Asymmetric amyloid fibril elongation: A new perspective on a symmetric world
Asymmetric amyloid fibril elongation: A new perspective on a symmetric world
复制标题
DOI：
10.1002/prot.22861
复制
发表时间：
2011-01-01
影响因子：
2.9
通讯作者：
Belfort, Georges
中科院分区：
文献类型：
--
作者：
Heldt, Caryn L.;Zhang, Shuqi;Belfort, Georges
淀粉样蛋白是通过错误折叠的蛋白质聚集而形成的不溶性纤维状蛋白质。它们积累在患有退行性疾病的个体的组织中，如帕金森氏症和阿尔茨海默氏症。本研究的目的是确定来自初始模型原纤维种子的原纤维生长是单向的还是双向的。关于淀粉样蛋白形成的流行理论是对称的原纤维从两端均等地伸长。这项研究提供了相反的证据;该过程主要是单向发生的，表明淀粉样纤维可能是不对称的，并且主要在一个方向上传播。将Alexa Fluor 568标记的胰岛素原纤维接种到天然胰岛素溶液中，并使其在65 ℃下伸长，同时监测原纤维生长的动力学。用硫黄素-T标记所得的伸长的原纤维，并且原纤维的荧光图像显示大部分伸长的原纤维仅沿种子的沿着延伸，剩余的标记的原纤维具有双向伸长或不伸长。使用晶体学模型，我们提供了一个结构上的解释胰岛素纤维的不对称生长。因此，与目前认为原纤维从原纤维两端对称生长的观点不同，这是第一个证据表明在溶液中形成的胰岛素淀粉样蛋白原纤维是不对称的，似乎只从一端生长。Proteins 2011; 79：92-98. (C)2010 Wiley-Liss，Inc.
Amyloids are insoluble, fibrous proteins formed through the aggregation of misfolded proteins. They accumulate in the tissue of individuals with degenerative diseases, such as Parkinson's and Alzheimer's. The purpose of this study was to determine whether fibril growth from an initial model fibril seed is unidirectional or bidirectional. The prevailing theory on amyloid formation is that a symmetric fibril elongates equally from both ends. This study provides evidence to the contrary; the process occurs predominately unidirectionally, demonstrating that amyloid fibrils may be asymmetric and propagate mostly in one direction. Alexa Fluor 568 labeled insulin fibrils were seeded into a native insulin solution and allowed to elongate at 65 degrees C while the kinetics of fibril growth was monitored. The resulting elongated fibrils were labeled with thioflavin-T, and the fluorescent images of the fibrils show that a majority of the elongated fibrils propagated along only one end of the seed, with the remaining labeled fibrils having bidirectional elongation or no elongation. Using a crystallographic model, we offer a structural explanation for asymmetric growth of the insulin fibrils. Thus, instead of the current view that fibrils grow symmetrically from both ends of the fibril, this is the first evidence that insulin amyloid fibrils formed in solution are asymmetric and appear to grow from only one end. Proteins 2011; 79: 92-98. (C) 2010 Wiley-Liss, Inc.