DOI: 10.1002/alz.071720 ISSN: 1552-5260

Abnormal Phosphorylation at Ser293 promotes the Oligomerization of Tau Repeat R2: A Computational Study

Viet H Man
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Geriatrics and Gerontology
  • Neurology (clinical)
  • Developmental Neuroscience
  • Health Policy
  • Epidemiology



In tauopathies such as Alzheimer’s disease (AD), aberrant phosphorylation causes the dissociation of tau protein from microtubules. The dissociated tau then aggregates into sequent forms from soluble oligomers to paired helical filaments (PHF), and insoluble neurofibrillary tangles (NFTs). NFTs is a hallmark of AD, while oligomers are found to be the most toxic form of the tau aggregates. Therefore, understanding tau oligomerization with regard of abnormal phosphorylation is important to therapeutic development of AD. In this study, we investigated the impact of phosphorylated Ser293, one of 40 aberrant phosphorylation sites of full‐length tau protein, on monomeric and dimeric structures of tau repeat R2 peptides


Wild‐type tau repeat R2 (wtR2) was taken from an experimental structure of R2‐microtubule complex (PDB code 6CVN). The phosphorylated Ser293 R2 peptide (pS293R2) was obtained by phosphorylating the wtR2 at Ser293 residue. Extensive replica exchange molecular dynamics simulations using all‐atom force field and explicit solvent were carried out for five systems including two monomers (wtR2 and pS293R2) and three dimers (wtR2+wtR2, wtR2+pS293R2, and pS293R2+ pS293R2). The structures of R2 monomers and dimers sampled by the simulations were characterized and compared.


For monomeric conformations, the phosphorylation enhances intramolecular interaction, compactness and β content. For dimeric cases, the phosphorylation increases intermolecular interaction, β‐sheet formation, and turn‐coil structural transition. Interestingly, the phosphorylated residue strongly interacts with cations, resulting in a pS293‐cation‐pS293 bridge in pS293R2+ pS293R2 system.


Our results suggest that abnormal phosphorylation at Ser293 accelerates the oligomerization of R2 peptides, and consequently it may promote tau aggregation. Furthermore, we also found a pS293‐cation‐pS293 bridge formed, thus uncovered the essential role of cation ions in the oligomerization of the phosphorylated R2 repeat. Our findings suggest that phosphorylation at Ser293 should be taken into consideration when screening the inhibitors of tau oligomerization.

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