Molecular Mechanisms of Sigma Factor Inhibition in a Gene Expression Switch

基因表达开关中 Sigma 因子抑制的分子机制

基本信息

批准号：
BB/N006267/1
负责人：
Rivka Isaacson
金额：
$ 45.14万
依托单位：
King's College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2016
资助国家：
英国
起止时间：
2016 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FN006267%2F1
关键词：
Molecular Mechanisms Sigma Factor Inhibition

项目摘要

We propose to study the way cells can completely transform their identity by activating a 'gene expression switch'. Such transformations are important to naturally maintain health e.g. in embryo development which begins with identical cells which then crucially change into the different types of cells that make up a developed human. Conversely, these transformations can cause harm e.g. when cells become cancerous or pathogens invade hosts. A gene expression switch involves a distinct programme of genetic instruction being deactivated and replaced with an alternative that leads to radical transformation of the cell's nature.In this study my group will examine a particular gene expression switch event in bacterial spore formation which is partially responsible for the persistence of 'hospital superbugs' as spores are a long-lived bacterial form, resistant to cleaning agents and thriving in patients depleted of natural gut microflora.In a gene expression switch there are specific proteins that choreograph genetic instruction in a highly regulated process. We intend to uncover the detailed molecular shapes of some of these proteins using indirect techniques as they are too small to see even using powerful microscopes. We specialise in measuring protein shapes and the way they fit together by producing them artificially in large quantities, with the help of bacteria which act as our 'protein factories'. We then deduce the proteins' molecular structures by processing their behaviour when we bounce X-rays off them or put them in strong magnetic fields. Each of these techniques has its strengths and weaknesses but our combined approach can yield complementary information filling in the gaps left by using just one of the methods. Collaborating with a microbiologist we will feed information into each others' experiments to build up a mechanistic picture of this gene expression switch in bacterial spore formation. For example, if we identify a mutation in one of our proteins that makes it bind more tightly to its partner our collaborator can make the same mutation within bacteria to test whether it has the predicted effect in living systems.By solving this jigsaw puzzle we hope to be in a stronger position to design novel antibiotics to attack the increasing problem of bacterial drug resistance and the project also has longer term implications for understanding gene expression switches in all aspects of health and disease.

我们建议研究细胞通过激活“基因表达开关”来完全改变其身份的方式。这种转变对于自然保持健康很重要，例如在胚胎发育中，始于相同的细胞，然后将其至关重要地变成构成人类的不同类型的细胞。相反，这些转变会导致伤害，例如当细胞变成癌或病原体入侵宿主时。基因表达转换涉及一个独特的遗传学指导程序，并用一种导致细胞性质的根本转化的替代方案取代。在基因表达开关中，有特定的蛋白质在高度调节的过程中编排遗传学指导。我们打算使用间接技术揭示其中一些蛋白质的详细分子形状，因为它们太小，甚至可以看到使用强大的显微镜。我们专注于测量蛋白质形状以及它们通过大量人工产生的蛋白质形状，借助细菌作为我们的“蛋白质工厂”。然后，当我们从X射线弹出X射线或将它们放置在强磁场中时，我们通过处理其行为来推断蛋白质的分子结构。这些技术中的每一个都有其优点和劣势，但是我们的合并方法可以通过仅使用其中一种方法来产生互补的信息填充所留下的空白。与微生物学家合作，我们将向彼此的实验提供信息，以建立细菌孢子形成中这种基因表达开关的机理图片。例如，如果我们确定了一种蛋白质中的突变，使其与其合作者更加紧密地结合我们的合作者可以使细菌中的相同突变测试，以测试它是否在生活系统中具有预测的效果。通过解决这种吉格索难题，我们希望我们希望在较长的疾病中攻击较长的疾病和较长的疾病，以促进了较长的疾病和一般性的变化。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Structure and Interactions of the TPR Domain of Sgt2 with Yeast Chaperones and Ybr137wp.

DOI：
10.3389/fmolb.2017.00068
发表时间：
2017
期刊：
Frontiers in molecular biosciences
影响因子：
5
作者：
Krysztofinska EM;Evans NJ;Thapaliya A;Murray JW;Morgan RML;Martinez-Lumbreras S;Isaacson RL
通讯作者：
Isaacson RL

A novel ClpC adaptor protein that functions in the developing Bacillus subtilis spore

DOI：
10.1101/2024.03.02.583065
发表时间：
2024-03-03
期刊：
bioRxiv
影响因子：
0
作者：
Massoni，Shawn C;Evans，Nicola;Camp，Amy H.
通讯作者：
Camp，Amy H.

A novel RNA polymerase-binding protein that interacts with a sigma-factor docking site.

DOI：
10.1111/mmi.13724
发表时间：
2017-08
期刊：
Molecular microbiology
影响因子：
3.6
作者：
Wang Erickson AF;Deighan P;Chen S;Barrasso K;Garcia CP;Martínez-Lumbreras S;Alfano C;Krysztofinska EM;Thapaliya A;Camp AH;Isaacson RL;Hochschild A;Losick R
通讯作者：
Losick R

Meeting Reports

会议报告