Pathogenic and non-pathogenic polyglutamine tracts have similar structural properties: Towards a length-dependent toxicity gradient
Pathogenic and non-pathogenic polyglutamine tracts have similar structural properties: Towards a length-dependent toxicity gradient
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DOI：
10.1016/j.jmb.2007.05.028
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发表时间：
2007-08-03
影响因子：
5.6
通讯作者：
Trottier, Yvon
中科院分区：
文献类型：
--
作者：
Klein, Fabrice A. C.;Pastore, Annalisa;Trottier, Yvon
异常扩增的多聚谷氨酰胺（polyQ）束为9种其他不相关的人类蛋白质提供毒性功能，并诱导进行性神经退行性疾病。在过去的十年中，有人提出，只有polyQ束长度超过特定的阈值采取特定的结构，这将是在polyQ疾病中观察到的明显的polyQ长度依赖性毒性阈值的原因。我们已经使用了生物化学和生物物理方法的组合来比较在各种条件下的致病性和非致病性长度的polyQ的结构特性。我们观察到，致病性和非致病性polyQ，作为可溶性物质和与合作伙伴的相互作用，在聚集过程中，或作为成熟的聚集体，显示非常相似的结构特性。PolyQ长度仅影响聚集动力学，并且在较小程度上影响聚集体的稳定性。因此，我们提出polyQ毒性不依赖于发生在特定阈值以上的结构转变，而是polyQ片段是固有的毒性序列，其有害作用随着它们的长度逐渐增加。我们讨论了polyQ属性和其他细胞因子如何解释存在一个明显的polyQ长度依赖性毒性阈值。(c)2007爱思唯尔有限公司保留所有权利。
Abnormally expanded polyglutamine (polyQ) tracts provide a gain of toxic functions to nine otherwise unrelated human proteins and induce progressive neurodegenerative diseases. Over the past ten years, it was suggested that only polyQ tracts longer than a specific threshold adopt a particular structure, which would be the cause of the apparent polyQ length-dependent toxicity threshold observed in polyQ diseases. We have used a combination of biochemical and biophysical approaches to compare the structural properties of polyQ of pathogenic and non-pathogenic lengths under various conditions. We observe that pathogenic and nonpathogenic polyQ, as soluble species and upon interaction with a partner, during aggregation, or as mature aggregates, display very similar structural properties. PolyQ length only influences the aggregation kinetics and, to a lesser extent, the stability of the aggregates. We thus propose that polyQ toxicity does not depend on a structural transition occurring above a specific threshold, but rather that polyQ tracts are inherently toxic sequences, whose deleterious effect gradually increases with their length. We discuss how polyQ properties and other cellular factors may explain the existence of an apparent polyQ length-dependent toxicity threshold. (c) 2007 Elsevier Ltd. All rights reserved.