Structural insight into tau protein's paradox of intrinsically disordered behavior, self-acetylation activity, and aggregation

Yin Luo, Buyong Ma, Ruth Nussinov, Guanghong Wei

Research output: Contribution to journalArticlepeer-review

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 Cα 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 (275VQIINK280 and 306VQIVYK311), crucial for tau aggregation. Together, they illuminate tau's perplexing behavior of how its disordered state can accomplish both roles. SECTION: Biophysical Chemistry and Biomolecules

Original languageEnglish
Pages (from-to)3026-3031
Number of pages6
JournalJournal of Physical Chemistry Letters
Volume5
Issue number17
DOIs
StatePublished - 4 Sep 2014

Fingerprint

Dive into the research topics of 'Structural insight into tau protein's paradox of intrinsically disordered behavior, self-acetylation activity, and aggregation'. Together they form a unique fingerprint.

Cite this