AUTHOR=Wang Meng , Pi Linyu , Lei Xiaowei , Li Lei , Xu Jing , Kuang Zhe , Zhang Cong , Li Liang , Zhang Chao 

TITLE=Functional Characterization of the Internal Symmetry of MRAP2 Antiparallel Homodimer

JOURNAL=Frontiers in Endocrinology

VOLUME=Volume 12 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2021.750797

DOI=10.3389/fendo.2021.750797

ISSN=1664-2392

ABSTRACT=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 to modulate the surface translocation and binding to a variety of endogenous or synthetic hormones of central MC4R signaling. MRAP2 are single transmembrane proteins and could form a functional symmetric antiparallel homodimer topology. Here we inverted the N-terminal, transmembrane and C-terminal domain and generated six distinct conformational variants of mouse MRAP2 protein to explore the functional orientations and the internal symmetry of MRAP2 dimers. These remoulded MRAP2 mutants showed proper assembling of antiparallel homodimer and binding to the MC4R, but slightly altered the regulatory profile on the surface expression and ligand stimulated cAMP cascades of MC4R. This study elucidated the importance of the orientation of each domain of single-transmembrane protein and revealed the pharmacological properties of the internal symmetry of antiparallel homodimer for MRAP2 proteins.