Evidence for a central role of PrP helix 2 in the nucleation of amyloid fibrils

What is it about?

Amyloid fibrils are associated with a wide variety of devastating neurodegenerative diseases such as Alzheimer's, Parkinson's and prion diseases. Oligomeric nuclei play as a particularly important role in the formation of amyloid fibrils, as the assembly of amyloidogenic proteins into these nuclei is the rate-limiting step of the overall reaction. Although recent studies have provided in-depth characterizations of amyloid fibrils in terms of the high-resolution structure and kinetics, the fundamental nature of these nuclei (e.g., structural features, aggregation states) remains poorly understood, largely due to the transient nature of the nucleus. To overcome this transient nature of the oligomeric nuclei, we developed a novel strategy based on the concepts of Φ-value analysis, a systematic mutagenesis-based method used widely to analyze the transition state structures during protein folding. We found that the structure of the transient nuclei could be inferred in a similar manner from the Φ-value analysis, as kinetically, the nuclei are an analogue of the transition state. Our results indicate that the oligomeric nuclei of human prion proteins form amyloid-like β-sheet structures specifically in the H2 region (residue 168-196), whereas the other regions exhibit relatively disordered structures in this state.

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