An Early Folding Contact between Phe19 and Leu34 is Critical for Amyloid-尾 Oligomer Toxicity

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• 作者：Anand K. Das ; Anoop Rawat ; Debanjan Bhowmik ; Rucha Pandit ; Daniel Huster ; Sudipta Maiti
• 刊名：ACS Chemical Neuroscience
• 出版年：2015
• 出版时间：August 19, 2015
• 年：2015
• 卷：6
• 期：8
• 页码：1290-1295
• 全文大小：290K
• ISSN：1948-7193

文摘

Small hydrophobic oligomers of aggregation-prone proteins are thought to be generically toxic. Here we examine this view by perturbing an early folding contact between Phe19 and Leu34 formed during the aggregation of Alzheimer鈥檚 amyloid-尾 (A尾₄₀) peptide. We find that even conservative single mutations altering this interaction can abolish A尾₄₀ toxicity. Significantly, the mutants are not distinguishable either by the oligomers size or by the end-state fibrillar structure from the wild type A尾₄₀. We trace the change in their toxicity to a drastic lowering of membrane affinity. Therefore, nonlocal folding contacts play a key role in steering the oligomeric intermediates through specific conformations with very different properties and toxicity levels. Our results suggest that engineering the folding energy landscape may provide an alternative route to Alzheimer therapeutics.