Mechanisms of membrane pore formation

膜孔形成机制

• 批准号: BB/D008573/1
• 负责人: Helen Saibil
• 金额: $ 64.57万
• 依托单位: Birkbeck, University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2006
• 资助国家: 英国
• 起止时间: 2006 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FD008573%2F1
• 关键词: Mechanisms; membrane; pore; formation

The amino acid sequence of a protein, determined by its genetic code, defines the structure and function of the protein. Usually, the native (correct) protein structure is unique, and is the most stable form for that particular protein. There are two distinct environments in which proteins are stable: water-soluble proteins are found in solution in cells and tissues, but membrane proteins are found in the oil-like layers of cellular membranes. Soluble proteins are much easier to work with and are much better understood than membrane proteins. Although membrane proteins play important roles in many key cellular functions such as detection and response to signals from the environment, communication between cells, and uptake of nutrients, only a tiny number of three-dimensional structures of membrane proteins are known in comparison to those of soluble proteins. The surface properties of soluble and membrane proteins are very different. A very interesting class of proteins break the general rule that proteins are either water-soluble or inserted into membranes. The bacterial toxins and certain proteins of the immune system are synthesised as individual, water-soluble proteins but in the course of their function, they assemble into rings that penetrate cell membranes and puncture holes through their target membranes. In the case of bacterial toxins, the role of such toxins is to release nutrients for the bacteria, incidentally killing the host cell. In the immune system, pore forming proteins are secreted in the course of immune surveillance when infected or cancerous cells are detected, in order to kill them. Thus, pore-forming proteins have evolved as part of the 'armaments race' between organisms and their pathogens. In this project, we are studying the structures of the pores formed by the bacterial toxin pneumolysin, an important factor in pneumonia and other diseases, and also by the immune system protein perforin, essential for the immune response to maintain the health of the organism. The pores are bound to model membranes, and we can study them by recording images of rapidly frozen suspensions of these membranes in an electron microscope. With suitable computer image processing we can determine their three-dimensional structures, which will give us an understanding of how these proteins change their shape and properties so dramatically, and how the membrane is punctured.

由其遗传密码决定的蛋白质的氨基酸序列定义了蛋白质的结构和功能。通常，天然（正确）蛋白质结构是独特的，并且是该特定蛋白质最稳定的形式。在两个不同的环境中，蛋白质是稳定的：在细胞和组织中的溶液中发现了水溶性蛋白，但是在细胞膜的油状层中发现了膜蛋白。可溶性蛋白质更容易使用，并且比膜蛋白更好地理解。尽管膜蛋白在许多关键的细胞功能中起着重要作用，例如检测和对来自环境的信号，细胞之间的通信和养分吸收的响应，但与膜蛋白的三维三维结构相比，与之相比仅与之相比。可溶性蛋白。可溶性和膜蛋白的表面特性非常不同。一类非常有趣的蛋白质打破了一般规则，即蛋白质要么是水溶性的，要么插入膜中。细菌毒素和免疫系统的某些蛋白质被合成为个体，水溶性蛋白，但在其功能过程中，它们将其组装成渗透细胞膜并通过靶膜穿刺孔的环。在细菌毒素的情况下，这种毒素的作用是释放细菌的营养素，偶然杀死宿主细胞。在免疫系统中，当检测到感染或癌细胞时，在免疫监测过程中分泌形成孔的蛋白质，以杀死它们。因此，形成孔隙的蛋白已作为生物体与病原体之间的“武器种族”的一部分进化。在这个项目中，我们正在研究细菌毒素肺炎蛋白（肺炎和其他疾病的重要因素，也是免疫系统蛋白穿孔的重要因素，这对于维持生物体健康的免疫反应至关重要。这些孔与膜建模，我们可以通过记录电子显微镜中这些膜的悬浮液的快速冷冻悬浮液的图像来研究它们。通过合适的计算机图像处理，我们可以确定它们的三维结构，这将使我们了解这些蛋白如何如此急剧地改变其形状和特性，以及如何刺穿膜。

项目成果

Intrinsically disordered protein threads through the bacterial outer-membrane porin OmpF.

• DOI: 10.1126/science.1237864
• 发表时间: 2013-06-28
• 期刊: Science (New York, N.Y.)
• 作者: Housden NG;Hopper JT;Lukoyanova N;Rodriguez-Larrea D;Wojdyla JA;Klein A;Kaminska R;Bayley H;Saibil HR;Robinson CV;Kleanthous C
• 通讯作者: Kleanthous C