Structural basis for TOR activation by the HSP90-R2TP-TTT molecular chaperone complex

细胞的正常和健康的功能是由大量的纳米分子机器控制的，这些机器由蛋白质分子组成，每个分子的形状和作用机制都由DNA中编码的遗传信息决定。组装许多这样的纳米机器需要被称为伴侣的特殊纳米机器的帮助，这些机器负责照顾组成蛋白质的成分，直到它们被需要，并确保正确的成分被组合到最终工作的纳米机器中。其中最重要的伴侣之一被称为HSP90。它负责帮助组装许多纳米机器，这些机器监测细胞的健康状况，并在细胞之间和细胞内传输信息。其中之一-TOR-对于监测细胞的营养健康特别重要，TOR的过度活动或缺陷与癌症、糖尿病和不健康衰老等疾病有关。我们希望了解HSP90伴侣如何与另外两台纳米机器R2TP和TTT合作，促进基于TOR的纳米机器的组装。为了做到这一点，我们将使用非常高的放大电子显微镜和强烈的X射线束，来观察所涉及的不同纳米机器的原子结构，找出哪些部件对活动至关重要，以及不同纳米机器的哪些部件在组装过程中相互接触。这些信息将帮助我们理解TOR是如何被这些伴侣调节的，并将为控制新药TOR活性的新方法指明方向。

The normal and healthy functioning of cells is controlled by a plethora of nano-molecuiar machines which are made up of protein molecules, each of whose shape and mechanism of action is defined by the genetic information encoded in DNA. Assembly of many of these nano-machines, requires help from specialised nano-machines called chaperones, which look after component proteins until they are required, and ensure that the correct components are combined into the final working nano-machine.One of the most important of these chaperones is called HSP90. This is responsible for assisting the assembly of many of the nano-machines that monitor the health of the cell and transmit messages between and within cells. One of these - TOR - is particularly important for monitoring the nutritional health of the cell, and over-activity or defects in TOR are associated with diseases such as cancer, diabetes and unhealthy ageing.We wish to understand how the HSP90 chaperone, with the collaboration of two other nano-machines R2TP and TTT, facilitates the assembly of nano-machines based around TOR. To do this we will use very high magnification electron microscopes and intense X-ray beams, to look at the atomic structures of the different nano-machines involved, to work out which parts are critical for activity, and which parts of different nano-machines make contact with each other during the assembly process. This information will help us understand how TOR is regulated by these chaperones, and will point at new ways of controlling TOR activity with novel drugs.