Regulation of the Hsp104 middle domain activity is critical for yeast prion propagation.
Regulation of the Hsp104 middle domain activity is critical for yeast prion propagation.
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DOI：
10.1371/journal.pone.0087521
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
True HL
中科院分区：
文献类型：
--
作者：
Dulle JE;Stein KC;True HL
分子伴侣在防止蛋白质错误折叠和聚集中起重要作用。事实上，一些蛋白质构象障碍已经与分子伴侣网络的变化有关。奇怪的是，在酵母中，伴侣蛋白也在促进朊病毒的维持和繁殖中发挥作用。虽然许多淀粉样蛋白与哺乳动物的疾病有关，但酵母朊病毒蛋白及其经历构象转化为朊病毒状态的能力被认为在酵母生物学中发挥功能性作用。伴侣蛋白Hsp 104是一种AAA+ ATP酶，是酵母朊病毒繁殖所必需的。Hsp 104将大的朊病毒聚集体片段化，产生一群较小的寡聚体，这些寡聚体可以更容易地转化可溶性单体并被传递到子细胞。在这里，我们表明，热休克蛋白104的中间（M）域，其流动性，朊病毒传播中起着不可或缺的一部分。我们产生并表征了Hsp 104的M结构域中的突变，这些突变被预测为稳定M结构域的抑制或去抑制构象（通过类比细菌中的ClpB）。我们表明，预测的稳定抑制构象抑制一般伴侣活性。然而，突变的去压抑的构象，对ATP水解和解聚有不同的影响，这表明M-结构域参与耦合这两个活动。有趣的是，我们发现M结构域的变化差异影响[PSI+]和[RNQ+]朊病毒的不同变体的传播，这表明某些朊病毒变体对M结构域迁移率的变化比其他变体更敏感。因此，我们提供的证据表明，Hsp 104的M-域的调节是至关重要的有效的朊病毒传播。这表明阐明M结构域的功能以理解Hsp 104在不同朊病毒和朊病毒变体的传播中的作用的重要性。
Molecular chaperones play a significant role in preventing protein misfolding and aggregation. Indeed, some protein conformational disorders have been linked to changes in the chaperone network. Curiously, in yeast, chaperones also play a role in promoting prion maintenance and propagation. While many amyloidogenic proteins are associated with disease in mammals, yeast prion proteins, and their ability to undergo conformational conversion into a prion state, are proposed to play a functional role in yeast biology. The chaperone Hsp104, a AAA+ ATPase, is essential for yeast prion propagation. Hsp104 fragments large prion aggregates to generate a population of smaller oligomers that can more readily convert soluble monomer and be transmitted to daughter cells. Here, we show that the middle (M) domain of Hsp104, and its mobility, plays an integral part in prion propagation. We generated and characterized mutations in the M-domain of Hsp104 that are predicted to stabilize either a repressed or de-repressed conformation of the M-domain (by analogy to ClpB in bacteria). We show that the predicted stabilization of the repressed conformation inhibits general chaperone activity. Mutation to the de-repressed conformation, however, has differential effects on ATP hydrolysis and disaggregation, suggesting that the M-domain is involved in coupling these two activities. Interestingly, we show that changes in the M-domain differentially affect the propagation of different variants of the [PSI+] and [RNQ+] prions, which indicates that some prion variants are more sensitive to changes in the M-domain mobility than others. Thus, we provide evidence that regulation of the M-domain of Hsp104 is critical for efficient prion propagation. This shows the importance of elucidating the function of the M-domain in order to understand the role of Hsp104 in the propagation of different prions and prion variants.
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DOI：
10.1083/jcb.201307040
发表时间：
2013-10-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Dulle JE;Bouttenot RE;Underwood LA;True HL
通讯作者：
True HL
影响因子：
2.5
作者：
Derkatch, IL;Bradley, ME;Liebman, SW
通讯作者：
Liebman, SW
影响因子：
64.5
作者：
DeSantis ME;Leung EH;Sweeny EA;Jackrel ME;Cushman-Nick M;Neuhaus-Follini A;Vashist S;Sochor MA;Knight MN;Shorter J
通讯作者：
Shorter J
新发现的朊病毒与酿酒酵母中染色质重塑因子 Swi1 相关
影响因子：
30.8
作者：
Du, Zhiqiang;Park, Kyung-Won;Li, Liming
通讯作者：
Li, Liming
影响因子：
3
作者：
Biter, Amadeo B.;Lee, Jungsoon;Lee, Sukyeong
通讯作者：
Lee, Sukyeong