Molecular Mechanism Study of β-amyloid Aggregation Inhibition by Transthyretin
10.16476/j.pibb.2023.0098
- VernacularTitle:转甲状腺素蛋白抑制β淀粉样蛋白聚集的分子机制研究
- Author:
Shuang-Yan ZHOU
1
;
Yao-Xin HUANG
1
;
Xin LI
1
;
Jia-Hui BAI
1
;
Shuai YUAN
1
Author Information
1. Chongqing Key Laboratory on Big Data for Bio Intelligence, Chongqing University of Posts and Telecommunications, Chongqing 400065, China
- Publication Type:Journal Article
- Keywords:
Alzheimer’s disease;
transthyretin;
neuroprotective effect;
amyloid beta protein;
molecular dynamics simulation
- From:
Progress in Biochemistry and Biophysics
2024;51(3):633-646
- CountryChina
- Language:Chinese
-
Abstract:
ObjectiveIt was reported that the transthyretin (TTR) has a neuroprotective effect on Alzheimer’s disease (AD), which is manifested by the ability of TTR to inhibit the pathological aggregation of amyloid beta protein (Aβ). In this work, we investigated the mechanism of the interactions between TTR and Aβ at the molecular level to reveal the neuroprotective effect of TTR on AD. MethodsProtein-protein docking was used to explore the models of interaction between different structural forms of TTR and Aβ, and molecular dynamics simulation was further applied to investigate the dynamic process of the interaction between the two. ResultsBoth TTR tetramer and monomer can interact with Aβ monomer, and the thyroxine-binding channel of TTR tetramer is the main binding site of Aβ monomer. In addition, the EF helix and EF loop of TTR tetramer were also able to bind Aβ monomer. When the TTR tetramer dissociates, the hydrophobic site of the internal TTR monomer is exposed, which has a strong affinity for Aβ monomer. For the interaction between Aβ aggregates and TTR, a higher degree of aggregation can be formed between TTR monomer and Aβ aggregates due to the β-sheet-rich property of TTR monomer and Aβ aggregates, which may therefore reduce the cytotoxicity of Aβ aggregates. ConclusionBoth TTR tetramer and monomer can inhibit Aβ aggregation by “sequestering” Aβ monomer, while TTR monomer can reduce the cytotoxicity of Aβ aggregates by forming large co-aggregation with Aβ aggregates. This work can provide an important theoretical basis for the design and discovery of anti-AD drugs based on the neuroprotective effects of TTR.
