Koldewey Philipp, Stull Frederick, Horowitz Scott, Martin Raoul, Bardwell James C A
Department of Molecular, Cellular and Developmental Biology, and the Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Molecular, Cellular and Developmental Biology, and the Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Cell. 2016 Jul 14;166(2):369-379. doi: 10.1016/j.cell.2016.05.054. Epub 2016 Jun 9.
It is still unclear what molecular forces drive chaperone-mediated protein folding. Here, we obtain a detailed mechanistic understanding of the forces that dictate the four key steps of chaperone-client interaction: initial binding, complex stabilization, folding, and release. Contrary to the common belief that chaperones recognize unfolding intermediates by their hydrophobic nature, we discover that the model chaperone Spy uses long-range electrostatic interactions to rapidly bind to its unfolded client protein Im7. Short-range hydrophobic interactions follow, which serve to stabilize the complex. Hydrophobic collapse of the client protein then drives its folding. By burying hydrophobic residues in its core, the client's affinity to Spy decreases, which causes client release. By allowing the client to fold itself, Spy circumvents the need for client-specific folding instructions. This mechanism might help explain how chaperones can facilitate the folding of various unrelated proteins.
目前仍不清楚是什么分子力驱动伴侣蛋白介导的蛋白质折叠。在此，我们对决定伴侣蛋白 - 底物相互作用四个关键步骤的力有了详细的机制理解：初始结合、复合物稳定、折叠和释放。与普遍认为伴侣蛋白通过其疏水性质识别未折叠中间体的观点相反，我们发现模型伴侣蛋白Spy利用长程静电相互作用快速结合其未折叠的底物蛋白Im7。随后是短程疏水相互作用，其作用是稳定复合物。底物蛋白的疏水塌缩进而驱动其折叠。通过将疏水残基埋入其核心，底物对Spy的亲和力降低，这导致底物释放。通过让底物自行折叠，Spy避免了对底物特异性折叠指令的需求。这种机制可能有助于解释伴侣蛋白如何促进各种不相关蛋白质的折叠。
