The melanocortin receptor accessory protein 2 (MRAP2) plays a pivotal role in the regulation of several G protein–coupled receptors 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 G protein–coupled receptors and will aid in elucidating the pathways involved in metabolic dysfunction.

中文翻译：

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黑皮质素受体辅助蛋白 2 的膜取向和寡聚化。

黑皮质素受体辅助蛋白 2 (MRAP2) 在调节对能量平衡和食物摄入至关重要的几种 G 蛋白偶联受体中起关键作用。MRAP2 功能丧失导致哺乳动物肥胖。MRAP2 及其同源物 MRAP1 具有不寻常的膜拓扑结构，并且是唯一已知的以两个方向进入膜的真核蛋白质。在这项研究中，我们证明了决定 MRAP1 的膜拓扑结构和二聚化的保守多元基序不控制 MRAP2 的膜取向和二聚化。我们还表明 MRAP2 通过其跨膜结构域二聚化，并且可以形成以平行方向排列 MRAP2 单体的高阶寡聚体。