The interactions of molecular chaperones with client proteins: why are they so weak?
The interactions of molecular chaperones with client proteins: why are they so weak?
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DOI：
10.1016/j.jbc.2021.101282
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发表时间：
2021-11
期刊：
影响因子：
--
通讯作者：
Gestwicki JE
中科院分区：
文献类型：
--
作者：
Arhar T;Shkedi A;Nadel CM;Gestwicki JE
分子伴侣的主要类别具有高度可变的序列，大小和形状，但它们都与未折叠的蛋白质结合，限制它们的聚集，并帮助它们折叠。尽管这一过程对蛋白质稳态至关重要，但尚不清楚伴侣蛋白如何指导这一过程，或者伴侣蛋白的不同家族是否使用类似的机制。这是第一次，NMR光谱学的最新进展已经能够详细研究未折叠的“客户”蛋白质如何与ATP依赖性和ATP非依赖性伴侣蛋白相互作用。在这里，我们回顾了四个不同的伴侣，间谍，触发因子，DnaK和HscA-HscB的例子，突出了它们的机制之间的相似性和差异。一个惊人的相似之处是，分子伴侣都与其客户端弱结合，使得分子伴侣-客户端相互作用容易被折叠状态下更强的分子内和分子间接触所击败。因此，这些相互作用的相对较弱的亲和力似乎为折叠过程提供了方向性。然而，也有关键的差异，特别是在伴侣如何释放客户端以及ATP循环如何影响该过程的细节方面。例如，Spy在很大程度上以折叠状态释放客户端，而客户端似乎在从Trigger Factor或DnaK释放时展开。总之，这些研究开始揭示分子伴侣如何使用弱相互作用来指导蛋白质折叠的相似性和差异。
The major classes of molecular chaperones have highly variable sequences, sizes, and shapes, yet they all bind to unfolded proteins, limit their aggregation, and assist in their folding. Despite the central importance of this process to protein homeostasis, it has not been clear exactly how chaperones guide this process or whether the diverse families of chaperones use similar mechanisms. For the first time, recent advances in NMR spectroscopy have enabled detailed studies of how unfolded, “client” proteins interact with both ATP-dependent and ATP-independent classes of chaperones. Here, we review examples from four distinct chaperones, Spy, Trigger Factor, DnaK, and HscA-HscB, highlighting the similarities and differences between their mechanisms. One striking similarity is that the chaperones all bind weakly to their clients, such that the chaperone–client interactions are readily outcompeted by stronger, intra- and intermolecular contacts in the folded state. Thus, the relatively weak affinity of these interactions seems to provide directionality to the folding process. However, there are also key differences, especially in the details of how the chaperones release clients and how ATP cycling impacts that process. For example, Spy releases clients in a largely folded state, while clients seem to be unfolded upon release from Trigger Factor or DnaK. Together, these studies are beginning to uncover the similarities and differences in how chaperones use weak interactions to guide protein folding.
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