Structural characterization of the partially folded intermediates of an immunoglobulin light chain leading to amyloid fibrillation and amorphous aggregation
Structural characterization of the partially folded intermediates of an immunoglobulin light chain leading to amyloid fibrillation and amorphous aggregation
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DOI：
10.1021/bi061716v
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发表时间：
2007-03-20
期刊：
影响因子：
2.9
通讯作者：
Fink, Anthony L.
中科院分区：
文献类型：
--
作者：
Qin, Zhijie;Hu, Dongmei;Fink, Anthony L.
免疫球蛋白轻链沉积疾病涉及轻链可变结构域的各种类型的细胞外沉积，包括淀粉样原纤维和无定形沉积物。轻链的热力学稳定性降低被认为是导致原纤化的主要因素。然而，轻链沉积疾病之间沉积物性质的差异提出了导致纤维状或无定形聚集的机制是否不同的问题。在这项研究中，我们产生了两个部分折叠的中间体的轻链可变结构域SMA在盐酸胍（GuHCl）的存在下，其特征在于它们的构象。更展开的中间体形成的原纤维最迅速，而更多的本地样的中间体主要导致无定形存款。结果还表明，单体，而不是二聚体状态，是关键的原纤化。数据还表明，原纤维伸长涉及添加部分未折叠的中间体，而不是天然状态。我们假设，一个更高度未折叠的中间体更适合于进行必要的拓扑重排，形成淀粉样蛋白原纤维比一个更结构化的，这也与增加不稳定。在轻链聚集的情况下，似乎更天然的中间构象更容易形成无定形沉积物。
Immunoglobulin light chain deposition diseases involve various types of extracellular deposition of light chain variable domains, including amyloid fibrils and amorphous deposits. The decreased thermodynamic stability of the light chain is believed to be the major factor leading to fibrillation. However, the differences in the nature of the deposits among the light chain deposition diseases raise the question of whether the mechanisms leading to fibrillar or amorphous aggregation is different. In this study, we generated two partially folded intermediates of the light chain variable domain SMA in the presence of guanidine hydrochloride (GuHCl) and characterized their conformations. The more unfolded intermediate formed fibrils most rapidly, while the more native-like intermediate predominantly led to amorphous deposits. The results also show that the monomeric, rather than the dimeric state, was critical for fibrillation. The data also indicate that fibril elongation involves addition of a partially unfolded intermediate, rather than the native state. We postulate that a more highly unfolded intermediate is more suited to undergo the topological rearrangements necessary to form amyloid fibrils than a more structured one and that this also correlates with increased destabilization. In the case of light chain aggregation, it appears that more native-like intermediate conformations are more prone to form amorphous deposits.