Designed Hsp90 heterodimers reveal an asymmetric ATPase-driven mechanism in vivo.
Designed Hsp90 heterodimers reveal an asymmetric ATPase-driven mechanism in vivo.
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DOI：
10.1016/j.molcel.2013.12.024
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发表时间：
2014-01-23
期刊：
影响因子：
16
通讯作者：
Bolon, Daniel N. A.
中科院分区：
文献类型：
--
作者：
Mishra, Parul;Bolon, Daniel N. A.
Hsp90 是一种同型二聚体 ATP 酶，在真核生物中对于经常参与信号转导（包括许多激酶和核类固醇激素受体）的客户蛋白的成熟至关重要。 ATP 与 Hsp90 结合的竞争性抑制剂可阻止客户成熟，并在临床试验中显示出作为抗癌药物的前景。然而，由于无法组装和研究特定组成的二聚体，因此很难研究 Hsp90 二聚体每个亚基中 ATP 结合和水解的作用。我们使用蛋白质工程来生成功能性 Hsp90 亚基，这些亚基优先组装为异二聚体。我们分析了其中一个亚基带有破坏性突变的二聚体，并观察到两个亚基的 ATP 结合对于酵母的功能至关重要，而 ATP 水解仅在一个亚基中需要。这些发现证明了对称和不对称 Hsp90 二聚体的重要功能贡献，并为未来研究 Hsp90 机制提供了有价值的试剂。
Hsp90 is a homo-dimeric ATPase that is essential in eukaryotes for the maturation of client proteins frequently involved in signal transduction including many kinases and nuclear steroid hormone receptors. Competitive inhibitors of ATP binding to Hsp90 prevent client maturation and show promise as anti-cancer agents in clinical trials. However, the role of ATP binding and hydrolysis in each subunit of the Hsp90 dimer has been difficult to investigate because of an inability to assemble and study dimers of defined composition. We used protein engineering to generate functional Hsp90 subunits that preferentially assemble as heterodimers. We analyzed dimers where one subunit harbors a disruptive mutation and observed that ATP binding by both subunits is essential for function in yeast, while ATP hydrolysis is only required in one subunit. These findings demonstrate important functional contributions from both symmetric and asymmetric Hsp90 dimers, and provide valuable reagents for future investigations of Hsp90 mechanism.
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