A common β-sheet architecture underlies in vitro and in vivo β2-microglobulin amyloid fibrils
A common β-sheet architecture underlies in vitro and in vivo β2-microglobulin amyloid fibrils
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DOI：
10.1074/jbc.m710351200
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发表时间：
2008-06-20
影响因子：
4.8
通讯作者：
Radford, Sheena E.
中科院分区：
文献类型：
--
作者：
Jahn, Thomas R.;Tennent, Glenys A.;Radford, Sheena E.
通常可溶性蛋白质错误折叠和聚集成淀粉样原纤维以及它们的沉积和积累是多种具有临床意义的疾病的基础。具有淀粉样蛋白样特性的纤维状聚集体也可以在体外由纯蛋白质和肽产生，包括那些未知与淀粉样变性相关的蛋白质和肽。尽管对体外形成的淀粉样蛋白样原纤维的生物物理学研究为淀粉样蛋白生成的分子机制和形成的原纤维的结构特性提供了重要的见解，但淀粉样蛋白生成蛋白通常暴露于温和或更极端的变性条件下以诱导体外快速原纤维形成。因此，所得组件的结构是否代表其天然的体内对应物，仍然是一个尚未解决的基本问题。在这里，我们使用傅里叶变换红外光谱表明，由自然折叠或展开的β（2）-微球蛋白（与透析相关淀粉样变性相关的蛋白质）在体外形成的淀粉样蛋白样原纤维采用相同的β-折叠结构。无论体外原纤维形成是自发发生还是来自种子反应，都观察到相同的β链特征。将这些光谱与从透析相关淀粉样变性患者中提取的淀粉样原纤维的光谱进行比较，发现相同的酰胺 I' 吸光度最大值，表明存在特征性且保守的淀粉样蛋白折叠。我们的结果证实了生物物理学研究对于研究 β(2)-微球蛋白原纤维形成的分子机制的相关性，有关这些知识可能有助于了解该蛋白质的病理学。
Misfolding and aggregation of normally soluble proteins into amyloid fibrils and their deposition and accumulation underlies a variety of clinically significant diseases. Fibrillar aggregates with amyloid-like properties can also be generated in vitro from pure proteins and peptides, including those not known to be associated with amyloidosis. Whereas biophysical studies of amyloid-like fibrils formed in vitro have provided important insights into the molecular mechanisms of amyloid generation and the structural properties of the fibrils formed, amyloidogenic proteins are typically exposed to mild or more extreme denaturing conditions to induce rapid fibril formation in vitro. Whether the structure of the resulting assemblies is representative of their natural in vivo counterparts, thus, remains a fundamental unresolved issue. Here we show using Fourier transform infrared spectroscopy that amyloid-like fibrils formed in vitro from natively folded or unfolded beta(2)-microglobulin (the protein associated with dialysis-related amyloidosis) adopt an identical beta-sheet architecture. The same beta-strand signature is observed whether fibril formation in vitro occurs spontaneously or from seeded reactions. Comparison of these spectra with those of amyloid fibrils extracted from patients with dialysis-related amyloidosis revealed an identical amide I' absorbance maximum, suggestive of a characteristic and conserved amyloid fold. Our results endorse the relevance of biophysical studies for the investigation of the molecular mechanisms of beta(2)-microglobulin fibrillogenesis, knowledge about which may inform understanding of the pathobiology of this protein.