Journal
CHINESE CHEMICAL LETTERS
Volume 29, Issue 7, Pages 1151-1154Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cclet.2018.04.005
Keywords
RAGE; Dimetization; TM plus JM domains; Lipid Regulation; Coarse-grained simulations
Categories
Funding
- National Natural Science Foundation of China [21672019, 21372026, 21402006]
- Fundamental Research Funds for the Central Universities [XK1701]
- CHEMCLOUDCOMPUTING
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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. (C) 2018 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
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