Department of Plastic and Reconstructive Surgery, Shanghai Institute of Precision Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Shanghai Key Laboratory of Signaling and Disease Research, Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.
J Cell Physiol. 2021 Sep;236(9):6472-6480. doi: 10.1002/jcp.30321. Epub 2021 Feb 8.
The melanocortin receptor accessory protein 2 (MRAP2) plays an essential role in the regulation of metabolic homeostasis and deletion of which results in severe obesity syndrome in mice and human. Mammalian MRAP2 is recognized as an endogenous physiological mediator through the potentiation of the MC4R signaling in vivo. Two isoforms of MRAP2 are identified in zebrafish genome, zMRAP2a and zMRAP2b. However, the mechanism of assembling dual topology and the regulatory roles of each complex on the melanocortin cascades remains unclear. In this study, we showed the bidirectional homo- and hetero-dimeric topologies of two zebrafish MRAP2 isoforms on the plasma membrane. Orientation fixed chimeric proteins could affect the trafficking and pharmacological properties of zMC4R signaling. Reciprocal replacement of zMRAP2a and zMRAP2b proteins elucidated the major participation of the carboxyl terminal as the functional domain for modulating zMC4R signaling. Our findings revealed the complex and dynamic conformational regulation of dual zebrafish MRAP2 proteins in vitro.
黑素皮质素受体辅助蛋白 2（MRAP2）在调节代谢稳态中发挥着重要作用，其缺失会导致小鼠和人类出现严重的肥胖综合征。哺乳动物的 MRAP2 被认为是一种内源性生理调节剂，通过增强 MC4R 信号在体内发挥作用。斑马鱼基因组中鉴定出两种 MRAP2 同工型，zMRAP2a 和 zMRAP2b。然而，双拓扑结构的组装机制以及每个复合物对黑素皮质素级联反应的调节作用尚不清楚。在这项研究中，我们在质膜上展示了两种斑马鱼 MRAP2 同工型的双向同源和异源二聚体拓扑结构。定向固定嵌合蛋白可以影响 zMC4R 信号的运输和药理学特性。zMRAP2a 和 zMRAP2b 蛋白的相互替换阐明了羧基末端作为调节 zMC4R 信号的功能域的主要参与。我们的发现揭示了双斑马鱼 MRAP2 蛋白在体外的复杂和动态构象调节。
