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bioRxiv · 10.1101/2023.12.13.571598

Ensemble-based design of tau to inhibit aggregation while preserving biological activity.

Bali, S.·Singh, R.·Wydorski, P. M.·Wosztyl, A.·Perez, V. A.·chen, d.·Rizo, J.·Joachimiak, L. A.
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Abstract

The microtubule-associated protein tau is implicated in neurodegenerative diseases characterized by amyloid formation. Mutations associated with frontotemporal dementia increase tau aggregation propensity and disrupt its endogenous microtubule-binding activity. However, the structural relationship between aggregation propensity and biological activity remains unclear. We employed a multi-disciplinary approach, including computational modeling, NMR, cross-linking mass spectrometry, and cell models to engineer tau sequences that modulate its structural ensemble. Our findings show that substitutions near the conserved PGGG {beta}-turn motif informed by tau isoform context reduce tau aggregation in vitro and cells and can even counteract aggregation induced by turn destabilizing disease-associated proline-to-serine mutations. Engineered tau sequences maintain microtubule binding and explain why 3R isoforms exhibit reduced pathogenesis compared to 4R. We propose a simple mechanism to reduce the formation of pathogenic species while preserving biological function, thus offering insights for therapeutic strategies aimed at reducing tau protein misfolding in neurodegenerative diseases. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=88 SRC="FIGDIR/small/571598v2_ufig1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@178a79org.highwire.dtl.DTLVardef@1842dc7org.highwire.dtl.DTLVardef@d9a32borg.highwire.dtl.DTLVardef@676dec_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Bali, S., Singh, R., Wydorski, P. M., Wosztyl, A., Perez, V. A., chen, d., Rizo, J., Joachimiak, L. A.. 2023-12-14. Ensemble-based design of tau to inhibit aggregation while preserving biological activity.. https://doi.org/10.1101/2023.12.13.571598

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