Heo, Chae Eun Han, Jong Yoon Lim, Sungsu Lee, Jeeyoung Im, Dongjoon Lee, Min Jae Kim, Yun Kyung Kim, Hugh I 2024-01-19T16:32:33Z 2024-01-19T16:32:33Z 2021-09-02 2020-10 1948-7193 https://pubs.kist.re.kr/handle/201004/118067 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. English American Chemical Society ATP Kinetically Modulates Pathogenic Tau Fibrillations Article 10.1021/acschemneuro.0c00479 1 ACS Chemical Neuroscience, v.11, no.19, pp.3144 - 3152 ACS Chemical Neuroscience 11 19 3144 3152 N scie scopus 000580513100023 2-s2.0-85092682533 Biochemistry & Molecular Biology Chemistry, Medicinal Neurosciences Biochemistry & Molecular Biology Pharmacology & Pharmacy Neurosciences & Neurology Article MEMORY PROTEIN AGGREGATION PHASE NEURODEGENERATION PHOSPHORYLATION SEPARATION INSIGHTS FIBRILS DISEASE BINDING tau amyloidogenic proteins mass spectrometry small-angle X-ray scattering Amyloid fibrillation biophysics