β-barrel Oligomers as Common Intermediates of Peptides Self-Assembling into Cross-β Aggregates

Oligomers populated during the early amyloid aggregation process are more toxic than mature fibrils, but pinpointing the exact toxic species among highly dynamic and heterogeneous aggregation intermediates remains a major challenge. β-barrel oligomers, structurally-determined recently for a slow-agg...

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Bibliographic Details
Published in:Scientific reports 2018-07, Vol.8 (1), p.10353-13, Article 10353
Main Authors: Sun, Yunxiang, Ge, Xinwei, Xing, Yanting, Wang, Bo, Ding, Feng
Format: Article
Language:English
Subjects:
Amyloid
Amyloidogenesis
Crystallin
Cytotoxicity
Fibrillogenesis
Fibrils
Hypotheses
Intermediates
Oligomerization
Peptides
Therapeutic applications
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Summary:Oligomers populated during the early amyloid aggregation process are more toxic than mature fibrils, but pinpointing the exact toxic species among highly dynamic and heterogeneous aggregation intermediates remains a major challenge. β-barrel oligomers, structurally-determined recently for a slow-aggregating peptide derived from αB crystallin, are attractive candidates for exerting amyloid toxicity due to their well-defined structures as therapeutic targets and compatibility to the "amyloid-pore" hypothesis of toxicity. To assess whether β-barrel oligomers are common intermediates to amyloid peptides - a necessary step toward associating β-barrel oligomers with general amyloid cytotoxicity, we computationally studied the oligomerization and fibrillization dynamics of seven well-studied fragments of amyloidogenic proteins with different experimentally-determined aggregation morphologies and cytotoxicity. In our molecular dynamics simulations, β-barrel oligomers were only observed in five peptides self-assembling into the characteristic cross-β aggregates, but not the other two that formed polymorphic β-rich aggregates as reported experimentally. Interestingly, the latter two peptides were previously found nontoxic. Hence, the observed correlation between β-barrel oligomers formation and cytotoxicity supports the hypothesis of β-barrel oligomers as the common toxic intermediates of amyloid aggregation.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-018-28649-7