Chow Michelle K M, Paulson Henry L, Bottomley Stephen P
Department of Biochemistry and Molecular Biology, Structural Biology Group, Monash University, Clayton Campus, PO Box 13D, Wellington Rd., 3800, Clayton, Vic., Australia.
J Mol Biol. 2004 Jan 2;335(1):333-41. doi: 10.1016/j.jmb.2003.08.064.
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.
ataxin-3是多聚谷氨酰胺蛋白家族的成员,该家族与至少九种不同的神经退行性疾病相关。在疾病状态下,多聚谷氨酰胺序列的扩增会导致神经元功能障碍和死亡,以及形成被称为核内包涵体的蛋白质聚集体。有趣的是,在这些核内包涵体中观察到了ataxin-3的扩增形式和未扩增形式。ataxin-3是最小的多聚谷氨酰胺疾病蛋白,其扩增形式会导致神经退行性疾病马查多-约瑟夫病。我们使用一种在其多聚谷氨酰胺序列中含有28个残基的非病理性变体,探究了ataxin-3的折叠和错误折叠途径。我们在此描述了为任何多聚谷氨酰胺蛋白描绘的第一条平衡折叠途径,并表明ataxin-3通过单个中间物种可逆地折叠。我们还进一步探究了该蛋白的错误折叠潜力,发现化学变性使ataxin-3部分去稳定会导致非病理性变体形成纤维状聚集体。这些结果为多聚谷氨酰胺扩增可能影响蛋白质稳定性和构象的潜在机制提供了见解。在多聚谷氨酰胺疾病的发展和发病机制的更广泛背景下考虑了这一结果的意义。