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

• Published in: Angewandte Chemie Vol. 128; no. 38; pp. 11734 - 11738
• Main Authors: Jiji, A. C., Shine, A., Vijayan, Vinesh
• Format: Journal Article
• Language: English
• Published: Weinheim Blackwell Publishing Ltd 12-09-2016; Wiley Subscription Services, Inc
• Subjects: Agglomeration; Alzheimer's disease; Alzheimer-Krankheit; Chemistry; cis-trans-Isomerie; Conformation; Fibrillenbildung; Fibrils; Intervention; Neurodegenerative diseases; Neurological diseases; NMR; NMR-Spektroskopie; Nuclear magnetic resonance; Peptide; Peptides; Proteins; Residues; Tau protein; Time dependence; Upstream
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.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.
So kommt man zusammen: Strukturstudien an von Tau‐Peptiden abgeleiteten Verbindungen ergaben, dass die Turn‐Konformation oberhalb des Hexapeptids entscheidend für die Ausbreitung von Fibrillen durch reißverschlussartige Assoziation ist. Die Aggregation einer Tau‐Peptid‐Mutante verläuft über die bevorzugte Wahl einer cis‐Peptidbindung vor der Aminosäure an Position 316.