期刊
ACS CHEMICAL NEUROSCIENCE
卷 6, 期 8, 页码 1290-1295出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.5b00074
关键词
Protein aggregation; neurodegeneration; folding landscape; small oligomers; membrane affinity; Alzheimer therapeutics
资金
- Department of Biotechnology, Government of India [BT/53/NE/TBP/2010]
- German Research Foundation [DFG SFB TRR 102, A6]
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's amyloid-beta (A beta(40)) peptide. We find that even conservative single mutations altering this interaction can abolish A beta(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 beta(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.
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