Deciphering the Effect of Lysine Acetylation on the Misfolding and Aggregation of Human Tau Fragment171IPAKTPPAPK180 Using Molecular Dynamic Simulation and the Markov State Model

Syed Jawad Ali Shah, Haiyang Zhong, Qianqian Zhang, Huanxiang Liu

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

The formation of neurofibrillary tangles (NFT) with β-sheet-rich structure caused by abnormal aggregation of misfolded microtubule-associated protein Tau is a hallmark of tauopathies, including Alzheimer’s Disease. It has been reported that acetylation, especially K174 located in the proline-rich region, can largely promote Tau aggregation. So far, the mechanism of the abnormal acetylation of Tau that affects its misfolding and aggregation is still unclear. Therefore, revealing the effect of acetylation on Tau aggregation could help elucidate the pathogenic mechanism of tauopathies. In this study, molecular dynamics simulation combined with multiple computational analytical methods were performed to reveal the effect of K174 acetylation on the spontaneous aggregation of Tau peptide171 IPAKTPPAPK180, and the dimerization mechanism as an early stage of the spontaneous aggregation was further specifically analyzed by Markov state model (MSM) analysis. The results showed that both the actual acetylation and the mutation mimicking the acetylated state at K174 induced the aggregation of the studied Tau fragment; however, the effect of actual acetylation on the aggregation was more pronounced. In addition, acetylated K174 plays a major contributing role in forming and stabilizing the antiparallel β-sheet dimer by forming several hydrogen bonds and side chain van der Waals interactions with residues I171, P172, A173 and T175 of the corresponding chain. In brief, this study uncovered the underlying mechanism of Tau peptide aggregation in response to the lysine K174 acetylation, which can deepen our understanding on the pathogenesis of tauopathies.

Original languageEnglish
Article number2399
JournalInternational Journal of Molecular Sciences
Volume23
Issue number5
DOIs
Publication statusPublished - 1 Mar 2022

Keywords

  • Acetylation
  • Aggregation
  • MD simulations
  • Markov state model
  • Post-translational modifications
  • Tau

Fingerprint

Dive into the research topics of 'Deciphering the Effect of Lysine Acetylation on the Misfolding and Aggregation of Human Tau Fragment171IPAKTPPAPK180 Using Molecular Dynamic Simulation and the Markov State Model'. Together they form a unique fingerprint.

Cite this