Tau local structure shields an amyloid-forming motif and controls aggregation propensity

Abstract

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 tau’s repeat domain at inter-repeat interfaces proximal to amyloidogenic sequences, such as 306 VQIVYK 311 . We use cross-linking mass spectrometry, recombinant protein and synthetic peptide systems, in silico modeling, and cell models to conclude that the aggregation-prone 306 VQIVYK 311 motif forms metastable compact structures with its upstream sequence that modulates aggregation propensity. We report that 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.

The mechanism of Hsp90-induced oligomerizaton of Tau

“…S6; (40,41)]: For Tau-17*-291* and Tau-17*-433*, the deviation between the experiment and the RC model indicates a considerable The systematic analysis of the experimental  eff values supports the paper-clip model proposed on the basis of FRET and NMR experiments for Tau in solution, where N and C termini are in proximity to each other, and Tau-RD is in an overall more compact fold than RC (7,8). On the one hand, these results demonstrate the capacity of the  eff approach for obtaining structural information from DEER traces reflecting vast protein ensembles, while on the other hand, they define the paper clip as a reference structural ensemble of Tau in solution, which is in agreement with the results obtained for the Tau structural ensemble in previous studies, suggesting a paper clip or S shape in solution (7,8,39,42).…”

The molecular mechanism of Hsp90-induced oligomerization of Tau

“…The systematic analysis of the experimental eff values supports the 'paper-clip' model proposed on the basis of FRET and NMR experiments for Tau in solution, where N-and Ctermini are in proximity to each other and Tau-RD in an overall more compact fold than RC (7,8). On the one hand these results demonstrate the capacity of the eff approach for obtaining structural information from DEER traces reflecting vast protein ensembles, while on the other hand they define the 'paper-clip' as a reference structural ensemble of Tau in solution, which is in agreement with the results obtained for the Tau structural ensemble in previous studies, suggesting a 'paper-clip' or S-shape in solution (7,8,39,42).…”

Tau amyloidogenesis begins with a loss of its conformational polymorphism

“…These data indicate that amyloid aggregation of tau is associated to unstructured and consequently expanded monomers, suggesting an alternative assembly pathway (Figure 3). Our results are supported by computational studies describing a shift in tau peptides carrying ∆ 280K or P301L towards more expanded conformations (Larini et al 2013;D. Chen et al 2019).…”

“…Computational studies have previously predicted this conformational diversity, in particular, for fragments containing the hexapeptides 275 VQIINK 280 or 306 VQIVYK 311 contained in the K18 fragment that we have analyzed here (Larini et al 2013;D. Chen et al 2019).…”