期刊
ACS CHEMICAL NEUROSCIENCE
卷 12, 期 11, 页码 1983-1988出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.1c00093
关键词
Tau protein; Alzheimer's disease; misfolding; histidine tautomerism
资金
- National Research Foundation (NRF) [2019R1A6A1A10073079]
- Korean government
The study reveals the significant impact of histidine tautomerism on the structure and aggregation tendency of tau protein, promoting the formation of NFTs. This suggests that the histidine tautomerism hypothesis may contribute to the misfolding of tau protein.
Self-assembly of hyperphosphorylated tau proteins into neurofibrillary tangles (NFT) is a hallmark of Alzheimer's disease. Previous studies suggest that the tau monomer may play an important role in NFTs formation in two general categories: inert (M-i) monomer and seed-competent (M-s) monomer. In the current study, replica-exchange molecular dynamics (REMD) were performed to investigate the effect of histidine tautomerism on the structures of a key fragment (R3) of tau protein and the transformation between different conformations. Based on the simulation results, we propose the histidine tautomerism hypothesis for tau protein misfolding. Histidine tautomerism greatly expands the conformational library, which triggers the emergence of conformations with higher aggregation tendency. Moreover, the conversions existing in both isomers and conformations may cause protein misfolding to occur more readily.
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