Open AccessStructural Insight into Tau Protein’s Paradox of Intrinsically Disordered Behavior, Self-Acetylation Activity, and Aggregation
Author(s) -
Yin Luo,
Buyong Ma,
Ruth Nussinov,
Guanghong Wei
Publication year - 2014
Publication title -
the journal of physical chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.563
H-Index - 203
ISSN - 1948-7185
DOI - 10.1021/jz501457f
Subject(s) - intrinsically disordered proteins , tau protein , chemistry , acetylation , protein aggregation , molecular dynamics , protein–protein interaction , biophysics , biochemistry , computational chemistry , alzheimer's disease , disease , biology , medicine , pathology , gene
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.