ATP Kinetically Modulates Pathogenic Tau Fibrillations

Title
ATP Kinetically Modulates Pathogenic Tau Fibrillations
Authors
김윤경임성수허채은한종윤이지영임동준이민재김준곤
Keywords
Amyloid fibrillation; biophysics, tau; amyloidogenic proteins; mass spectrometry; small-angle X-ray scattering
Issue Date
2020-10
Publisher
ACS Chemical Neuroscience
Citation
VOL 11-3152
Abstract
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 found abundantly in the cytosol of cells, catalyzes fibrillation of tau as well as human islet amyloid polypeptide, a representative of basic intrinsically disordered proteins. Our results showed that ATP attracts multiple lysine residues of the four-repeat domain of tau (K18) via supramolecular complexation, thereby forming dimers that are converted to nuclei and accelerate fibril elongation. However, ATP was not directly incorporated into the K18 fibrils, suggesting that ATP plays the role of a catalyst, rather than a reactant, during 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 changes and fibrillation of tau.
URI
http://pubs.kist.re.kr/handle/201004/72668
ISSN
1948-7193
Appears in Collections:
KIST Publication > Article
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