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

• Published in: Angewandte Chemie International Edition 2016-09, Vol.55 (38), p.11562-11566
• Main Authors: Jiji, A. C., Shine, A., Vijayan, Vinesh
• Format: Article
• Language: English
• Subjects: Agglomeration; Alzheimer's disease; cis-trans isomerism; Conformation; fibrillation; Fibrils; Intervention; Neurodegenerative diseases; Neurological diseases; NMR; NMR spectroscopy; Nuclear magnetic resonance; Peptides; Proteins; Tau protein
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201606544

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. Let's get together: Structural studies on tau‐derived peptides show that the turn conformation upstream of the hexapeptide is critical for the propagation of fibrils under a zipper‐like mechanism of association. Aggregation of a mutant tau peptide proceeds through preferential selection of a cis peptide bond preceding the amino acid at position 316.