Structural Insight into Tau Protein’s Paradox of Intrinsically Disordered Behavior, Self-Acetylation Activity, and Aggregation

High Resolution Image Download MS PowerPoint Slide Tau is an intrinsically disordered protein (IDP) implicated in Alzheimer’s disease. Recently, tau proteins were discovered to be able to catalyze self-acetylation, which may promote its pathological aggregation. Understanding the paradox of tau’s random-like conformations, aggregation propensity, and enzymatic activity are challenging questions. We characterized the atomic structures of two truncated tau constructs, K18 and K19, consisting of, respectively, only the four- and three-repeats of tau protein, providing structural insights into tau’s paradox. Extensive 4.8 μs replica-exchange molecular dynamics simulations of the tau proteins achieved quantitative correlation with experimental C α chemical shifts. Our results revealed (1) dynamically ordered conformations with close lysine–cysteine distances essential for tau self-acetylation and (2) high β-sheet content and large hydrophobic surface exposure for the two critical hexapeptides ( 275 VQIINK 280 and 306 VQIVYK 311 ), crucial for tau aggregation. Together, they illuminate tau’s perplexing behavior of how its disordered state can accomplish both roles.