Toxic fibrillar oligomers of amyloid-β have cross-β structure
Toxic fibrillar oligomers of amyloid-β have cross-β structure
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DOI：
10.1073/pnas.1203193109
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发表时间：
2012-05-15
影响因子：
11.1
通讯作者：
Eisenberg, David
中科院分区：
文献类型：
--
作者：
Stroud, James C.;Liu, Cong;Eisenberg, David
虽然淀粉样蛋白纤维在神经退行性疾病中被发现，但有证据表明淀粉样蛋白形成蛋白的可溶性寡聚体是细胞毒性物质。在这里，我们确定了我们制备的有毒淀粉样蛋白-β（1-42）（A β 42）纤维状寡聚体（TABFO）与成熟淀粉样蛋白纤维共享交叉β结构，其中相邻的β-折叠通过蛋白质侧链的相互渗透而粘附。我们通过X射线粉末衍射、透射电镜、圆二色谱、红外光谱、色谱、构象抗体和细胞毒性等方法研究了TABFO的结构和性质。在TABFO中，Abeta 42分子堆叠成由成对的螺旋β-片层组成的短原丝，这些螺旋β-片层相互缠绕形成超螺旋。包裹导致沿超螺旋轴沿着形成一个孔，这为了解Abeta如何形成致病性淀粉样蛋白孔提供了线索。我们的模型与Abeta 42纤维状低聚物的许多性质一致，包括异质性大小、播种纤维状低聚物新群体的能力和纤维状形态。
Although amyloid fibers are found in neurodegenerative diseases, evidence points to soluble oligomers of amyloid-forming proteins as the cytotoxic species. Here, we establish that our preparation of toxic amyloid-beta(1-42) (Abeta42) fibrillar oligomers (TABFOs) shares with mature amyloid fibrils the cross-beta structure, in which adjacent beta-sheets adhere by interpenetration of protein side chains. We study the structure and properties of TABFOs by powder X-ray diffraction, EM, circular dichroism, FTIR spectroscopy, chromatography, conformational antibodies, and celluar toxicity. In TABFOs, Abeta42 molecules stack into short protofilaments consisting of pairs of helical beta-sheets that wrap around each other to form a superhelix. Wrapping results in a hole along the superhelix axis, providing insight into how Abeta may form pathogenic amyloid pores. Our model is consistent with numerous properties of Abeta42 fibrillar oligomers, including heterogenous size, ability to seed new populations of fibrillar oligomers, and fiber-like morphology.