The Structures of the E22螖 Mutant-Type Amyloid-尾 Alloforms and the Impact of E22螖 Mutation on the Structures of the Wild-Type Amyloid-尾 Alloforms
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- 作者：Orkid Coskuner ; Olivia Wise-Scira ; George Perry ; Taizo Kitahara
- 刊名：ACS Chemical Neuroscience
- 出版年：2013
- 出版时间：February 20, 2013
- 年：2013
- 卷：4
- 期：2
- 页码：310-320
- 全文大小：676K
- 年卷期：v.4,no.2(February 20, 2013)
- ISSN：1948-7193
文摘
Structural differences between the intrinsically disordered fibrillogenic wild-type A尾40 and A尾42 peptides are linked to Alzheimer鈥檚 disease. Recently, the E22螖 genetic missense mutation was detected in patients exhibiting Alzheimer鈥檚-disease type dementia. However, detailed knowledge about the E22螖 mutant-type A尾40 and A尾42 alloform structures as well as the differences from the wild-type A尾40 and A尾42 alloform structures is currently lacking. In this study, we present the structures of the E22螖 mutant-type A尾40 and A尾42 alloforms as well as the impact of E22螖 mutation on the wild-type A尾40 and A尾42 alloform structures. For this purpose, we performed extensive microsecond-time scale parallel tempering molecular dynamics simulations coupled with thermodynamic calculations. For studying the residual secondary structure component transition stabilities, we developed and applied a new theoretical strategy in our studies. We find that the E22螖 mutant-type A尾40 might have a higher tendency toward aggregation due to more abundant 尾-sheet formation in the C-terminal region in comparison to the E22螖 mutant-type A尾42 peptide. More abundant 伪-helix is formed in the mid-domain regions of the E22螖 mutant-type A尾 alloforms rather than in their wild-type forms. The turn structure at Ala21-Ala30 of the wild-type A尾, which has been linked to the aggregation process, is less abundant upon E22螖 mutation of both A尾 alloforms. Intramolecular interactions between the N-terminal and central hydrophobic core (CHC), N- and C-terminal, and CHC and C-terminal regions are less abundant or disappear in the E22螖 mutant-type A尾 alloform structures. The thermodynamic trends indicate that the wild-type A尾42 tends to aggregate more than the wild-type A尾40 peptide, which is in agreement with experiments. However, this trend is vice versa for the E22螖 mutant-type alloforms. The structural properties of the E22螖 mutant-type A尾40 and A尾42 peptides reported herein may prove useful for the development of new drugs to block the formation of toxic E22螖 mutant-type oligomers by either stabilizing helical or destabilizing 尾-sheet structure in the C-terminal region of these two mutant alloforms.