Abstract

The aggregation of peptides and proteins into amyloid fibrils is a molecular self-assembly phenomenon associated with both biological function and malfunction, notably in the context of neurodegenerative diseases. Oligomeric species formed early in the aggregation process are generally associated with cytotoxicity. Extrinsic molecules such as peptides have been found to influence amyloid formation kinetics and regulate this cellular process. Here, we use single-molecule FRET and bulk assays combined with global kinetic analysis to study quantitatively the effect of an 8-residue peptide (LQVNIGNR) on fibril formation by the yeast prion protein Ure2. This peptide, which is derived from a segment of the Ure2 prion domain, forms vesicular assemblies that accelerate fibril formation of Ure2 by promoting conformational conversion of oligomeric intermediates into fibrillar species in a catalytic manner. This reduces oligomer longevity and consequently ameliorates cytotoxicity. The LQVNIGNR peptide was found to accelerate fibril formation of unrelated proteins including Tau and α-Synuclein, suggesting a general ability to catalyse fibrillation. This study provides a general strategy for investigating the microscopic mechanism of extrinsic factors on amyloid aggregation. This approach can readily be applied to other amyloid systems and demonstrates that acceleration of oligomer conversion is a promising strategy to reduce amyloid toxicity.

Highlights

  • IntroductionThe aggregation of polypeptide chains into β-sheet rich amyloid fibrils is associated with a series of neurodegenerative disorders including Alzheimer’s disease and Parkinson’s disease, but is related to a range of cellular functions in living organisms.[1,2,3] Microscopic reactions underlying the assembly process of amyloidogenic proteins are

  • The aggregation of polypeptide chains into β-sheet rich amyloid fibrils is associated with a series of neurodegenerative disorders including Alzheimer’s disease and Parkinson’s disease, but is related to a range of cellular functions in living organisms.[1,2,3] Microscopic reactions underlying the assembly process of amyloidogenic proteins areDue to the generic toxicity of amyloid oligomers,[13] significant efforts have been devoted to finding inhibitors of the aggregation process

  • A β-sheet-forming region involving residues 8–12 has been suggested to be crucial for fibril formation of Ure2.26 we designed several peptides derived from these regions with different lengths and hydrophobicities (Table S1†) as potential candidates to modulate the fibril formation of Ure[2]

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Summary

Introduction

The aggregation of polypeptide chains into β-sheet rich amyloid fibrils is associated with a series of neurodegenerative disorders including Alzheimer’s disease and Parkinson’s disease, but is related to a range of cellular functions in living organisms.[1,2,3] Microscopic reactions underlying the assembly process of amyloidogenic proteins are. Due to the generic toxicity of amyloid oligomers,[13] significant efforts have been devoted to finding inhibitors of the aggregation process Extrinsic factors such as small molecules, peptides and antibodies have been shown to inhibit the aggregation of many amyloidogenic proteins, including the Aβ peptide, α-Synuclein and islet amyloid polypeptide (IAPP) associated with Alzheimer’s disease, Parkinson’s disease, and type II diabetes, respectively.[14] Of these factors, short peptides Paper. We show how the concerted use of single molecule spectroscopy and kinetic analysis can allow the modulation of individual molecular level processes in the formation and depletion of oligomers to be defined in quantitative detail

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