Insight into Molecular Basis of Curing of [PSI+] Prion by Overexpression of 104-kDa Heat Shock Protein (Hsp104)
Insight into Molecular Basis of Curing of [PSI+] Prion by Overexpression of 104-kDa Heat Shock Protein (Hsp104)
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DOI：
10.1074/jbc.m111.302869
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发表时间：
2012-01-02
影响因子：
4.8
通讯作者：
Glover, John R.
中科院分区：
文献类型：
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作者：
Helsen, Christopher W.;Glover, John R.
酵母朊病毒是一个强大的模型，用于了解与许多人类神经退行性疾病相关的蛋白质聚集的动力学。AAA+蛋白解聚酶Hsp 104可以切断由酵母朊病毒产生的淀粉样纤维。这一作用导致“种子”的繁殖，这些种子在出芽过程中被传递到子细胞。Hsp 104的过表达消除了[PSI+]朊病毒，但不消除其他朊病毒。使用生物化学方法，我们确定了Hsp 104结合位点的高度带电的中间域Sup 35，蛋白质决定簇[PSI+]。缺失中间结构域的短片段（氨基酸129-148）减少了Hsp 104结合，并强烈影响中间结构域刺激Hsp 104的ATP酶活性的能力。在酵母中，由缺乏该片段的Sup 35维持的[PSI+]，像其他朊病毒一样，由Hsp 104繁殖，但不能被Hsp 104过表达治愈。这些结果提供了新的见解的神秘特异性的热休克蛋白104介导的酵母朊病毒的治疗和揭示的局限性的能力，热休克蛋白104消除其他聚集倾向蛋白质产生的聚集体。
Yeast prions are a powerful model for understanding the dynamics of protein aggregation associated with a number of human neurodegenerative disorders. The AAA+ protein disaggregase Hsp104 can sever the amyloid fibrils produced by yeast prions. This action results in the propagation of "seeds" that are transmitted to daughter cells during budding. Overexpression of Hsp104 eliminates the [PSI+] prion but not other prions. Using biochemical methods we identified Hsp104 binding sites in the highly charged middle domain of Sup35, the protein determinant of [PSI+]. Deletion of a short segment of the middle domain (amino acids 129-148) diminishes Hsp104 binding and strongly affects the ability of the middle domain to stimulate the ATPase activity of Hsp104. In yeast, [PSI+] maintained by Sup35 lacking this segment, like other prions, is propagated by Hsp104 but cannot be cured by Hsp104 overexpression. These results provide new insight into the enigmatic specificity of Hsp104-mediated curing of yeast prions and sheds light on the limitations of the ability of Hsp104 to eliminate aggregates produced by other aggregation-prone proteins.