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Sequential assembly of the bacterial flagellum outside the living cell

细菌鞭毛在活细胞外的顺序组装

基本信息

批准号：
BB/M007197/1
负责人：
Gillian Fraser
金额：
$ 43.11万
依托单位：
University of Cambridge
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2015
资助国家：
英国
起止时间：
2015 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FM007197%2F1
关键词：
Sequential assembly bacterial flagellum outside

项目摘要

Bacteria are the smallest of all cells and live lives of feast and famine. To survive they must sense and adapt quickly to their ever-changing external environment. To find food and escape danger, many bacteria build on their cell surface long rotating propellers called flagella, which allow them to move rapidly over surfaces and through liquids. Motility driven by surface flagella is important to colonization of rich niches in human, animal and plant hosts by disease-causing (pathogenic) bacteria. Both biologists and physicists have long found flagella fascinating as they illustrate beautifully how complex biological structures, comprising a number of discrete substructures, are assembled meticulously from thousands of distinct protein subunit building blocks to operate as tiny rotary 'nanomachines' outside the living cell. They have even been claimed by creationists, who cite their exquisite structural-functional complexity as evidence against slow evolution! Remarkably, the flagellum is fundamentally self-assembling and this feat of nanoscale construction is rendered even more astonishing by the fact that each new subunit building block, made inside the cell, must travel up to 20 times the length of the cell through a narrow central channel in the growing flagellum to incorporate at its tip far outside the cell. Until recently, the mystery was how the subunit building blocks travel through the long channeI where there is no discernable energy source to propel them. We have discovered that this is powered by the subunits themselves, as they link in a chain that is pulled to the flagellum tip. We now propose to use molecular, biochemical and structural biology approaches to build on this completely new and unanticipated chain mechanism for flagellum growth to address a major open question concerning the assembly of the complex flagellum structure: how are the many different subunit building blocks incorporated into the flagellum in the correct sequence? The proposed work has the potential to reveal new aspects of flagellum assembly and provide a deeper understanding of how multi-component biological machines can be assembled beyond the surface of living cells. Findings from this work could, ultimately, be exploited to discover new molecules to block the function of such machines, leading to the development of new drug therapies to treat bacterial infections.

细菌是所有细胞中最小的一种，它们过着饱餐和饥饿的生活。为了生存，它们必须迅速感知和适应不断变化的外部环境。为了寻找食物和逃避危险，许多细菌在其细胞表面建立了称为鞭毛的长旋转螺旋桨，这使它们能够在表面和液体中快速移动。由表面鞭毛驱动的运动对于致病细菌在人类、动物和植物宿主中的丰富小生境的定殖是重要的。生物学家和物理学家长期以来都发现鞭毛很吸引人，因为它们美丽地说明了复杂的生物结构，包括许多离散的子结构，是如何从数千个不同的蛋白质亚基构建模块中精心组装起来的，作为活细胞外的微小旋转“纳米机器”。它们甚至被神创论者所宣称，他们引用它们精致的结构-功能复杂性作为反对缓慢进化的证据！值得注意的是，鞭毛基本上是自组装的，而这种纳米级结构的壮举更令人惊讶的是，细胞内产生的每个新的亚基构建块必须通过生长中的鞭毛中的狭窄中央通道行进到细胞长度的20倍，才能在远离细胞的尖端合并。直到最近，这个谜团还是亚基构建块如何在没有可识别的能量源推动它们的情况下通过长长的通道。我们已经发现，这是由亚基本身提供动力的，因为它们连接在一条链中，被拉到鞭毛尖端。我们现在建议使用分子，生物化学和结构生物学的方法，建立在这个全新的和意想不到的链机制鞭毛生长，以解决一个重大的开放问题，关于组装的复杂鞭毛结构：如何将许多不同的亚基构建块纳入鞭毛的正确序列？这项工作有可能揭示鞭毛组装的新方面，并更深入地了解多组分生物机器如何在活细胞表面之外组装。这项工作的发现最终可以用来发现新的分子来阻止这些机器的功能，从而开发出新的药物疗法来治疗细菌感染。