Dual Role of Ribosome-Binding Domain of NAC as a Potent Suppressor of Protein Aggregation and Aging-Related Proteinopathies
Dual Role of Ribosome-Binding Domain of NAC as a Potent Suppressor of Protein Aggregation and Aging-Related Proteinopathies
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DOI：
10.1016/j.molcel.2019.03.012
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发表时间：
2019-05-16
期刊：
影响因子：
16
通讯作者：
Deuerling, Elke
中科院分区：
文献类型：
--
作者：
Shen, Koning;Gamerdinger, Martin;Deuerling, Elke
新生多肽相关复合物（NAC）是一种保守的核糖体相关蛋白生物合成因子。NAC是否发挥分子伴侣活性，以及这种功能是否仅限于从头蛋白质合成尚不清楚。在这里，我们证明，NAC直接发挥分子伴侣活性对结构多样的模型基板，包括聚谷氨酰胺（PolyQ）蛋白，萤火虫荧光素酶，和A β 40。引人注目的是，我们确定了带正电荷的核糖体结合域的N端的β NAC亚基（N-β NAC）作为一个主要的伴侣实体的NAC。N-beta NAC本身在体外抑制PolyQ扩增蛋白的聚集，并且该结构域的正电荷对于该活性是关键的。此外，我们还发现NAC在体内也发挥核糖体非依赖性伴侣功能。一致地，我们发现，相当一部分的NAC是非核糖体结合在高等真核生物。总之，NAC是与人类疾病如亨廷顿病和脊髓小脑共济失调相关的突变PolyQ-扩增蛋白的聚集和蛋白毒性的有效抑制剂。
The nascent polypeptide-associated complex (NAC) is a conserved ribosome-associated protein biogenesis factor. Whether NAC exerts chaperone activity and whether this function is restricted to de novo protein synthesis is unknown. Here, we demonstrate that NAC directly exerts chaperone activity toward structurally diverse model substrates including poly-glutamine (PolyQ) proteins, firefly luciferase, and A beta 40. Strikingly, we identified the positively charged ribosome-binding domain in the N terminus of the beta NAC subunit (N-beta NAC) as a major chaperone entity of NAC. N-beta NAC by itself suppressed aggregation of PolyQ-expanded proteins in vitro, and the positive charge of this domain was critical for this activity. Moreover, we found that NAC also exerts a ribo-some-independent chaperone function in vivo. Consistently, we found that a substantial fraction of NAC is non-ribosomal bound in higher eukaryotes. In sum, NAC is a potent suppressor of aggregation and proteotoxicity of mutant PolyQ-expanded proteins associated with human diseases like Huntington's disease and spinocerebellar ataxias.