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  Disease‐associated tau phosphorylation hinders tubulin assembly within tau condensates

Savastano, A., Flores, D., Kadavath, H., Biernat, J., Mandelkow, E., & Zweckstetter, M. (2021). Disease‐associated tau phosphorylation hinders tubulin assembly within tau condensates. Angewandte Chemie International Edition, 60(2), 726-730. doi:10.1002/anie.202011157.

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Savastano, A., Author
Flores, D., Author
Kadavath, H., Author
Biernat, J., Author
Mandelkow, E., Author
Zweckstetter, M.1, Author              
Affiliations:
1Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society, ou_578571              

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Free keywords: DP; liquid-liquid phase separation; NMR spectroscopy; phosphorylation; tau
 Abstract: Cellular condensation of intrinsically disordered proteins (IDPs) through liquid–liquid phase separation (LLPS) allows dynamic compartmentalization and regulation of biological processes. The IDP tau, which promotes the assembly of microtubules and is hyperphosphorylated in Alzheimer's disease, undergoes LLPS in solution and on the surface of microtubules. Little is known, however, about the influence of tau phosphorylation on its ability to nucleate microtubule bundles in conditions of tau LLPS. Herein, we show that unmodified tau as well as tau phosphorylated at disease‐associated epitopes condense into liquid‐like droplets. Although tubulin partitioned into and reached high concentrations inside all tau droplets, it was unable to grow into microtubules form the inside of droplets formed by tau phosphorylated at the AT180 epitope (T231/S235). In contrast, neither phosphorylation of tau in the repeat domain nor at its tyrosine residues inhibited the assembly of tubulin from tau droplets. Because LLPS of IDPs has been shown to promote different types of cytoskeletal assembly, our study suggests that IDP phosphorylation might be a broadly used mechanism for the modulation of condensate‐mediated cytoskeletal assembly.

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Language(s): eng - English
 Dates: 2020-10-052021-01-11
 Publication Status: Published in print
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 Rev. Type: Peer
 Identifiers: DOI: 10.1002/anie.202011157
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Project name : -
Grant ID : 787679 - LLPS-NMR
Funding program : Horizon 2020 (H2020)
Funding organization : European Commission (EC)

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Title: Angewandte Chemie International Edition
Source Genre: Journal
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Pages: - Volume / Issue: 60 (2) Sequence Number: - Start / End Page: 726 - 730 Identifier: -