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首页> 外文期刊>Journal of Molecular Biology >Destabilization of a Non-pathological Variant of Ataxin-3 Results in Fibrillogenesis via a Partially Folded Intermediate: A Model for Misfolding in Polyglutamine Disease.
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Destabilization of a Non-pathological Variant of Ataxin-3 Results in Fibrillogenesis via a Partially Folded Intermediate: A Model for Misfolding in Polyglutamine Disease.

机译：Ataxin-3的非病理变异的不稳定导致通过部分折叠的中间体产生原纤维形成：一种在聚谷氨酰胺疾病中错误折叠的模型。

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摘要

Ataxin-3 is a member of the polyglutamine family of proteins, which are associated with at least nine different neurodegenerative diseases. In the disease state, expansion of the polyglutamine tract leads to dysfunction and death of neurons, as well as formation of proteinaceous aggregates known as nuclear inclusions. Intriguingly, both expanded and non-expanded forms of ataxin-3 are observed within these nuclear inclusions. Ataxin-3 is the smallest of the polyglutamine disease proteins and in its expanded form causes the neurodegenerative disorder Machado-Joseph disease. Using a non-pathological variant containing 28 residues in its polyglutamine tract, we have probed the folding and misfolding pathways of ataxin-3. We describe here the first equilibrium folding pathway delineated for any polyglutamine protein and show that ataxin-3 folds reversibly via a single intermediate species. We have also explored further the misfolding potential of the protein and found that partial destabilization of ataxin-3 by chemical denaturation leads to the formation of fibrillar aggregates by the non-pathological variant. These results provide an insight into the possible mechanisms by which polyglutamine expansion may affect the stability and conformation of the protein. The implications of this are considered in the wider context of the development and pathogenesis of polyglutamine diseases.
机译：Ataxin-3是多聚谷氨酰胺蛋白质家族的成员，该家族与至少九种不同的神经退行性疾病有关。在疾病状态下，聚谷氨酰胺束的扩张导致神经元的功能障碍和死亡，以及形成称为核内含物的蛋白质聚集体。有趣的是，在这些核内含物中都观察到了紫杉素3的扩展形式和非扩展形式。 Ataxin-3是最小的多聚谷氨酰胺疾病蛋白，其扩展形式可引起神经退行性疾病马查多-约瑟夫病。使用在其聚谷氨酰胺束中包含28个残基的非病理变异体，我们探究了ataxin-3的折叠和错折叠途径。我们在这里描述了针对任何聚谷氨酰胺蛋白的第一个平衡折叠途径，并显示了ataxin-3通过单个中间物种可逆地折叠。我们还进一步研究了该蛋白的错误折叠潜力，并发现通过化学变性使紫杉素3的部分失稳导致非病理性变体形成纤维状聚集体。这些结果提供了对聚谷氨酰胺扩展可能影响蛋白质稳定性和构象的可能机制的见解。在聚谷氨酰胺疾病的发展和发病机理的更广泛的背景下考虑了这一含义。

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