An Azobenzene Photoswitch Sheds Light on Turn Nucleation in Amyloid-尾 Self-Assembly
详细信息 查看全文
- 作者：Todd M. Doran ; Elizabeth A. Anderson ; Sarah E. Latchney ; Lisa A. Opanashuk ; Bradley L. Nilsson
- 刊名：ACS Chemical Neuroscience
- 出版年：2012
- 出版时间：March 21, 2012
- 年：2012
- 卷：3
- 期：3
- 页码：211-220
- 全文大小：490K
- 年卷期：v.3,no.3(March 21, 2012)
- ISSN：1948-7193
文摘
Amyloid-尾 (A尾) self-assembly into cross-尾 amyloid fibrils is implicated in a causative role in Alzheimer鈥檚 disease pathology. Uncertainties persist regarding the mechanisms of amyloid self-assembly and the role of metastable prefibrillar aggregates. A尾 fibrils feature a sheet-turn-sheet motif in the constituent 尾-strands; as such, turn nucleation has been proposed as a rate-limiting step in the self-assembly pathway. Herein, we report the use of an azobenzene 尾-hairpin mimetic to study the role turn nucleation plays on A尾 self-assembly. [3-(3-Aminomethyl)phenylazo]phenylacetic acid (AMPP) was incorporated into the putative turn region of A尾42 to elicit temporal control over A尾42 turn nucleation; it was hypothesized that self-assembly would be favored in the cis-AMPP conformation if 尾-hairpin formation occurs during A尾 self-assembly and that the trans-AMPP conformer would display attenuated fibrillization propensity. It was unexpectedly observed that the trans-AMPP A尾42 conformer forms fibrillar constructs that are similar in almost all characteristics, including cytotoxicity, to wild-type A尾42. Conversely, the cis-AMPP A尾42 congeners formed nonfibrillar, amorphous aggregates that exhibited no cytotoxicity. Additionally, cis-trans photoisomerization resulted in rapid formation of native-like amyloid fibrils and trans鈥揷is conversion in the fibril state reduced the population of native-like fibrils. Thus, temporal photocontrol over A尾 turn conformation provides significant insight into A尾 self-assembly. Specifically, A尾 mutants that adopt stable 尾-turns form aggregate structures that are unable to enter folding pathways leading to cross-尾 fibrils and cytotoxic prefibrillar intermediates.