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

HSP90-R2TP-TTT 分子伴侣复合物激活 TOR 的结构基础

• 批准号: BB/R01678X/1
• 负责人: Laurence Pearl
• 金额: $ 97.25万
• 依托单位: University of Sussex
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FR01678X%2F1
• 关键词: Structural; basis; TOR; activation; HSP90

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.

细胞的正常和健康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，每个蛋白质分子的形状和作用机制都由DNA中编码的遗传信息定义。组装这些纳米机器，需要专门的纳米机器的帮助，称为分子伴侣，它会照顾组成蛋白质，直到它们被需要，并确保正确的组件被组合成最终的工作纳米机器。其中最重要的分子伴侣之一是称为HSP 90。它负责协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递信息。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，糖尿病和不健康的衰老等疾病有关。我们希望了解HSP 90伴侣如何与其他两个纳米机器R2 TP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率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，找出哪些部分对活动至关重要，以及不同纳米机器的哪些部分在组装过程中相互接触。这些信息将帮助我们了解TOR是如何被这些分子伴侣调节的，并将指出用新药控制TOR活性的新方法。

项目成果

Structure of the TELO2-TTI1-TTI2 complex and its function in TOR recruitment to the R2TP chaperone.

• DOI: 10.1016/j.celrep.2021.109317
• 发表时间: 2021-07-06
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Pal M;Muñoz-Hernandez H;Bjorklund D;Zhou L;Degliesposti G;Skehel JM;Hesketh EL;Thompson RF;Pearl LH;Llorca O;Prodromou C
• 通讯作者: Prodromou C