Hsp70 chaperones are non-equilibrium machines that achieve ultra-affinity by energy consumption.
Hsp70 chaperones are non-equilibrium machines that achieve ultra-affinity by energy consumption.
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DOI：
10.7554/elife.02218
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发表时间：
2014-05-27
期刊：
影响因子：
7.7
通讯作者：
Barducci A
中科院分区：
文献类型：
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作者：
De Los Rios P;Barducci A
70 - 千道尔顿热休克蛋白是由ATP驱动的分子伴侣，执行无数重要的细胞任务。尽管结构和生化研究已对其功能机制有了一些了解，但由于ATP水解而产生的能量消耗所起作用这一根本问题仍未得到解决。在此我们明确了由于ATP水解导致的Hsp70的非平衡性质与其功能的决定性特征，即对其底物的高亲和力之间的联系。相对于平衡情况，能量消耗确实可使伴侣 - 底物复合物的解离常数降低几个数量级。我们发现观察到这种超高亲和力的生化要求与细胞内的生理条件相符。我们的结果使一些实验观察结果合理化，并为进一步分析伴侣功能背后的非平衡效应铺平了道路。
DOI: http://dx.doi.org/10.7554/eLife.02218.001
蛋白质在细胞中执行众多重要任务。这些任务中的大多数要求蛋白质具有非常特定的结构，该结构由化学和物理相互作用的平衡来维持。然而，这种微妙的平衡易受过热、细胞pH值变化以及某些化学物质的影响。结果，蛋白质可能会失去其特定结构并停止工作。
细胞利用一组称为伴侣蛋白的特殊蛋白质来检查其他蛋白质是否具有正确结构，并对那些结构不正确的蛋白质进行“重折叠”。Hsp70伴侣蛋白家族需要能量来完成其工作，它从一种叫做ATP的分子中获取能量。然而，Hsp70的确切工作方式以及如何使用这种能量尚未完全被理解。
一个主要的谜题是Hsp70如何与蛋白质结合以使其折叠。先前的实验表明，如果Hsp70能够在由ATP控制的复杂循环中采用不同结构，这种结合会特别有效。现在，德洛斯里奥斯（De Los Rios）和巴尔杜奇（Barducci）揭示，ATP分子分解所释放的能量使这种超高效的结合得以发生。根据所提出的模型，在细胞中通常存在的一些条件下这是可能的。这些条件包括Hsp70蛋白比目标蛋白多得多，以及以极高的速率从ATP产生能量。Hsp70能够形成的不同结构的特定动力学特性也至关重要。
更广泛地说，能量消耗增强结合的原理可能扩展到伴侣蛋白之外，并代表其他生物分子系统的一种通用机制。
DOI: http://dx.doi.org/10.7554/eLife.02218.002
70-kDa Heat shock proteins are ATP-driven molecular chaperones that perform a myriad of essential cellular tasks. Although structural and biochemical studies have shed some light on their functional mechanism, the fundamental issue of the role of energy consumption, due to ATP-hydrolysis, has remained unaddressed. Here we establish a clear connection between the non-equilibrium nature of Hsp70, due to ATP hydrolysis, and the determining feature of its function, namely its high affinity for its substrates. Energy consumption can indeed decrease the dissociation constant of the chaperone-substrate complex by several orders of magnitude with respect to an equilibrium scenario. We find that the biochemical requirements for observing such ultra-affinity coincide with the physiological conditions in the cell. Our results rationalize several experimental observations and pave the way for further analysis of non-equilibrium effects underlying chaperone functions. DOI: http://dx.doi.org/10.7554/eLife.02218.001 Proteins perform numerous essential tasks in cells. Most of these tasks require the protein to have a very specific structure, which is maintained by a balance of chemical and physical interactions. However, this delicate balance is vulnerable to excessive heat, changes in the pH of the cell, and certain chemicals. As a consequence, proteins could lose their specific structure and stop working. Cells employ a group of specialized proteins—called chaperones—to check that other proteins have the correct structure, and to ‘refold’ those that do not. The Hsp70 chaperone family needs energy to do its job, and it gets this energy from a molecule called ATP. However, the exact way that Hsp70s work and use this energy is not fully understood. One major puzzle is how Hsp70 binds to a protein to fold it up. Previous experiments suggested that this binding is particularly effective if Hsp70 can adopt different structures as part of a complex cycle governed by ATP. Now, De Los Rios and Barducci reveal that the energy released from breaking down ATP molecules enables this extra-efficient binding to occur. According to the proposed model, this is possible under some conditions that are normally found in cells. These include having many more Hsp70 proteins than target proteins, and producing energy at extremely high rates from ATP. The specific kinetic properties of the different structures Hsp70 can form are also crucial. More generally, the principle that energy consumption enhances binding could be extended beyond chaperone proteins and represent a general mechanism for other biomolecular systems. DOI: http://dx.doi.org/10.7554/eLife.02218.002