Noncanonical binding of BiP ATPase domain to Ire1 and Perk is dissociated by unfolded protein CH1 to initiate ER stress signaling.
Noncanonical binding of BiP ATPase domain to Ire1 and Perk is dissociated by unfolded protein CH1 to initiate ER stress signaling.
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作者：
Carrara M;Prischi F;Nowak PR;Kopp MC;Ali MM
未折叠蛋白反应（UPR）是一个重要的细胞信号系统，它能检测内质网（ER）内错误折叠蛋白的积累，并启动细胞反应以维持内稳态。细胞如何检测错误折叠蛋白的积累仍不清楚。在这项研究中，我们发现内质网伴侣蛋白BiP的ATP酶结构域与UPR传感器Ire1和Perk的腔内结构域之间存在一种非经典的相互作用，当真正的内质网未折叠蛋白CH1与BiP的经典底物结合结构域结合时，这种相互作用会解离。与伴侣蛋白和底物之间的相互作用不同，我们发现BiP与UPR传感器之间的相互作用不受核苷酸的影响。因此，我们发现BiP是一种具有双重功能的UPR传感器，它通过与底物的经典结合来感知未折叠蛋白，并将这一事件转化为与Ire1和Perk的非经典信号相互作用。我们的观察结果表明BiP是检测内质网应激的关键成分，并提出了一种UPR诱导的变构机制。
DOI: http://dx.doi.org/10.7554/eLife.03522.001
蛋白质在细胞中执行许多重要任务，但为了能够发挥作用，它们首先必须正确折叠成特定的三维形状。在细胞内，许多蛋白质在“伴侣”蛋白的帮助下进行折叠。如果任何蛋白质折叠错误，细胞的正常运作可能会被扰乱，这可能会损害细胞。如果细胞突然需要大量蛋白质合成，这种情况更有可能发生，因为这可能会使伴侣蛋白不堪重负。
在人类和其他真核生物中，许多蛋白质在内质网这个细胞内的区域中折叠。在这个区域内有一个称为未折叠蛋白反应的系统，它能检测错误折叠的蛋白质并提高细胞重新折叠它们的能力。作为这个系统的一部分，两种传感器蛋白能检测错误折叠蛋白何时存在，但它们如何做到这一点尚不清楚。有人提出一种名为BiP的伴侣蛋白可能能够激活这些传感器蛋白以启动未折叠蛋白反应。
在这项研究中，卡拉拉等人在实验室利用一种人工设置研究了传感器蛋白和BiP。实验表明，两种传感器蛋白都能与BiP伴侣蛋白的一个称为ATP酶结构域的部分结合。然而，在存在未折叠蛋白的情况下，BiP停止与传感器蛋白相互作用，这可能使传感器蛋白能够激活未折叠蛋白反应。实验还表明，BiP必须与未折叠蛋白结合才能激活未折叠蛋白反应。
卡拉拉等人的研究结果表明，BiP在细胞中具有双重作用：通过与未折叠蛋白结合来感知它们，然后激活触发未折叠蛋白反应的传感器蛋白。
总之，这些结果为细胞如何检测和应对内质网内错误折叠的蛋白质提出了一个新模型，并可能为治疗由蛋白质折叠缺陷引起的疾病提供新的靶点。
DOI: http://dx.doi.org/10.7554/eLife.03522.002
The unfolded protein response (UPR) is an essential cell signaling system that detects the accumulation of misfolded proteins within the endoplasmic reticulum (ER) and initiates a cellular response in order to maintain homeostasis. How cells detect the accumulation of misfolded proteins remains unclear. In this study, we identify a noncanonical interaction between the ATPase domain of the ER chaperone BiP and the luminal domains of the UPR sensors Ire1 and Perk that dissociates when authentic ER unfolded protein CH1 binds to the canonical substrate binding domain of BiP. Unlike the interaction between chaperone and substrates, we found that the interaction between BiP and UPR sensors was unaffected by nucleotides. Thus, we discover that BiP is dual functional UPR sensor, sensing unfolded proteins by canonical binding to substrates and transducing this event to noncanonical, signaling interaction to Ire1 and Perk. Our observations implicate BiP as the key component for detecting ER stress and suggest an allosteric mechanism for UPR induction. DOI: http://dx.doi.org/10.7554/eLife.03522.001 Proteins perform many essential tasks in cells, but to be able to work they first have to correctly fold into a specific three-dimensional shape. Within the cell, many proteins are folded with the help of ‘chaperone’ proteins. If any proteins fold incorrectly, the normal workings of the cell can be disturbed, which may damage the cell. This is more likely to happen if a cell suddenly requires a large number of proteins to be made, which can overwhelm the chaperone proteins. In humans and other eukaryotic organisms, many proteins are folded in a compartment within the cell called the endoplasmic reticulum. Inside this compartment there is a system called the unfolded protein response that detects misfolded proteins and boosts the cell's capacity to re-fold them. As part of this system, two sensor proteins detect when misfolded proteins are present, but it is not clear how they do so. It has been suggested that a chaperone protein called BiP may be able to activate these sensor proteins in order to turn on the unfolded protein response. In this study, Carrara et al. studied the sensor proteins and BiP using an artificial set-up in the laboratory. The experiments show that both of the sensor proteins can bind to a section of the BiP chaperone called the ATPase domain. However, in the presence of an unfolded protein, BiP stopped interacting with the sensor proteins, which could allow the sensor proteins to activate the unfolded protein response. The experiments also show that BiP must bind to the unfolded protein to activate the unfolded protein response. Carrara et al.'s findings suggest that BiP has a dual role in cells: to sense unfolded proteins by binding to them, and then to activate the sensor proteins that trigger the unfolded protein response. Together, these results suggest a new model for how cells detect and respond to misfolded proteins within the endoplasmic reticulum, and may provide new targets for therapies to treat diseases caused by defects in protein folding. DOI: http://dx.doi.org/10.7554/eLife.03522.002