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

## TL;DR

This study shows that phosphorylation at S293 in tau protein promotes harmful clumping, similar to another site (S289), and suggests it should be considered in drug development for Alzheimer's.

## Contribution

The novel contribution is identifying how phosphorylation at S293 drives tau oligomerization and comparing its effects to S289.

## Key findings

- Phosphorylation at S293 promotes R2 peptide oligomerization similar to S289.
- Na+ bridges pS293 residues in R2 dimers, forming a pS293--Na+-pS293 triad.
- Phosphorylation at S293 alters secondary structure profiles of R2 peptides differently than S289.

## 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.