Functional Characterization of the Internal Symmetry of MRAP2 Antiparallel Homodimer.

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

doi:10.3389/fendo.2021.750797

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 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.

Highlights

Melanocortins consist of four pro-opiomelanocortin (POMC)-derived natural agonists (a, b, and g-MSH and ACTH) and two antagonists (Agouti and AgRP) through tissue-specific posttranslational processing and modification [1]
We co-transfected the mMC4R and mouse MRAP2 (mMRAP2) plasmids into HEK293 cells to examine the interaction of the Melanocortin receptor accessory protein 2 (MRAP2) variants with their G-protein-coupled receptor (GPCR) targets
melanocortin-4 receptor (MC4R) plays an important role through MRAP2 in maintaining mammalian energy homeostasis

Summary

Introduction

Melanocortins consist of four pro-opiomelanocortin (POMC)-derived natural agonists (a-, b-, and g-MSH and ACTH) and two antagonists (Agouti and AgRP) through tissue-specific posttranslational processing and modification [1]. The biological activity and physiological roles of melanocortins are mediated by five melanocortin receptors (MCRs) in mammals (MC1R– MC5R) [2]. In the skin and hair follicles, alpha melanocyte-stimulating hormone (a-MSH)simulated MC1R signaling results in melanin production producing black skin or hair [3]. MC2R is required for adrenocortical steroidogenesis in the adrenal gland, and melanocortin-3 receptor (MC3R) and MC4R are essential for appetite control and energy homeostasis in the central nervous system.Mutations of MC4R have been reported as the most prevalent forms of monogenic. Internal Symmetry of MRAP2 Homodimer obesity in humans, and the physiological roles of MC4R in regulating energy balance are well known and widely reported [4, 5]. MC5R plays an important role in the exocrine secretion of the skin [9, 10]

Methods

Results

Conclusion