title: Structural Insight into Tau Protein's Paradox of Intrinsically Disordered Behavior, Self-Acetylation Activity, and Aggregation.
abstract: 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 Cαchemical 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 (275VQIINK280and306VQIVYK311), crucial for tau aggregation. Together, they illuminate tau's perplexing behavior of how its disordered state can accomplish both roles.
authors.affiliation: State Key Laboratory of Surface Physics, Key Laboratory for Computational Physical Sciences (MOE), and Department of Physics, Fudan University , Shanghai, People's Republic of China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Basic Science Program, Leidos Biomedical Research, Inc. Cancer and Inflammation Program, National Cancer Institute , Frederick, Maryland 21702, United States.
authors.forename: Buyong
authors.initials: B
authors.lastname: Ma
authors.affiliation: Basic Science Program, Leidos Biomedical Research, Inc. Cancer and Inflammation Program, National Cancer Institute , Frederick, Maryland 21702, United States ; Sackler Institute of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University , Tel Aviv 69978, Israel.
authors.forename: Ruth
authors.initials: R
authors.lastname: Nussinov
authors.affiliation: State Key Laboratory of Surface Physics, Key Laboratory for Computational Physical Sciences (MOE), and Department of Physics, Fudan University , Shanghai, People's Republic of China.
authors.forename: Guanghong
authors.initials: G
authors.lastname: Wei