Misfolding and Self-Assembly Dynamics of Microtubule-Binding Repeats of the Alzheimer-Related Protein Tau

Overview

Journal J Chem Inf Model

Publisher American Chemical Society

Specialties Chemistry
Medical Informatics

Date 2021 May 25

PMID 34032430

Citations 9

Authors

Huan He

Yuying Liu

Yunxiang Sun

Feng Ding

Affiliations

Soon will be listed here.

Abstract

Pathological aggregation of intrinsically disordered tau protein, driven by the interactions between microtubule-binding (MTB) domains, is associated with Alzheimer's disease. The MTB domain contains either three or four repeats with sequence similarities. Compared to amyloid β, many aspects of the misfolding and aggregation mechanisms of tau are largely unknown. In this study, we systematically investigated the dynamics of monomer misfolding and dimerization of each MTB repeat using atomistic discrete molecular dynamic simulations. Our results revealed that all the four repeat monomers (R1-R4) were very dynamic, featuring frequent conformational conversion and lacking stable conformations. While R1, R2, and R4 monomers occasionally adopted partially helical conformations, R3 monomers frequently formed β-sheets. In dimerization simulations, R3 displayed the strongest aggregation propensity with high β-sheet contents, while R1 was the least prone to aggregation. The R2 and R4 dimers contained both helix and β-sheet structures. The β-sheets in R4 assemblies were dominant with β-hairpin conformation. In R2 and R3 dimers, intermolecular β-sheets were mainly driven by residues around the paired helical filament (PHF) regions. Residues around the PHF6* in R2 and PHF6 in R3 had significantly higher intermolecular contacts than other regions, suggesting that these residues play a key role in the amyloid aggregation of tau. Our results on the structural ensembles and early aggregation dynamics of each tau MTB repeat will help understand the nucleation and fibrillization of tau.

Citing Articles

Pathological Impact of Tau Proteolytical Process on Neuronal and Mitochondrial Function: a Crucial Role in Alzheimer's Disease.

Olesen M, Quintanilla R Mol Neurobiol. 2023; 60(10):5691-5707.

PMID: 37332018 DOI: 10.1007/s12035-023-03434-4.

Molecular Mechanism of Tau Misfolding and Aggregation: Insights from Molecular Dynamics Simulation.

Zhong H, Liu H, Liu H Curr Med Chem. 2023; 31(20):2855-2871.

PMID: 37031392 DOI: 10.2174/0929867330666230409145247.

Recent Advances in Molecular Dynamics Simulations of Tau Fibrils and Oligomers.

Barredo P, Balanay M Membranes (Basel). 2023; 13(3).

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Differential Binding and Conformational Dynamics of Tau Microtubule-Binding Repeats with a Preformed Amyloid-β Fibril Seed.

Song Z, Gatch A, Sun Y, Ding F ACS Chem Neurosci. 2023; 14(7):1321-1330.

PMID: 36975100 PMC: 10119806. DOI: 10.1021/acschemneuro.3c00014.

Phosphorylation at Ser289 Enhances the Oligomerization of Tau Repeat R2.

Man V, He X, Han F, Cai L, Wang L, Niu T J Chem Inf Model. 2023; 63(4):1351-1361.

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