A Common β-Sheet Architecture Underlies in Vitro and in Vivo β2-Microglobulin Amyloid Fibrils*S⃞
A Common β-Sheet Architecture Underlies in Vitro and in Vivo β2-Microglobulin Amyloid Fibrils*S⃞
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体外和体内 β2-微球蛋白淀粉样原纤维*S⃞ 中常见的 β-片层结构
DOI：
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发表时间：
2008
影响因子：
4.8
通讯作者：
S. Radford
中科院分区：
文献类型：
--
作者：
T. Jahn;G. Tennent;S. Radford
正常的可溶性蛋白质错误折叠和聚集成淀粉样蛋白纤维，其沉积和堆积是各种临床上重要疾病的基础。具有淀粉样属性的纤维状聚集体也可以在体外从纯蛋白质和多肽中产生，包括那些未知与淀粉样变性相关的蛋白质和多肽。虽然对体外形成的淀粉样纤维的生物物理研究已经为淀粉样蛋白生成的分子机制和形成的纤维的结构特性提供了重要的见解，但淀粉样蛋白通常暴露在温和或更极端的变性条件下，以在体外诱导快速纤维形成。因此，所得到的组装体的结构是否代表它们在体内的天然对应物，仍然是一个根本的悬而未决的问题。在这里，我们使用傅立叶变换红外光谱显示，由自然折叠或去折叠的β2-微球蛋白(与透析相关的淀粉样变性相关的蛋白质)在体外形成的淀粉样纤维采用相同的β-Sheet结构。无论体外纤维的形成是自发的还是种子反应的，都可以观察到相同的β-链特征。将这些光谱与从透析相关的淀粉样变性患者中提取的淀粉样纤维的光谱进行比较，发现了相同的酰胺I吸收峰，提示存在一种特征和保守的淀粉样折叠。我们的结果支持生物物理研究与研究β2-微球蛋白纤维形成的分子机制的相关性，了解这些知识可能有助于理解该蛋白的病理生物学。
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 β2-microglobulin (the protein associated with dialysis-related amyloidosis) adopt an identical β-sheet architecture. The same β-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 β2-microglobulin fibrillogenesis, knowledge about which may inform understanding of the pathobiology of this protein.
影响因子：
15
作者：
van der Wel, Patrick C. A.;Lewandowski, Jozef R.;Griffin, Robert G.
通讯作者：
Griffin, Robert G.
影响因子：
2.9
作者：
Ha, Chanki;Ryu, Jungki;Park, Chan Beum
通讯作者：
Park, Chan Beum
影响因子：
2.9
作者：
SANTORO, MM;BOLEN, DW
通讯作者：
BOLEN, DW