Kinase-specific phosphorylation of tau outside the amyloid core encodes fibril fold selection

Authors

Ramesh, R., Banerjee, S., Gajula Balija, M. B., Chakraborty, P., Dienemann, C., Landau, M., Zweckstetter, M.

Abstract

Tauopathies are defined by the accumulation of filamentous tau assemblies that adopt disease-specific molecular conformations, or tau strains. Although tau is extensively hyperphosphorylated in Alzheimer's disease, how phosphorylation patterns influence tau folding and strain selection remains unclear. Here, we show that site-specific phosphorylation of 0N3R tau by extracellular signal-regulated kinase 2 (ERK2), occurring predominantly within the proline-rich region and largely excluding the microtubule-binding domain, is sufficient to direct tau assembly into a structurally homogeneous fibril conformation. Residue-resolved NMR spectroscopy identifies a defined and quantifiable ERK2 phosphorylation pattern in the proline-rich region of tau. Cryo-electron microscopy at 3.0 [A] resolution reveals that ERK2-phosphorylated 3R tau assembles into filaments with an ordered cross-{beta} fold adopting an Alzheimer's disease PHF fold, despite the absence of phospho-sites within the fibril core. These filaments exhibit robust seeding activity in tau biosensor cells. Together, these results demonstrate that kinase-specific phosphorylation outside the amyloid core can be sufficient to bias tau toward a defined fibril structure, establishing a direct mechanistic link between kinase specificity, post-translational modification, and tau strain formation.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 05 Aug 2026.

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