Effects of PTMs on Tau Protein Aggregation: Insights from HCG and Atomistic MD Simulations
Louet, A. A. B.; Stuke, J.; Pietrek, L.; Vendruscolo, M.; Hummer, G.
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Post-translational modifications (PTMs) of the tau protein are increasingly recognized as pivotal regulators in the onset and progression of tauopathies, such as Alzheimers disease (AD). To systematically evaluate the structural and functional consequences of specific PTMs, we generated and analyzed seven distinctly modified variants of the tau-K32 construct. These included phosphorylation at Ser202/Thr205, phosphorylation at Ser258/Ser262/Ser356, full phosphorylation at all reported Ser/Thr sites, acetylation at Lys274/Lys281, acetylation at Lys280, full acetylation at all sites, and an unmodified control. Selection of PTM sites was guided by prior experimental literature. By incorporating fully modified tau models, we assessed the global impact of widespread modifications on structural properties and aggregation behavior. Our findings establish a comparative framework for understanding how discrete and cumulative PTMs modulate tau aggregation and provide mechanistic insight into PTM-induced tau dysfunction relevant to neurodegenerative diseases.
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