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Folding and insertion of a bacterial inner-membrane protein

细菌内膜蛋白的折叠和插入

基本信息

批准号：
BB/G011281/1
负责人：
Cheryl Woolhead
金额：
$ 47.89万
依托单位：
University of Glasgow
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2010
资助国家：
英国
起止时间：
2010 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FG011281%2F1
关键词：
Folding insertion bacterial inner membrane

项目摘要

All cells are surrounded by lipid based membranes which act to separate the cells internal contents from the extra cellular environment. Proteins embedded in these membranes act as gate keepers, controlling the flow of materials, information and energy between cells. When these proteins are functioning normally they are vital to the health of the cell, however specific defects in these proteins are associated with many known disease states. As such it is not surprising that membrane proteins are a major target for drug development and approximately 60% of all drugs on the market today act against these proteins. Although approximately one third of the genome of any organism encodes membrane proteins, relative to soluble proteins, very little information is know about their structures and functions. In fact less than 1% of all high resolution structures solved to date are those of membrane proteins. The elucidation of more information about how these proteins are synthesized and what factors determine their accurate targeting and insertion into the correct membrane will greatly aid our understanding of these proteins and will yield new information about their structure/function relationship, which may help in the design of better more effective drugs. This proposal is directed towards understanding the folding of a membrane protein from the earliest stage of its synthesis, when it is still contained within the ribosome, until it is fully integrated into its destination membrane. The more specific aims of the study are: 1. To study the folding of a bacterial membrane protein as it is being made by the ribosome. The time and location of the secondary structure formation will be critical to its interaction with targeting and insertion machinery. 2. To investigate which other proteins either within the ribosome or the cell cytoplasm aid the newly synthesized protein in travelling to the membrane. 3. To study the structure of the membrane insertase to see how it functions to facilitate protein insertion. 4. To investigate changes in the structure of the membrane protein as it comes into contact with its target membrane and is ultimately inserted

所有细胞都被脂质基膜包围，其作用是将细胞内部内容物与细胞外环境分开。嵌入这些膜中的蛋白质充当守门人，控制细胞之间的物质，信息和能量的流动。当这些蛋白质正常发挥作用时，它们对细胞的健康至关重要，然而这些蛋白质中的特定缺陷与许多已知的疾病状态有关。因此，膜蛋白是药物开发的主要目标并不奇怪，目前市场上大约60%的药物都是针对这些蛋白质的。尽管任何生物体的基因组的大约三分之一编码膜蛋白，相对于可溶性蛋白，对它们的结构和功能的了解很少。事实上，到目前为止，只有不到1%的高分辨率结构是膜蛋白。这些蛋白质是如何合成的，以及哪些因素决定了它们的准确靶向和插入正确的膜的更多信息的阐明将大大有助于我们对这些蛋白质的理解，并将产生关于它们的结构/功能关系的新信息，这可能有助于设计更好更有效的药物。该建议旨在理解膜蛋白从其合成的最早阶段（当其仍包含在核糖体中时）直到其完全整合到其目的膜中的折叠。本研究的具体目标是：1。研究细菌膜蛋白在核糖体作用下的折叠过程。二级结构形成的时间和位置对其与靶向和插入机制的相互作用至关重要。2.研究核糖体或细胞质中的哪些其他蛋白质有助于新合成的蛋白质进入细胞膜。3.研究膜插入酶的结构，以了解它如何促进蛋白质插入。4.研究膜蛋白与其靶膜接触并最终插入时膜蛋白结构的变化