Aggregation of polyglutamine-expanded ataxin-3 sequesters its specific interacting partners into inclusions: implication in a loss-of-function pathology.
Aggregation of polyglutamine-expanded ataxin-3 sequesters its specific interacting partners into inclusions: implication in a loss-of-function pathology.
复制标题
聚谷氨酰胺扩增的 ataxin-3 的聚集将其特定的相互作用伙伴隔离到内含物中：对功能丧失病理学的影响
DOI：
10.1038/srep06410
复制
发表时间：
2014-09-18
影响因子：
4.6
通讯作者：
Hu HY
中科院分区：
文献类型：
--
作者：
Yang H;Li JJ;Liu S;Zhao J;Jiang YJ;Song AX;Hu HY
多聚谷氨酰胺（polyQ）束的扩张可能导致蛋白质错误折叠和聚集，从而导致细胞毒性和神经变性，但其潜在机制仍有待阐明。我们应用ataxin-3（Atx 3），一种含有polyQ的蛋白质，作为研究正常细胞蛋白质螯合的模型。我们发现由polyQ扩增的Atx 3形成的聚集体通过体外和细胞中的特异性相互作用将其相互作用伴侣（如P97/VCP和泛素缀合物）隔离到蛋白质内含物中。此外，这种特定的封存会损害P97下调neddylation的正常细胞功能。然而，Atx 3中polyQ道的扩展并不改变其周围区域的构象以及与相互作用伙伴的相互作用亲和力，尽管它确实促进了Atx 3蛋白的错误折叠和聚集。因此，我们提出了polyQ疾病的功能丧失病理学，即通过polyQ聚集体将细胞必需蛋白质通过特异性相互作用隔离到内含物中，导致相应蛋白质的功能障碍，并因此导致神经变性。
Expansion of polyglutamine (polyQ) tract may cause protein misfolding and aggregation that lead to cytotoxicity and neurodegeneration, but the underlying mechanism remains to be elucidated. We applied ataxin-3 (Atx3), a polyQ tract-containing protein, as a model to study sequestration of normal cellular proteins. We found that the aggregates formed by polyQ-expanded Atx3 sequester its interacting partners, such as P97/VCP and ubiquitin conjugates, into the protein inclusions through specific interactions both in vitro and in cells. Moreover, this specific sequestration impairs the normal cellular function of P97 in down-regulating neddylation. However, expansion of polyQ tract in Atx3 does not alter the conformation of its surrounding regions and the interaction affinities with the interacting partners, although it indeed facilitates misfolding and aggregation of the Atx3 protein. Thus, we propose a loss-of-function pathology for polyQ diseases that sequestration of the cellular essential proteins via specific interactions into inclusions by the polyQ aggregates causes dysfunction of the corresponding proteins, and consequently leads to neurodegeneration.