A Key Role for Lysine Residues in Amyloid 尾-Protein Folding, Assembly, and Toxicity
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- 作者：Sharmistha Sinha ; Dahabada H. J. Lopes ; Gal Bitan
- 刊名：ACS Chemical Neuroscience
- 出版年：2012
- 出版时间：June 20, 2012
- 年：2012
- 卷：3
- 期：6
- 页码：473-481
- 全文大小：517K
- 年卷期：v.3,no.6(June 20, 2012)
- ISSN：1948-7193
文摘
A combination of hydrophobic and electrostatic interactions is important in initiating the aberrant self-assembly process that leads to formation of toxic oligomers and aggregates by multiple disease-related proteins, including amyloid 尾-protein (A尾), whose self-assembly is believed to initiate brain pathogenesis in Alzheimer鈥檚 disease. Lys residues play key roles in this process and participate in both types of interaction. They also are the target of our recently reported molecular tweezer inhibitors. To obtain further insight into the role of the two Lys residues in A尾 assembly and toxicity, here we substituted each by Ala in both A尾40 and A尾42 and studied the impact of the substitution on A尾 oligomerization, aggregation, and toxicity. Our data show that each substitution has a major impact on A尾 assembly and toxicity, with significant differences depending on peptide length (40 versus 42 amino acids) and the position of the substitution. In particular, Lys16鈫扐la substitution dramatically reduces A尾 toxicity. The data support the use of compounds targeting Lys residues specifically as inhibitors of A尾 toxicity and suggest that exploring the role of Lys residues in other disease-related amyloidogenic proteins may help understanding the mechanisms of aggregation and toxicity of these proteins.