Specific phosphorylation patterns control the interplay between aggregation and condensation of Tau-R4 peptides

Abstract

Specific phosphorylation patterns regulate the activity of proteins and play a central role in protein self-assembly. In Tau, such patterns drive the formation of disease-related condensates and aggregates. Understanding their functional impact is essential for studying Tauopathies such as Alzheimer's Disease. Here we show how specific phosphorylation patterns regulate Tau self-assembly and control the interplay between its aggregation and condensation, using a peptide-based approach that allows systematic analysis of libraries of specific phosphorylation patterns at the domain level and is complementary to the current protein-level methods. We applied our methodology to study the effect of specific phosphorylations on the aggregation and condensation of the R4 domain of Tau that is pivotal for its self-assembly, forming the β-helix motif that is common to various Tau patient fibrils. Using advanced phosphopeptide synthesis methods developed in our labs, we generated a library of multi-phosphorylated peptides derived from Tau R4. We found that phosphorylation at Ser341 promotes aggregation, while Ser352 enhances condensation. Phosphorylation at Ser356 inhibits both processes. The source of these different outcomes is the distinct microenvironments around each phosphorylated site. Our results provide a residue-level resolution of how the decision between Tau condensation and aggregation is being made. This was possible by using our peptide-based approach, which is complementary to protein-level method and enables efficient identification of active phosphorylation patterns. These can later be studied at the protein level.

Graphical abstract: Specific phosphorylation patterns control the interplay between aggregation and condensation of Tau-R4 peptides

Supplementary files

Article information

Article type
Paper
Submitted
27 May 2025
Accepted
18 Jun 2025
First published
19 Jun 2025
This article is Open Access
Creative Commons BY-NC license

Org. Biomol. Chem., 2025, Advance Article

Specific phosphorylation patterns control the interplay between aggregation and condensation of Tau-R4 peptides

S. G. Bressler, D. Grunhaus, A. Aviram, S. G. D. Rüdiger, M. Hurevich and A. Friedler, Org. Biomol. Chem., 2025, Advance Article , DOI: 10.1039/D5OB00885A

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