food intake. MRAP2 loss-of-function results in obesity in mammals. MRAP2 and its homolog MRAP1 have an unusual membrane topology and are the only known eukaryotic proteins that thread into the membrane in both orientations. In this study, we demonstrate that the conserved polybasic motif that dictates the membrane topology and dimerization of MRAP1 does not control the membrane orientation and dimerization of MRAP2. We also show that MRAP2 dimerizes through its transmembrane domain and can form higher order oligomers that arrange MRAP2 monomers in a parallel orientation. Investigating the molecular details of MRAP2 structure is essential for understanding the mechanism by which it regulates GPCRs and will aid in elucidating the pathways involved in metabolic dysfunction.

中文翻译：

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黑素皮质素受体附件蛋白2的膜取向和寡聚化

黑皮质素受体辅助蛋白2（MRAP2）在调节几个G蛋白偶联受体（GPCR）中起着关键作用，这对于能量平衡和食物摄入至关重要。MRAP2功能丧失导致哺乳动物肥胖。MRAP2及其同系物MRAP1具有异常的膜拓扑结构，并且是唯一已知的在两个方向上都穿入膜的真核蛋白。在这项研究中，我们证明了支配MRAP1的膜拓扑结构和二聚化的保守多元基序不能控制MRAP2的膜取向和二聚化。我们还显示MRAP2通过其跨膜结构域二聚化，并可以形成以平行方向排列MRAP2单体的高阶低聚物。