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submitted on 14.03.2020 and posted on 16.03.2020by Jong Yoon Han,, Chae Eun Heo, Sungsu Lim, Jeeyoung Lee, Iryna Martsishevska, Dongjoon Im, Min Jae Lee, Yun Kyung Kim, Hugh I. Kim
Advanced understanding of
Alzheimer’s disease (AD) and several tauopathies over the past decades
indicates the pathological importance of tau aggregation in these diseases.
Herein, we demonstrated that adenosine triphosphate (ATP), a highly charged
anionic molecule abundant in the cytosol of cells, catalyses tau fibrillation via
supramolecular complexation with basic residues of tau. Our results showed that
ATP attracts multiple lysine residues of four-repeat domain of tau (K18),
thereby immediately forming dimers which convert to nuclei to accelerate fibril
elongation. However, ATP was not directly incorporated in the K18 fibrils
suggesting a catalytic role of ATP in K18 fibrillation. We also characterized
the correlation between ATP dyshomeostasis and tau aggregation in the cellular
environment. Our multiple biophysical approaches, including native mass
spectrometry (MS), small-angle X-ray scattering (SAXS), and molecular dynamics
(MD) simulation, provided insights into the molecular-level influence of ATP on
the structural change and fibrillation of tau.