Native tau structure is disrupted by disease-associated mutations that promote aggregation
Tauopathies are neurodegenerative diseases characterized by intracellular amyloid deposits of tau protein. Missense mutations in the tau gene (MAPT) correlate with aggregation propensity and cause dominantly inherited tauopathies, but their biophysical mechanism driving amyloid formation is poorly understood. Many disease-associated mutations localize within taus repeat domain at inter-repeat interfaces proximal to amyloidogenic sequences, such as 306VQIVYK311. Using cross-linking mass spectrometry, intramolecular FRET, recombinant protein and synthetic peptide systems, in silico modeling, and cell models, we conclude that the aggregation prone 306VQIVYK311 motif forms metastable compact structures with the upstream sequence that modulates aggregation propensity. Disease-associated mutations, isomerization of a critical proline, or alternative splicing are all sufficient to destabilize this local structure and trigger spontaneous aggregation. These findings provide a biophysical framework to explain the basis of early conformational changes that may underlie genetic and sporadic tau pathogenesis.