Regulatory Circuits of the AAA+ Disaggregase Hsp104
Regulatory Circuits of the AAA+ Disaggregase Hsp104
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AAA 解聚酶 Hsp104 的调节电路
DOI：
--
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发表时间：
2011
影响因子：
4.8
通讯作者：
S. Walter
中科院分区：
文献类型：
--
作者：
Titus M. Franzmann;A. Czekalla;S. Walter
酵母Hsp104是AAA+分子伴侣，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。每个原型包含两个AAA+模块，NBD 1和NBD 2。Hsp104将ATP提供的能量转化为机械力，用于将多肽穿过其轴向通道，从而破坏蛋白质聚集体。但其12个AAA+结构域的作用如何协调以催化解聚仍然没有解释。在这里，我们确定了一个复杂的变构网络组成的三个不同的途径，感知AAA+模块的核苷酸状态，并通过热休克蛋白104六聚体传输此信息。由于这种通信，NBD 1和NBD 2各自采用两种不同的构象（松弛和紧张），这两种构象都是受神经调节的。网络中的关键元素是NBD1-ATP状态，它使HSP 104能够从几乎不活跃的[RT]状态切换到高度活跃的[TR]状态。这种协同开关涉及顺式和反式原聚体相互作用，并为Hsp104提供催化解聚的机械支架。它为多肽结合准备分子伴侣，并激活NBD 2以产生分解蛋白质聚集体所需的动力冲程。NBD 1中的ATP水解解决了高亲和力[TR]状态，并将伴侣蛋白转换回低亲和力[RT]状态。我们的模型整合了以前无法解释的观察结果，并提供了第一个全面的1类AAA+蛋白质中核苷酸相关变构信号的图谱。
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 [RT] state to a highly active [TR] 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 [TR] state and switches the chaperone back into the low affinity [RT] state. Our model integrates previously unexplained observations and provides the first comprehensive map of nucleotide-related allosteric signals in a class-1 AAA+ protein.
影响因子：
5.6
作者：
Sielaff B;Tsai FT
通讯作者：
Tsai FT
影响因子：
56.9
作者：
SANCHEZ, Y;LINDQUIST, SL
通讯作者：
LINDQUIST, SL
亚基相互作用影响 Hsp104 的生化和生物学特性。
DOI：
10.1073/pnas.98.3.914
发表时间：
2001
影响因子：
11.1
作者：
Schirmer,EC;Ware,DM;Queitsch,C;Kowal,AS;Lindquist,SL
通讯作者：
Lindquist,SL