Application of modular isoxazoline-beta2,2-aminoacid-based peptidomimetics as chemical model systems for studying the tau misfolding
Tau is a microtubule-associated protein essential for regulating microtubule dynamics and axonal transport in neurons. In tauopathies, the transition of tau from a physiological to a pathological form remains unclear, though the hexapeptides PHF6 and PHF6* are key in triggering aggregation. These sequences are shielded by a beta-hairpin structure in the native state but expose hydrophobic residues during misfolding, promoting self-assembly. This study employs a non-natural beta2-amino acid to induce PHF6 and PHF6* into either extended or beta-hairpin conformations. The extended form triggers tau aggregation without additives, acting as a seed-competent monomer model system. Conversely, the beta-hairpin preserves tau in a soluble monomeric state. Additionally, a beta-hairpin mimic inspired by Hsp90 showed potential as a chaperone mimic and inhibitor of tau aggregation, offering insights into corrective folding and aggregation modulation in neuronal
environments.
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