Abstract
Abnormal aggregation of the microtubule-associated protein Tau is closely associated with tauopathies, including Alzheimer’s disease and chronic traumatic encephalopathy. The hexapeptide 275VQIINK280 (PHF6*), a fibril-nucleating core motif of Tau, has been shown to play a vital role in the aggregation of Tau. Mounting experiment evidence demonstrated the acetylation of a single-lysine residue K280 in the PHF6* was a critical event for the formation of pathological Tau amyloid deposits. However, the underlying mechanisms by which K280 acetylation affects Tau aggregation at the atomic level remain elusive. In this work, we performed replica exchange molecular dynamics simulations to investigate the influence of acetylation of K280 on the aggregation of PHF6*. Our simulations show that acetylation of K280 not only enhances the self-assembly capability of PHF6* peptides but also increases the β-sheet structure propensity of the PHF6*. The inter-molecular interactions among PHF6* peptides are strengthened by the acetylation of K280, resulting in an increased ordered β-sheet-rich conformations of the PHF6* assemblies along with a decrease of the structural diversity. The residue-pairwise contact frequency analysis shows that K280 acetylation increases the interactions among the hydrophobic chemical groups from PHF6* peptides, which promotes the aggregation of PHF6*. This study offers mechanistic insights into the effects of acetylation on the aggregation of PHF6*, which will be helpful for an in-depth understanding of the relationship between acetylation and Tau aggregation at the molecular level.
Highlights
Tau, a microtubule-associated protein first discovered in 1975, was found to be critical for the assembly and stabilization of microtubules (Weingarten et al, 1975)
These results demonstrate that K280 acetylation markedly increases the β-sheet probability and facilitates the β-sheet formation of PHF6* peptides
We found that SC-SC contact numbers in two systems are much higher than the MC-SC contact numbers, and K280 acetylation leads to a higher increment of SC-SC contact numbers than that of MC-SC, revealing SC-SC interaction plays an important role in the formation of PHF6* oligomers
Summary
A microtubule-associated protein first discovered in 1975, was found to be critical for the assembly and stabilization of microtubules (Weingarten et al, 1975). Recent advances revealed that Tau played an important role in a diverse range of molecular pathways including cell signalling, synaptic plasticity, and regulation of genomic stability (Brandt and Lee, 1993; Bhaskar et al, 2005; Regan et al, 2017). The physiological functions of Tau are regulated by various post-translational modifications (PTMs), including phosphorylation, acetylation, glycation, nitration, O-GlcNAcylation, oxidation, ubiquitination, SUMOylation and methylation. Wesseling et al generated a high-resolution quantitative proteomics map of 95 PTMs on multiple isoforms of Tau, and demonstrated that these modifications occurred in an ordered manner and led to Tau aggregation (Wesseling et al, 2020)
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