Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition.
Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition.
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DOI：
10.1016/j.cell.2012.06.047
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发表时间：
2012-08-31
期刊：
影响因子：
64.5
通讯作者：
Lindquist S
中科院分区：
文献类型：
--
作者：
Taipale M;Krykbaeva I;Koeva M;Kayatekin C;Westover KD;Karras GI;Lindquist S
HSP90是一种分子伴侣，与许多称为客户的底物蛋白相关联。它在人类生物学和医学中发挥着许多重要作用，但HSP90识别客户端的决定因素仍然令人沮丧地难以捉摸。我们系统地和定量地调查了大多数人类激酶，转录因子，和E3连接酶与HSP 90及其辅伴侣CDC 37的相互作用。出乎意料的是，更多的激酶比转录因子结合HSP 90。CDC37与激酶相互作用，但不与转录因子或E3连接酶相互作用。HSP90：：激酶相互作用在100倍范围内连续变化，并提供了研究客户蛋白识别的平台。在野生型的客户端，热休克蛋白90不结合特定的序列基序，而是与内在不稳定的激酶。稳定的激酶在其活性或非活性构象与不同的小分子减少热休克蛋白90协会。我们的研究结果建立热休克蛋白90客户端识别作为一个组合的过程：CDC37提供识别的激酶家族，而热力学参数确定客户端结合的家庭。
HSP90 is a molecular chaperone that associates with numerous substrate proteins called clients. It plays many important roles in human biology and medicine, but determinants of client recognition by HSP90 have remained frustratingly elusive. We systematically and quantitatively surveyed most human kinases, transcription factors, and E3 ligases for interaction with HSP90 and its cochaperone CDC37. Unexpectedly, many more kinases than transcription factors bound HSP90. CDC37 interacted with kinases, but not with transcription factors or E3 ligases. HSP90::kinase interactions varied continuously over a 100-fold range and provided a platform to study client protein recognition. In wild-type clients, HSP90 did not bind particular sequence motifs, but rather associated with intrinsically unstable kinases. Stabilization of the kinase in either its active or inactive conformation with diverse small molecules decreased HSP90 association. Our results establish HSP90 client recognition as a combinatorial process: CDC37 provides recognition of the kinase family, whereas thermodynamic parameters determine client binding within the family.
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DOI：
10.1073/pnas.0708800104
发表时间：
2007-12-18
影响因子：
11.1
作者：
Fedorov, Oleg;Marsden, Brian;Knapp, Stefan
通讯作者：
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影响因子：
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影响因子：
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作者：
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影响因子：
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作者：
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通讯作者：
Buchner, Johannes
影响因子：
5.6
作者：
Falsone, SF;Leptihn, S;Buchner, J
通讯作者：
Buchner, J