Structural characterization of a misfolded intermediate populated during the folding process of a PDZ domain
Structural characterization of a misfolded intermediate populated during the folding process of a PDZ domain
复制标题
DOI：
10.1038/nsmb.1956
复制
发表时间：
2010-12-01
影响因子：
16.8
通讯作者：
Vendruscolo, Michele
中科院分区：
文献类型：
--
作者：
Gianni, Stefano;Ivarsson, Ylva;Vendruscolo, Michele
在蛋白质折叠过程中瞬时填充的错误折叠状态可能容易聚集，并与包括阿尔茨海默氏症和帕金森氏症在内的一系列错误折叠障碍有关。然而，尽管它们很重要，但由于它们的短暂性质，这些国家的结构和形成机制在很大程度上没有得到详细的描述。在这里，我们介绍了PDZ结构域折叠过程中涉及的所有主要态的结构，其中包括一个偏离路径的错误折叠的中间体。通过使用动力学、蛋白质工程、生物物理和计算技术的组合，我们证明了错误折叠的中间体的特征是N-末端的β-发夹被替代地堆积在其他类似天然的支架上。我们的结果提出了一种错误折叠的瞬时紧凑态的形成机制，通过这种机制，错误折叠的结构元素与更多扩展的类自然区域组装在一起。
Incorrectly folded states transiently populated during the protein folding process are potentially prone to aggregation and have been implicated in a range of misfolding disorders that include Alzheimer's and Parkinson's diseases. Despite their importance, however, the structures of these states and the mechanism of their formation have largely escaped detailed characterization because of their short-lived nature. Here we present the structures of all the major states involved in the folding process of a PDZ domain, which include an off-pathway misfolded intermediate. By using a combination of kinetic, protein engineering, biophysical and computational techniques, we show that the misfolded intermediate is characterized by an alternative packing of the N-terminal beta-hairpin onto an otherwise native-like scaffold. Our results suggest a mechanism of formation of incorrectly folded transient compact states by which misfolded structural elements are assembled together with more extended native-like regions.