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ATP Kinetically Modulates Pathogenic Tau Fibrillations

preprint
submitted on 14.03.2020 and posted on 16.03.2020 by 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.

Funding

National Research Foundation of Korea (2019R1A2C2086193)

NST of Korea (CRC-15-04-KIST)

History

Email Address of Submitting Author

hughkim@korea.ac.kr

Institution

Korea university

Country

Republic of Korea

ORCID For Submitting Author

0000-0001-9205-1806

Declaration of Conflict of Interest

no conflict of interest

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