Department of Plastic and Reconstructive Surgery, Shanghai Institute of Precision Medicine, Shanghai Ninth People's Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.
Front Endocrinol (Lausanne). 2021 Oct 25;12:750797. doi: 10.3389/fendo.2021.750797. eCollection 2021.
The melanocortin receptors are defined as a series of vital pharmaceutical targets to regulate neuronal appetite and maintain controllable body weight for mammals and teleosts. Melanocortin receptor accessory protein 2 (MRAP2) functions as an essential accessory player that modulates the surface translocation and binding to a variety of endogenous or synthetic hormones of central melanocortin-4 receptor (MC4R) signaling. MRAP2 is a single-transmembrane protein and could form a functional symmetric antiparallel homodimer topology. Here, we inverted the N-terminal, transmembrane, and C-terminal domains and generated six distinct conformational variants of the mouse MRAP2 to explore the functional orientations and the internal symmetry of MRAP2 dimers. These remolded MRAP2 mutants showed proper assembly of the antiparallel homodimer and binding to the MC4R, but slightly altered the regulatory profile on the surface expression and the ligand-stimulated cAMP cascades of MC4R. This study elucidated the importance of the orientation of each domain of the single-transmembrane protein and revealed the pharmacological properties of the internal symmetry of the antiparallel homodimer for MRAP2.
黑皮质素受体被定义为一系列重要的药物靶点，可调节哺乳动物和硬骨鱼的神经元食欲和控制体重。黑皮质素受体辅助蛋白 2（MRAP2）作为一种必需的辅助因子，调节中枢黑皮质素-4 受体（MC4R）信号传导中各种内源性或合成激素的表面转位和结合。MRAP2 是一种单跨膜蛋白，可形成功能对称的反平行同源二聚体拓扑结构。在这里，我们反转了 N 端、跨膜和 C 端结构域，并生成了六种不同的小鼠 MRAP2 构象变体，以探索 MRAP2 二聚体的功能取向和内部对称性。这些改造后的 MRAP2 突变体显示出反平行同源二聚体的正确组装，并与 MC4R 结合，但略微改变了 MC4R 表面表达和配体刺激的 cAMP 级联的调节谱。这项研究阐明了单跨膜蛋白每个结构域的取向的重要性，并揭示了 MRAP2 反平行同源二聚体内部对称性的药理学特性。
