Proposal for a role of the Hsp90/Hsp70-based chaperone machinery in making triage decisions when proteins undergo oxidative and toxic damage.
Proposal for a role of the Hsp90/Hsp70-based chaperone machinery in making triage decisions when proteins undergo oxidative and toxic damage.
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DOI：
10.1258/ebm.2009.009250
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发表时间：
2010-03
期刊：
影响因子：
--
通讯作者：
Osawa Y
中科院分区：
文献类型：
--
作者：
Pratt WB;Morishima Y;Peng HM;Osawa Y
基于Hsp 90/Hsp 70的分子伴侣机制在信号蛋白功能、运输和周转中起着公认的作用。最近的一些观察结果也支持这样的观点，即Hsp 90和Hsp 70在损伤和异常蛋白的分类中发挥关键作用，通过泛素-蛋白酶体途径降解。在20世纪90年代中期，发现Hsp 70是短寿命和异常蛋白的泛素依赖性降解所必需的，并且很明显，Hsp 90的抑制一致地导致Hsp 90客户蛋白的蛋白酶体降解。随后，CHIP和parkin被证明是Hsp 70结合的泛素E3连接酶，其将带泛素电荷的E2酶引导至Hsp 70结合的客户蛋白。Hsp 90的稳定作用反映了伴侣蛋白与客户蛋白的配体结合裂缝的相互作用。这些疏水裂缝必须是开放的，以允许配体通过蛋白质内部的结合位点，它们是构象不稳定的固有位点。热休克蛋白90稳定裂缝的开放状态，并防止热休克蛋白70依赖的泛素化。在我们这里提出的模型中，进行性氧化事件导致裂缝开放作为蛋白质解折叠的初始步骤，只要Hsp 90可以相互作用以稳定裂缝，它将缓冲氧化损伤的影响。当裂缝打开使得Hsp 90不能再相互作用时，Hsp 70依赖性泛素化发生。我们总结的证据表明，热休克蛋白90非常动态地与各种蛋白质，不是经典的热休克蛋白90客户端，我们表明，这种动态循环与热休克蛋白90保护芯片介导的泛素化。迄今为止，科学兴趣集中在经典客户蛋白的严格调控上，这些客户蛋白具有亚稳态裂缝并且本质上是短暂的。但是，认识到热休克蛋白90循环动态与更长的寿命的蛋白质更稳定的裂缝允许扩展的分类模型的质量控制受损的蛋白质一般。
The Hsp90/Hsp70-based chaperone machinery plays a well established role in signaling protein function, trafficking and turnover. A number of recent observations also support the notion that Hsp90 and Hsp70 play key roles in the triage of damaged and aberrant proteins for degradation via the ubiquitin-proteasome pathway. In the mid 1990s, it was discovered that Hsp70 is required for ubiquitin-dependent degradation of short lived and abnormal proteins, and it became clear that inhibition of Hsp90 uniformly leads to the proteasomal degradation of Hsp90 client proteins. Subsequently, CHIP and parkin were shown to be Hsp70-binding ubiquitin E3 ligases that direct ubiquitin-charged E2 enzymes to the Hsp70-bound client protein. The stabilizing effect of Hsp90 reflects the interaction of the chaperone with the ligand binding cleft of the client protein. These hydrophobic clefts must be open to allow passage of ligands to binding sites in the protein interior, and they are inherent sites of conformational instability. Hsp90 stabilizes the open state of the cleft and prevents Hsp70-dependent ubiquitination. In the model we present here, progressive oxidative events result in cleft opening as the initial step in protein unfolding, and as long as Hsp90 can interact to stabilize the cleft, it will buffer the effect of oxidative damage. When cleft opening is such that Hsp90 can no longer interact, Hsp70-dependent ubiquitination occurs. We summarize evidence that Hsp90 interacts very dynamically with a variety of proteins that are not classic Hsp90 clients, and we show that this dynamic cycling with Hsp90 protects against CHIP-mediated ubiquitination. Scientific interest to date has focused on stringent regulation of the classic client proteins, which have metastable clefts and are inherently short lived. But, the recognition that Hsp90 cycles dynamically with longer lived proteins with more stable clefts permits extension of the triage model to the quality control of damaged proteins in general.
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影响因子：
21.3
作者：
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通讯作者：
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