Aberrant S293 Phosphorylation Drives Oligomerization of Tau Repeat R2: Insights from Molecular Dynamics Simulations

Area of Science:

• Neuroscience
• Biochemistry
• Molecular Biology

Background:

• Alzheimer's disease (AD) is characterized by aberrant tau protein phosphorylation.
• Phosphorylation causes tau to detach from microtubules, leading to toxic aggregates.
• Previous work examined S289 phosphorylation; this study focuses on S293.

Purpose of the Study:

• To investigate the effect of S293 phosphorylation on tau repeat R2 peptide oligomerization.
• To compare the impact of S293 phosphorylation with S289 phosphorylation.
• To inform the development of inhibitors for tau oligomerization.

Main Methods:

• Computational modeling and analysis of tau repeat R2 peptides.
• Investigating the role of aberrant phosphorylation at S293.
• Comparing wild-type R2 peptides with phosphorylated R2 peptides (pS293).

Main Results:

• S293 phosphorylation promotes tau R2 peptide oligomerization, similar to S289.
• Phosphorylation enhances intramolecular/intermolecular interactions and beta-sheet formation.
• A pS293-Na+-pS293 triad was observed in R2 dimers, facilitating oligomerization.
• S293 phosphorylation has a distinct effect on secondary structure compared to S289.

Conclusions:

• Aberrant phosphorylation at S293 is a significant factor in tau aggregation.
• S293 phosphorylation influences tau peptide secondary structure differently than S289.
• Targeting S293 phosphorylation may be a viable strategy for Alzheimer's disease treatment.