The endoplasmic reticulum chaperone BiP is a closure-accelerating cochaperone of Grp94.
The endoplasmic reticulum chaperone BiP is a closure-accelerating cochaperone of Grp94.
复制标题
DOI：
10.1073/pnas.2118793119
复制
发表时间：
2022-02-01
影响因子：
11.1
通讯作者：
Street TO
中科院分区：
文献类型：
--
作者：
Huang B;Sun M;Hoxie R;Kotler JLM;Friedman LJ;Gelles J;Street TO
内质网(ER)是分泌蛋白质(如激素胰岛素)和膜结合蛋白折叠的部位。内质网中依赖于ATP的伴侣有助于蛋白质折叠。这项研究描述了两个关键的ER伴侣，Bip和Grp94是如何在分子水平上协同工作的。Bip与Grp94结合，使Grp94能够改变构象和水解三磷酸腺苷。简而言之，Bip提供了一个信号来启动Grp94的构象变化，这是帮助其他蛋白质折叠所必需的。这一发现有助于解释两个伴侣如何在蛋白质折叠中协同工作。由于Bip和Grp94是高度保守的伴侣蛋白家族的成员，这些发现可能为伴侣蛋白在内质网之外的折叠提供了洞察力。HSP70和HSP90分子伴侣为细胞质、内质网和线粒体提供蛋白质质量控制。HSP90的活性通常被辅伴蛋白增强，辅伴蛋白驱动依赖于ATP的关闭和捕获客户蛋白所需的构象变化。当与HSP70一起工作时，HSP90的活性也得到了增强，但在这种情况下，其潜在的机制解释尚不清楚。在这里，我们研究了ER特异的Hsp70/Hsp90同源蛋白(Bip/Grp94)，发现Bip本身作为辅伴侣加速Grp94的关闭。Bip核苷酸结合域与Grp94中间结构域相互作用，负责Grp94关闭的加速。一个客户蛋白启动了Bip/Grp94系统的协调步骤，其中客户与Bip的结合导致构象变化，使Bip能够与Grp94结合并加速其依赖于ATP的关闭。单分子荧光共振能量转移测量表明，BiP通过稳定高能构象中间体来加速Grp94的关闭，否则它就会成为关闭的能量屏障。这些发现解释了Bip和Grp94成对工作时活性增强的原因，并证明了高能构象状态在控制Grp94构象周期的时间上的重要性。鉴于Hsp70/Hsp90系统的高度保守性，其他Hsp70也可能同时充当Hsp90的伴侣和加速关闭的辅伴侣的双重角色。
The endoplasmic reticulum (ER) is the site at which secreted proteins (such as the hormone insulin) and membrane-bound proteins are folded. ATP-dependent chaperones within the ER help proteins fold. This study describes how two key ER chaperones, BiP and Grp94, work together at a molecular level. BiP binds to Grp94, which enables Grp94 to change conformation and hydrolyze ATP. In short, BiP provides a signal to switch on Grp94 conformational changes that are required to help other proteins fold. This finding helps explain how two chaperones can work together collaboratively in protein folding. Because BiP and Grp94 are members of highly conserved chaperone families, these findings may provide insight into chaperone-assisted protein folding beyond the ER. Hsp70 and Hsp90 chaperones provide protein quality control to the cytoplasm, endoplasmic reticulum (ER), and mitochondria. Hsp90 activity is often enhanced by cochaperones that drive conformational changes needed for ATP-dependent closure and capture of client proteins. Hsp90 activity is also enhanced when working with Hsp70, but, in this case, the underlying mechanistic explanation is poorly understood. Here we examine the ER-specific Hsp70/Hsp90 paralogs (BiP/Grp94) and discover that BiP itself acts as a cochaperone that accelerates Grp94 closure. The BiP nucleotide binding domain, which interacts with the Grp94 middle domain, is responsible for Grp94 closure acceleration. A client protein initiates a coordinated progression of steps for the BiP/Grp94 system, in which client binding to BiP causes a conformational change that enables BiP to bind to Grp94 and accelerate its ATP-dependent closure. Single-molecule fluorescence resonance energy transfer measurements show that BiP accelerates Grp94 closure by stabilizing a high-energy conformational intermediate that otherwise acts as an energetic barrier to closure. These findings provide an explanation for enhanced activity of BiP and Grp94 when working as a pair, and demonstrate the importance of a high-energy conformational state in controlling the timing of the Grp94 conformational cycle. Given the high conservation of the Hsp70/Hsp90 system, other Hsp70s may also serve dual roles as both chaperones and closure-accelerating cochaperones to their Hsp90 counterparts.
登录
查看更多内容
影响因子：
64.5
作者：
Kirschke E;Goswami D;Southworth D;Griffin PR;Agard DA
通讯作者：
Agard DA
影响因子：
16
作者：
Lavery, Laura A.;Partridge, James R.;Ramelot, Theresa A.;Elnatan, Daniel;Kennedy, Michael A.;Agard, David A.
通讯作者：
Agard, David A.
DOI：
10.1073/pnas.1916030116
发表时间：
2020-01-07
影响因子：
11.1
作者：
Giannoulis, Angeliki;Feintuch, Akiva;Goldfarb, Daniella
通讯作者：
Goldfarb, Daniella
影响因子：
5.6
作者：
Kravats, Andrea N.;Doyle, Shannon M.;Wickner, Sue
通讯作者：
Wickner, Sue
影响因子：
4.8
作者：
Leskovar, Adriane;Wegele, Harald;Reinstein, Jochen
通讯作者：
Reinstein, Jochen