Acetylation of Lysine Residues within the MT‐binding Repeats Specifically Modulates the Structure Ensemble of Tau

Abstract

The microtubule associated protein tau is expressed primarily in the central nervous system and promotes microtubule (MT) assembly. The aberrant accumulation of tau protein and formation of insoluble aggregates are pathological hallmarks of neurodegenerative tauopathies including Alzheimer's disease. Six tau isoforms are generated by mRNA alternative splicing containing either three (3R tau) or four (4R tau) MT‐binding repeats and various number of N‐terminal exons (0N, 1N and 2N). K18 and K19 are the truncated constructs of 4R tau and 3R tau, consisting of only the four and three repeats, respectively. K18 and K19 form amyloid fibrils with cross‐β structure, constituting the core of tau filaments. Recent studies have shown that acetylation of specific lysine residues within the MT‐binding repeats could either promote or inhibit tau aggregation and tau mediated microtubule assembly. Here, we investigated the effect of lysine acetylation on the structure of tau K18 by a combination of biophysical structure characterization and molecular dynamics simulation. Radius of gyration derived from small angle X‐ray scattering (SAXS) showed that the structures of acetylation mimic tau species (K274Q/K321Q and K280Q/K281Q/K369Q) were more extended than the WT protein. Although the influence of lysine acetylation on the intramolecular interactions was mainly local, long range perturbations were also observed from NMR chemical shift analysis. Molecular dynamic simulations in explicit solvent revealed site specific modulation in the structure ensemble of tau repeats, where K280Q/K281Q mutation led to compaction of repeat R2 and K321Q mutation led to extension of repeat R3. Statistics on the lifetime and distance of residue contacts and secondary structure components were performed to investigate the changes in structure and dynamics upon acetylation. These results show that the effect of acetylation on tau structure was site specific, which may promote or reduce aggregation by exposing or shielding the aggregation prone segments.Support or Funding InformationThis work was supported by National Natural Science Foundation of China (Grant number: 21603121) and Hubei University of Technology.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.