The discovery of G-protein coupled receptor (GPCR) accessory proteins has fundamentally redefined the pharmacological concept of GPCR signaling, demonstrating a more complex molecular basis for receptor specificity on the plasma membrane and impressionable downstream intracellular cascades. GPCR accessory proteins not only contribute to the proper folding and trafficking of receptors, but also exhibit selectable receptor preferences. The melanocortin receptor accessory proteins (MRAP1 and MRAP2) as well as receptor activity-modifying proteins (RAMPs) are two well-known single transmembrane partners for the regulation of the melanocortin receptors (MC1R-MC5R) and the glucagon receptor (GCGR), respectively. Especially, MRAP family participates in the pathological control of multiple endocrine disorders and RAMPs contribute to the endogenous regulation of glucose homeostasis. However, the precise mechanisms by which the MRAP and RAMP proteins regulate receptor signaling at the atomic resolution remain unknown. Recent progress made in the determination of RAMP2-bound GCGR complexes published on Cell (Krishna Kumar et al., 2023) unraveled the importance of RAMP2 for the promotion of extracellular receptor dynamics leading to cytoplasmic surface inactivation. Moreover, the new findings on Cell Research (Luo et al., 2023) of the adrenocorticotropic hormone (ACTH)-bound MC2R-Gs-MRAP1 complex disclosed the essential role of MRAP1 for MC2R activation and specificity of ligand recognition. In this article, we reviewed a series of key findings of MRAP proteins in the last decade, and the recent structural investigation of MRAP-MC2R and RAMP-GCGR functional complex and the expanded identification of new GPCR partners of MRAP proteins. In-depth understanding of GPCR modulation by single transmembrane accessory proteins will provide valuable insights for the therapeutic drug development to treat multiple GPCR associated human disorders.

中文翻译：

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单跨膜 GPCR 调节蛋白：既不单一也不简单。

G 蛋白偶联受体 (GPCR) 辅助蛋白的发现从根本上重新定义了 GPCR 信号的药理学概念，证明了质膜上受体特异性和易受影响的下游细胞内级联的更复杂的分子基础。GPCR 辅助蛋白不仅有助于受体的正确折叠和运输，而且还表现出可选择的受体偏好。黑皮质素受体辅助蛋白（MRAP1 和 MRAP2）以及受体活性修饰蛋白（RAMP）是两个众所周知的单一跨膜伙伴，分别用于调节黑皮质素受体（MC1R-MC5R）和胰高血糖素受体（GCGR） . 尤其，MRAP家族参与多种内分泌失调的病理控制，RAMPs参与葡萄糖稳态的内源性调节。然而，MRAP 和 RAMP 蛋白在原子分辨率下调节受体信号的确切机制仍然未知。最近发表在 Cell 上的 RAMP2 结合 GCGR 复合物测定取得的进展（Krishna Kumar 等人，2023 年）揭示了 RAMP2 对于促进导致细胞质表面失活的细胞外受体动力学的重要性。此外，关于促肾上腺皮质激素 (ACTH) 结合的 MC2R-Gs-MRAP1 复合物的细胞研究 (Luo et al., 2023) 的新发现揭示了 MRAP1 对 MC2R 激活和配体识别特异性的重要作用。在本文中，我们回顾了过去十年 MRAP 蛋白的一系列重要发现，以及最近对 MRAP-MC2R 和 RAMP-GCGR 功能复合物的结构研究以及对 MRAP 蛋白新 GPCR 伙伴的扩展鉴定。深入了解单个跨膜辅助蛋白对 GPCR 的调节将为治疗多种 GPCR 相关人类疾病的治疗药物开发提供有价值的见解。