Behrends Christian, Langer Carola A, Boteva Raina, Böttcher Ulrike M, Stemp Markus J, Schaffar Gregor, Rao Bharathi Vasudeva, Giese Armin, Kretzschmar Hans, Siegers Katja, Hartl F Ulrich
Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Am Klopferspitz 18, D-82152 Martinsried.
Mol Cell. 2006 Sep 15;23(6):887-97. doi: 10.1016/j.molcel.2006.08.017.
Aberrant folding and fibrillar aggregation by polyglutamine (polyQ) expansion proteins are associated with cytotoxicity in Huntington's disease and other neurodegenerative disorders. Hsp70 chaperones have an inhibitory effect on fibril formation and can alleviate polyQ cytotoxicity. Here we show that the cytosolic chaperonin, TRiC, functions synergistically with Hsp70 in this process and is limiting in suppressing polyQ toxicity in a yeast model. In vitro reconstitution experiments revealed that TRiC, in cooperation with the Hsp70 system, promotes the assembly of polyQ-expanded fragments of huntingtin (Htt) into soluble oligomers of approximately 500 kDa. Similar oligomers were observed in yeast cells upon TRiC overexpression and were found to be benign, in contrast to conformationally distinct Htt oligomers of approximately 200 kDa, which accumulated at normal TRiC levels and correlated with inhibition of cell growth. We suggest that TRiC cooperates with the Hsp70 system as a key component in the cellular defense against amyloid-like protein misfolding.
聚谷氨酰胺（polyQ）扩展蛋白的异常折叠和纤维状聚集与亨廷顿舞蹈症及其他神经退行性疾病中的细胞毒性相关。热休克蛋白70（Hsp70）伴侣蛋白对纤维形成具有抑制作用，并能减轻聚谷氨酰胺的细胞毒性。在此我们表明，胞质伴侣蛋白TRiC在此过程中与Hsp70协同发挥作用，并且在酵母模型中，它在抑制聚谷氨酰胺毒性方面存在局限性。体外重组实验表明，TRiC与Hsp70系统协同作用，促进亨廷顿蛋白（Htt）的聚谷氨酰胺扩展片段组装成约500 kDa的可溶性寡聚体。TRiC过表达时，在酵母细胞中观察到了类似的寡聚体，并且发现它们是良性的，这与构象不同的约200 kDa的Htt寡聚体形成对比，后者在正常TRiC水平下积累并与细胞生长抑制相关。我们认为，TRiC作为细胞防御淀粉样蛋白错误折叠的关键成分，与Hsp70系统协同发挥作用。
