Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, Padualaan 8, 3584 CH Utrecht, the Netherlands; Science for Life, Utrecht University, Padualaan 8, 3584 CH Utrecht, the Netherlands.
Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH-Alliance, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany.
Mol Cell. 2018 May 3;70(3):545-552.e9. doi: 10.1016/j.molcel.2018.03.028. Epub 2018 Apr 26.
Protein folding in the cell requires ATP-driven chaperone machines such as the conserved Hsp70 and Hsp90. It is enigmatic how these machines fold proteins. Here, we show that Hsp90 takes a key role in protein folding by breaking an Hsp70-inflicted folding block, empowering protein clients to fold on their own. At physiological concentrations, Hsp70 stalls productive folding by binding hydrophobic, core-forming segments. Hsp90 breaks this deadlock and restarts folding. Remarkably, neither Hsp70 nor Hsp90 alters the folding rate despite ensuring high folding yields. In fact, ATP-dependent chaperoning is restricted to the early folding phase. Thus, the Hsp70-Hsp90 cascade does not fold proteins, but instead prepares them for spontaneous, productive folding. This stop-start mechanism is conserved from bacteria to man, assigning also a general function to bacterial Hsp90, HtpG. We speculate that the decreasing hydrophobicity along the Hsp70-Hsp90 cascade may be crucial for enabling spontaneous folding.
细胞中的蛋白质折叠需要 ATP 驱动的伴侣机器，如保守的 HSP70 和 HSP90。这些机器如何折叠蛋白质仍然是一个谜。在这里，我们表明 HSP90 通过打破 HSP70 造成的折叠障碍，发挥关键作用，使蛋白质客户能够自行折叠。在生理浓度下，HSP70 通过结合疏水性、形成核心的片段来阻碍有效的折叠。HSP90 打破了这种僵局并重新开始折叠。值得注意的是，尽管确保了高折叠产率，但 Hsp70 和 Hsp90 都不会改变折叠速率。事实上，ATP 依赖性伴侣只限于早期折叠阶段。因此，Hsp70-Hsp90 级联本身并不折叠蛋白质，而是为蛋白质的自发、有效折叠做准备。这种停停走走的机制从细菌到人都得到了保守，赋予了细菌 HSP90（HtpG）的一般功能。我们推测，Hsp70-Hsp90 级联中沿疏水度的降低对于实现自发折叠可能至关重要。
