Regulatory Circuits of the AAA plus Disaggregase Hsp104
Regulatory Circuits of the AAA plus Disaggregase Hsp104
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DOI：
10.1074/jbc.m110.216176
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发表时间：
2011-05-20
影响因子：
4.8
通讯作者：
Walter, Stefan G.
中科院分区：
文献类型：
--
作者：
Franzmann, Titus M.;Czekalla, Anna;Walter, Stefan G.
酵母 Hsp104 是一种 AAA+ 伴侣，可将蛋白质从聚集状态中拯救出来。六个原聚体结合形成功能性六聚体。每个原体包含两个 AAA+ 模块：NBD1 和 NBD2。 Hsp104 将 ATP 提供的能量转化为机械力，用于使多肽穿过其轴向通道，从而破坏蛋白质聚集体。但其 12 个 AAA+ 域的作用如何协调以催化分解仍不清楚。在这里，我们确定了一个复杂的变构网络，该网络由三个不同的途径组成，可感知 AAA+ 模块的核苷酸状态并通过 Hsp104 六聚体传输此信息。由于这种交流，NBD1 和 NBD2 各自采用两种相互调节的不同构象（放松和紧张）。网络中的关键元素是 NBD1-ATP 状态，它使 Hsp104 能够从几乎不活跃的 [(T)(R)] 状态切换到高度活跃的 [(R)(T)] 状态。这种协同转换涉及顺式和反式原体相互作用，并为 Hsp104 提供催化解聚的机械支架。它为多肽结合准备伴侣并激活 NBD2 以产生分解蛋白质聚集体所需的动力冲程。 NBD1 中的 ATP 水解解析了高亲和力 [(R)(T)] 状态，并将分子伴侣切换回低亲和力 [(T)(R)] 状态。我们的模型整合了之前无法解释的观察结果，并提供了 1 类 AAA+ 蛋白中核苷酸相关变构信号的第一个全面图谱。
Yeast Hsp104 is an AAA+ chaperone that rescues proteins from the aggregated state. Six protomers associate to form the functional hexamer. Each protomer contains two AAA+ modules, NBD1 and NBD2. Hsp104 converts energy provided by ATP into mechanical force used to thread polypeptides through its axial channel, thereby disrupting protein aggregates. But how the action of its 12 AAA+ domains is co-ordinated to catalyze disaggregation remained unexplained. Here, we identify a sophisticated allosteric network consisting of three distinct pathways that senses the nucleotide state of AAA+ modules and transmits this information across the Hsp104 hexamer. As a result of this communication, NBD1 and NBD2 each adopt two distinct conformations (relaxed and tense) that are reciprocally regulated. The key element in the network is the NBD1-ATP state that enables Hsp104 to switch from a barely active [(T)(R)] state to a highly active [(R)(T)] state. This concerted switch involves both cis and trans protomer interactions and provides Hsp104 with the mechanistic scaffold to catalyze disaggregation. It prepares the chaperone for polypeptide binding and activates NBD2 to generate the power strokes required to resolve protein aggregates. ATP hydrolysis in NBD1 resolves the high affinity [(R)(T)] state and switches the chaperone back into the low affinity [(T)(R)] state. Our model integrates previously unexplained observations and provides the first comprehensive map of nucleotide-related allosteric signals in a class-1 AAA+ protein.