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

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. 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 design tau sequences that stabilize its structural ensemble. Our findings reveal that substitutions near the conserved 'PGGG' beta-turn motif can modulate local conformation, more stably engaging in interactions with the ³⁰⁶VQIVYK³¹¹ amyloid motif to decrease aggregation in vitro a

SUBMITTER: Bali S 

PROVIDER: S-EPMC10836093 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature