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冷冻电镜成像阿尔茨海默病淀粉样β 42 寡聚体在功能和结构相关支架上的显示。

Cryo-electron Microscopy Imaging of Alzheimer's Amyloid-beta 42 Oligomer Displayed on a Functionally and Structurally Relevant Scaffold.

机构信息

Department of Biology and Chemistry, Paul Scherrer Institute, 5232, Villigen, Switzerland.

Department of Biochemistry, University of Washington, Seattle, WA, 98195, USA.

出版信息

Angew Chem Int Ed Engl. 2021 Aug 16;60(34):18680-18687. doi: 10.1002/anie.202104497. Epub 2021 Jul 12.

DOI:10.1002/anie.202104497
PMID:34042235
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8457241/
Abstract

Amyloid-β peptide (Aβ) oligomers are pathogenic species of amyloid aggregates in Alzheimer's disease. Like certain protein toxins, Aβ oligomers permeabilize cellular membranes, presumably through a pore formation mechanism. Owing to their structural and stoichiometric heterogeneity, the structure of these pores remains to be characterized. We studied a functional Aβ42-pore equivalent, created by fusing Aβ42 to the oligomerizing, soluble domain of the α-hemolysin (αHL) toxin. Our data reveal Aβ42-αHL oligomers to share major structural, functional, and biological properties with wild-type Aβ42-pores. Single-particle cryo-EM analysis of Aβ42-αHL oligomers (with an overall 3.3 Å resolution) reveals the Aβ42-pore region to be intrinsically flexible. The Aβ42-αHL oligomers will allow many of the features of the wild-type amyloid oligomers to be studied that cannot be otherwise, and may be a highly specific antigen for the development of immuno-base diagnostics and therapies.

摘要

淀粉样蛋白-β肽 (Aβ) 寡聚物是阿尔茨海默病中淀粉样蛋白聚集的致病物种。与某些蛋白毒素类似，Aβ 寡聚物使细胞膜穿孔，推测是通过形成孔的机制。由于其结构和化学计量的异质性，这些孔的结构仍有待表征。我们研究了一种功能性的 Aβ42 孔等效物，它是通过将 Aβ42 融合到 α-溶血素 (αHL) 毒素的寡聚可溶性结构域而创建的。我们的数据表明，Aβ42-αHL 寡聚物与野生型 Aβ42 孔具有主要的结构、功能和生物学特性。对 Aβ42-αHL 寡聚物（整体分辨率为 3.3Å）的单颗粒 cryo-EM 分析表明，Aβ42 孔区域具有内在的灵活性。Aβ42-αHL 寡聚物将允许研究许多无法通过其他方式研究的野生型淀粉样寡聚物的特征，并且可能是开发免疫基础诊断和治疗方法的高度特异性抗原。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/18f0/8457241/eb7a02c19507/ANIE-60-18680-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/18f0/8457241/abdb545b1131/ANIE-60-18680-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/18f0/8457241/c008702e6b6b/ANIE-60-18680-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/18f0/8457241/f1f1435c1145/ANIE-60-18680-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/18f0/8457241/2a5a3db81f63/ANIE-60-18680-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/18f0/8457241/bc8acd625826/ANIE-60-18680-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/18f0/8457241/eb7a02c19507/ANIE-60-18680-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/18f0/8457241/abdb545b1131/ANIE-60-18680-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/18f0/8457241/c008702e6b6b/ANIE-60-18680-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/18f0/8457241/f1f1435c1145/ANIE-60-18680-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/18f0/8457241/2a5a3db81f63/ANIE-60-18680-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/18f0/8457241/bc8acd625826/ANIE-60-18680-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/18f0/8457241/eb7a02c19507/ANIE-60-18680-g004.jpg

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2
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3
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5
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