Direct Observation of Aggregation‐Induced Backbone Conformational Changes in Tau Peptides

Abstract

In tau proteins, the hexapeptides in the R2 and R3 repeats are known to initiate tau fibril formation, which causes a class of neurodegenerative diseases called the taupathies. We show that in R3, in addition to the presence of the hexapeptides, the correct turn conformation upstream to it is also essential for producing prion-like fibrils that are capable of propagation. A time-dependent NMR aggregation assay of a slow fibril forming R3-S316P peptide revealed a trans to cis equilibrium shift in the peptide-bond conformation preceding P316 during the growth phase of the aggregation process. S316 was identified as the key residue in the turn that confers templating capacity on R3 fibrils to accelerate the aggregation of the R3-S316P peptide. These results on the specific interactions and conformational changes responsible for tau aggregation could prove useful for developing an efficient therapeutic intervention in Alzheimer's disease.

InP Quantum Dots: Probing the Active Domain of Tau Peptide Using Energy Transfer

“…The 20 amino acid peptide, chosen in the current investigation (Tau 305–324 ), contains the short amino acid sequence 306 VQIVYK 311 which plays a crucial role in its nucleation and self-assembly, leading to β-sheet formation. Recent investigations using the above sequence have shown that the Tau peptide undergoes conformational changes in the presence of heparin, leading to the initiation of aggregation. , However, the conventional methods for detecting aggregation (for, e.g., CD, Thio T assay) require higher concentrations of peptide. On addition of heparin to the Rh-PP-InP construct, an inhibition of energy transfer occurs, which is probed using emission spectroscopy.…”

Secondary-structure prediction revisited: Theoretical β-sheet propensity and coil propensity represent structures of amyloids and aid in elucidating phenomena involved in interspecies transmission of prions

“…Because these findings suggested that Pc values may significantly affect cross-seeding efficiency, we reviewed a series of cross-seeding experiments of an amyloidogenic peptide derived from tau protein (R3) and its variants, e.g. C-terminally-truncated variants and substitution variants with the serine at residue 316 replaced by either proline (R3-S316P) or alanine (R3-S316A) [ 16 ]. Experiments showed that fibril formation by R3-316P alone was very slow but could be enhanced by adding fibrils of wild-type R3 or other variants as a seed.…”

“…C . Pβ graphs of tau-derived amyloidogenic peptide, R3, and its substitution variants, R3-S316A and R3-S316P, whose serine residue at the codon 316 was replaced with alanine or proline, respectively [ 16 ]. The two variants had Pβ peaks at different positions (red and blue arrows).…”

Deciphering the Structure and Formation of Amyloids in Neurodegenerative Diseases With Chemical Biology Tools

“…Altogether, these data demonstrate the major effect of P32 conformation on β2m aggregation ( Torbeev and Hilvert, 2013 ). To study the role in the aggregation process of a kink within the R3 repeat of the tau protein, at residue S316, a peptide was used containing a S316P mutation ( Jiji et al, 2016 ). In the peptide wherein (2S,4S)-fluoroproline at position 316 was introduced, the cis conformation is favored compared to regular prolines and the modified peptide aggregates twice as fast.…”