Sequence-Dependent Conformational Properties of PGGG Motif in Tau Repeats: Insights from Molecular Dynamics Simulations of Narrow Pick Filament.

Abstract

Tauopathies are a class of neurodegenerative diseases correlated with the presence of pathological Tau fibrils as a diagnostic marker. The microtubule-binding repeat region of Tau protein, which includes R1, R2, R3, and R4 repeats, constitutes the core of these fibrils. Each repeat consists of a semiconserved C-terminal hexapeptide flanked by KxGS and PGGG motifs. Previous studies have shown the influence of these peptides on protein aggregation, yet their repeat-specific properties are less explored. Using molecular dynamics, we probed the sequence-specific influence of the C-terminal hexapeptide (264ENLKHQ269) in determining the compact local conformation of the R1 repeat of the narrow Pick filament (NPF) with a homologous E264G mutation. In addition to that, we also studied the influence of 262S phosphorylation on this conformation as the phosphorylation is proposed to alleviate the pathogenesis of Pick's disease. Interestingly, we determined that E264G mutation induces a conformational shift of 270PGGG273 from a turn to a random coil. This conformational dependence is experimentally verified with the R1R3-E264G mutant construct, which displayed accelerated aggregation compared with the R1R3 wild-type construct. A significant delay in aggregation of the R1R3-G326E mutant further demonstrates the importance of 326G in determining the conformation of the R3 repeat. Thus, we conclude that the conformational properties of the PGGG motif in Tau repeats are strongly dependent on the repeat-specific sequence of the C-terminal hexapeptide.