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Updated: Jan 14, 2026
In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
Published on: January 2, 2015
Aberrant S293 Phosphorylation Drives Oligomerization of Tau Repeat R2: Insights from Molecular Dynamics Simulations
Viet Hoang Man1, Xibing He1, Phuong H Nguyen2
1Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States.
Abstract:
Aberrant phosphorylation, which is absent in healthy brains but present exclusively in the brains of individuals with Alzheimer's disease (AD), plays a critical role in AD development. It causes the dissociation of tau protein from microtubules, followed by the aggregation of tau protein into brain-toxic oligomers and fibrils. In our previous study, we investigated the impact of abnormal phosphorylation at S289 (pS289) on the oligomerization of tau repeat R2 peptides. In this work, we continue to investigate the effect of aberrant phosphorylation at residue S293 (pS293) on the R2 peptides. Our result indicated that pS293 also promotes oligomerization, which is similar to pS289. Both the phosphorylation-enhanced intramolecular and intermolecular interactions and β-sheet formation of phosphorylated R2 compared to that of the wild type. We observed that Na+ can bridge two pS293 residues to form pS293--Na+-pS293 triad in the R2 dimer, a phenomenon also observed for the pS289 R2 dimer. However, the impact of pS293 was different from that of pS289 in terms of the secondary structural profile of both monomeric and dimeric R2 peptides. Our findings suggest that phosphorylation at S293 should be taken into consideration in the inhibitor screening of tau oligomerization.
Insights
Aberrant phosphorylation at S293 in tau protein promotes its aggregation, similar to S289. This finding is crucial for developing Alzheimer's disease (AD) therapies targeting tau oligomerization.
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.
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