A study of the lipid-mediated dimerization of the RAGE TM plus JM domains by molecular dynamic simulations

作者：Chen, Jialin; Sun, Fude; Chen, Peng; Chai, Mengya; Xu, Lida^*; Luo, Shi-Zhong^*

来源：Chinese Chemical Letters, 2018, 29(7): 1151-1154.

DOI：10.1016/j.cclet.2018.04.005

• RAGE
• Dimetization
• TM plus JM domains
• Lipid Regulation
• Coarse-grained simulations

Receptor for Advanced Glycation End-products (RAGE) binds to a number of ligand families to display important roles in hyperglycemia, senescence, inflammation, neurodegeneration and cancer. It is reported that RAGE regulates the related biological processes via homo-dimerization by the transmembrane (TM) domain, and evidence further shows that the intracellular domain of RAGE has an influence on the dimerization activity of RAGE. In this study, we explored the underlying interaction mechanism of RAGE TM domains by multiscale coarse-grained (CG) dynamic simulations. Two switching packing modes of the TM dimeric conformations were observed. Through a series of site-directed mutations, we further emphasized the key roles of the A(342)xxxG(346)xxG(349)xxxT(353)XXL(356)XXXV(360) motif in the left-handed configuration and the L(345)xxxG(349)xxG(352)xxxL(356) motif in the right-handed configuration. In addition, we revealed that the juxtamembrane UM) domain within JM-A375 can determine the RAGE TM dimeric structure. Overall, we provide the molecular insights into the switching dimerization of RAGE TM domains, as well as the regulation from the JM domains mediated by the anionic lipids.

• 出版日期2018-7
• 单位北京化工大学