Structural Characterization of the Partially Folded Intermediates of an Immunoglobulin Light Chain Leading to Amyloid Fibrillation and Amorphous Aggregation

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• 作者：Zhijie Qin ; Dongmei Hu ; Min Zhu ; Anthony L. Fink
• 刊名：Biochemistry
• 出版年：2007
• 出版时间：March 20, 2007
• 年：2007
• 卷：46
• 期：11
• 页码：3521 - 3531
• 全文大小：324K
• 年卷期：v.46,no.11(March 20, 2007)
• ISSN：1520-4995

文摘

Immunoglobulin light chain deposition diseases involve various types of extracellular depositionof light chain variable domains, including amyloid fibrils and amorphous deposits. The decreasedthermodynamic 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 questionof whether the mechanisms leading to fibrillar or amorphous aggregation is different. In this study, wegenerated two partially folded intermediates of the light chain variable domain SMA in the presence ofguanidine hydrochloride (GuHCl) and characterized their conformations. The more unfolded intermediateformed fibrils most rapidly, while the more native-like intermediate predominantly led to amorphousdeposits. 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, ratherthan the native state. We postulate that a more highly unfolded intermediate is more suited to undergo thetopological rearrangements necessary to form amyloid fibrils than a more structured one and that thisalso correlates with increased destabilization. In the case of light chain aggregation, it appears that morenative-like intermediate conformations are more prone to form amorphous deposits.