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

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 beta, 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 beta-sheets. In dimerization simulations, R3 displayed the strongest aggregation propensity with high beta-sheet contents, while R1 was the least prone to aggregation. The R2 and R4 dimers contained both helix and beta-sheet structures. The beta-sheets in R4 assemblies were dominant with beta-hairpin conformation. In R2 and R3 dimers, intermolecular beta-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.

Automated summary

Pathological aggregation of intrinsically disordered tau protein, driven by the interactions between microtubule-binding (MTB) domains, is associated with Alzheimer's disease. Our results from atomistic discrete molecular dynamics simulations show that all four repeat monomers of tau are dynamic, with R3 displaying the strongest aggregation propensity. R1 is the least prone to aggregation, while R2 and R4 dimers contain both helix and beta-sheet structures.