Tam Stephen, Geller Ron, Spiess Christoph, Frydman Judith
Biophysics Graduate Program, Stanford University, Stanford, California 94305, USA.
Nat Cell Biol. 2006 Oct;8(10):1155-62. doi: 10.1038/ncb1477. Epub 2006 Sep 17.
Misfolding and aggregation of proteins containing expanded polyglutamine repeats underlie Huntington's disease and other neurodegenerative disorders. Here, we show that the hetero-oligomeric chaperonin TRiC (also known as CCT) physically interacts with polyglutamine-expanded variants of huntingtin (Htt) and effectively inhibits their aggregation. Depletion of TRiC enhances polyglutamine aggregation in yeast and mammalian cells. Conversely, overexpression of a single TRiC subunit, CCT1, is sufficient to remodel Htt-aggregate morphology in vivo and in vitro, and reduces Htt-induced toxicity in neuronal cells. Because TRiC acts during de novo protein biogenesis, this chaperonin may have an early role preventing Htt access to pathogenic conformations. Based on the specificity of the Htt-CCT1 interaction, the CCT1 substrate-binding domain may provide a versatile scaffold for therapeutic inhibitors of neurodegenerative disease.
含有扩展型聚谷氨酰胺重复序列的蛋白质错误折叠和聚集是亨廷顿舞蹈症及其他神经退行性疾病的基础。在此，我们表明异源寡聚伴侣蛋白TRiC（也称为CCT）与亨廷顿蛋白（Htt）的聚谷氨酰胺扩展变体发生物理相互作用，并有效抑制其聚集。TRiC的缺失会增强酵母和哺乳动物细胞中的聚谷氨酰胺聚集。相反，单个TRiC亚基CCT1的过表达足以在体内和体外重塑Htt聚集体形态，并降低Htt在神经元细胞中诱导的毒性。由于TRiC在新生蛋白质生物合成过程中发挥作用，这种伴侣蛋白可能在防止Htt进入致病构象方面具有早期作用。基于Htt与CCT1相互作用的特异性，CCT1底物结合结构域可能为神经退行性疾病的治疗抑制剂提供一个通用支架。
