Visualizing and trapping transient oligomers in amyloid assembly pathways.
Visualizing and trapping transient oligomers in amyloid assembly pathways.
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DOI：
10.1016/j.bpc.2020.106505
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发表时间：
2021-01
影响因子：
3.8
通讯作者：
Radford SE
中科院分区：
文献类型：
--
作者：
Cawood EE;Karamanos TK;Wilson AJ;Radford SE
在淀粉样蛋白纤维组装过程中形成的低聚物被认为是淀粉样蛋白疾病的关键贡献者。然而，由于这些中间体的短暂性和异质性，了解它们的形成方式、结构和毒性机制面临着重大挑战。在这里，我们讨论了解决这些挑战的两种不同策略：使用(1)能够在复杂混合物中检测低密度物种的方法，如核磁共振、单粒子方法（包括荧光和力谱）和质谱；(2)化学和生物工具，使淀粉样蛋白的能量景观偏向于特定的低聚物状态。虽然前一种方法非常适合跟踪淀粉样蛋白组装的动力学和获得低分辨率的结构信息，但后者能够生产用于高分辨率结构研究和推断结构-毒性关系的低聚物样品。总之，这些不同的方法应该能够更清楚地了解低聚中间体在淀粉样蛋白形成和疾病中的性质和作用。方法研究瞬时淀粉样蛋白低聚物的结构、毒性和动力学。核磁共振和单粒子方法可以表征低密度的低聚物。化学工具/抗体稳定低聚物用于结构和毒性研究需要多种方法的结合来充分表征淀粉样蛋白组装途径。
Oligomers which form during amyloid fibril assembly are considered to be key contributors towards amyloid disease. However, understanding how such intermediates form, their structure, and mechanisms of toxicity presents significant challenges due to their transient and heterogeneous nature. Here, we discuss two different strategies for addressing these challenges: use of (1) methods capable of detecting lowly-populated species within complex mixtures, such as NMR, single particle methods (including fluorescence and force spectroscopy), and mass spectrometry; and (2) chemical and biological tools to bias the amyloid energy landscape towards specific oligomeric states. While the former methods are well suited to following the kinetics of amyloid assembly and obtaining low-resolution structural information, the latter are capable of producing oligomer samples for high-resolution structural studies and inferring structure-toxicity relationships. Together, these different approaches should enable a clearer picture to be gained of the nature and role of oligomeric intermediates in amyloid formation and disease. Methods to study structure, toxicity, and kinetics of transient amyloid oligomers. NMR and single particle methods can characterize lowly-populated oligomers. Chemical tools/antibodies stabilize oligomers for structural and toxicity studies A combination of methods is needed to fully characterize amyloid assembly pathways.
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影响因子：
6.1
作者：
Anthis NJ;Clore GM
通讯作者：
Clore GM
影响因子：
7.7
作者：
Brumshtein B;Esswein SR;Salwinski L;Phillips ML;Ly AT;Cascio D;Sawaya MR;Eisenberg DS
通讯作者：
Eisenberg DS
DOI：
10.1039/a707586c
发表时间：
1998-05-01
期刊：
JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 2
影响因子：
--
作者：
Admasu, A;Gudmundsdottir, AD;Crocker, PJ
通讯作者：
Crocker, PJ
影响因子：
16.8
作者：
通讯作者：
--
DOI：
10.1073/pnas.1121005109
发表时间：
2012-06-12
影响因子：
11.1
作者：
Bulawa, Christine E.;Connelly, Stephen;Labaudiniere, Richard
通讯作者：
Labaudiniere, Richard