Uncovering the Effect of pS202/pT205/pS208 Triple Phosphorylations on the Conformational Features of the Key Fragment G192-T212 of Tau Protein.

Abstract

Microtubule-associated protein tau is abnormally phosphorylated and forms the aggregates of paired helical filaments in Alzheimer's disease (AD) and other tauopathies. So far, the relationship and mechanism between the abnormal phosphorylation of tau and fibril formation is still unclear. Therefore, studying the effect of phosphorylation on the structure of tau protein is helpful to elucidate the pathogenic mechanism of tauopathies. It has been shown that pS202/pT205/pS208 triple phosphorylations located in the proline-rich region can promote tau aggregation. In this work, the effect of triple phosphorylations on tau structure was investigated by molecular dynamics simulations combined with multiple analytical methods of trajectories. The results showed that the conformational diversity of G192-T212 fragments decreased after phosphorylation compared with that of the wild-type. Moreover, the dynamic network and hydrogen bond analyses showed that the addition of pS208 phosphorylation can destroy the key hydrogen bonds and the network structure formed centered on pT205 at the C-terminal of the pS202/pT205 double phosphorylated peptide and then destroy the turn structure formed in the region of G207-R211. The destruction of this turn structure is considered to be the main reason for the aggregation of pS202/pT205/pS208 triple phosphorylations. For the pS202/pT205/pS208 triple phosphorylated system, the G207-R211 region is a coil structure, which is more extended and prone to aggregation. In a word, our results reveal the mechanism that pS202/pT205/pS208 triple phosphorylations promote tau aggregation at the atomic level, which can provide useful theoretical guidance for the rational design of effective therapeutic drugs against AD and other tauopathies.

• Authors: Hongli Liu, Qin Li, Chunmei Xiong, Haiyang Zhong, Qianqian Zhang, Huanxiang Liu, Xiaojun Yao
• Journal: ACS chemical neuroscience (ACS Chem Neurosci) Vol. 12 Issue 6 Pg. 1039-1048 (03 17 2021) ISSN: 1948-7193 [Electronic] United States
• PMID: 33663205 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• tau Proteins

Topics

• Alzheimer Disease (metabolism)
• Humans
• Molecular Dynamics Simulation
• Neurofibrillary Tangles (metabolism)
• Phosphorylation
• tau Proteins (metabolism)