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Nature's solution to the iron problem: Mechanisms of iron management in ferritins

铁问题的自然解决方案：铁蛋白中铁的管理机制

基本信息

批准号：
BB/I021884/1
负责人：
Nicolas Le Brun
金额：
$ 43.18万
依托单位：
University of East Anglia
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2012
资助国家：
英国
起止时间：
2012 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FI021884%2F1
关键词：
Nature solution iron problem Mechanisms

项目摘要

Iron is essential for virtually all forms of life, playing central roles in many of the reactions on which life depends. Although this metal is highly abundant in the earth's crust, it is largely 'locked up' in minerals that are highly insoluble and this severely limits its availability to living organisms. The scarcity of iron has led to the evolution in microbes of many ingenious mechanisms to obtain sufficient quantities to sustain growth. These include the secretion and re-absorption of small organic molecules that can bind iron very tightly and therefore hoover up what iron there is. Pathogenic bacteria can effectively steal iron from iron-containing proteins in their hosts, and the success of such mechanisms is a key determinant of whether or not a successful infection is established. Another important aspect of how cells overcome the iron problem, is their ability to store iron. This is achieved through a remarkable family of proteins known as ferritins. These can be thought of as being football-like molecules with a hollow centre, inside which thousands of iron atoms can be stored in the form of an iron mineral - one that would form insoluble precipititates were it not for the solubilising effect of the protein coat. The storage of iron serves two important functions. Firstly, it enables microbes to draw on reserves when iron in the immediate environment becomes particularly low, and secondly, it overcomes the potential toxicity of iron that results from the very properties that make it useful to life: without proper control, iron can lead to the generation of reactive oxygen species that can cause severe cellular damage. In this research we propose to better understand how two particular ferritins from two very different microbes take up iron and orchestrate the deposition of their iron mineral cargo, and how they subsequently release it. One of these is from the organism Escherichia coli - a bacterium that has for decades been a workhorse for understanding cellular processes, but which can also be pathogenic. The other ferritin is one that was very recently identified in phytoplankton. These organisms are responsible for a large proportion of the primary production of organic molecules from carbon dioxide in the oceans. Furthermore, they also form spectacular blooms in areas of temporary nutrient sufficiency. In many areas, the growth limiting nutrient is iron and it is now known that the presence of ferritin in these phytoplankton is crucial for their ability to utilise temporarily available iron. This research will lead to a significant advance in our understanding of iron cycling processes and of the relationship between structural and functional properties of ferritins. This will also have more general impact in understanding the reactivities of iron proteins and in protein-driven biomineralisation processes.

铁对几乎所有形式的生命都是必不可少的，在生命所依赖的许多反应中起着核心作用。虽然这种金属在地壳中含量很高，但它大部分被“锁”在高度不溶的矿物质中，这严重限制了它对生物体的可用性。铁的缺乏导致微生物进化出许多巧妙的机制，以获得足够的量来维持生长。这包括小有机分子的分泌和再吸收，这些小有机分子可以非常紧密地结合铁，从而吸收铁。致病菌可以有效地从宿主体内含铁蛋白中窃取铁，这种机制的成功与否是感染能否成功建立的关键决定因素。细胞如何克服缺铁问题的另一个重要方面是它们储存铁的能力。这是通过铁蛋白家族来实现的。它们可以被认为是像足球一样的分子，中间有一个中空的中心，里面有成千上万的铁原子可以以铁矿物的形式储存——如果没有蛋白质外壳的溶解作用，这种铁原子就会形成不可溶的沉淀物。铁的储存有两个重要功能。首先，当周围环境中的铁含量特别低时，它使微生物能够利用储备；其次，它克服了铁的潜在毒性，这种毒性是由铁对生命有用的特性造成的：如果没有适当的控制，铁会导致活性氧的产生，从而导致严重的细胞损伤。在这项研究中，我们建议更好地了解来自两种非常不同的微生物的两种特定铁蛋白如何吸收铁并协调其铁矿货物的沉积，以及它们随后如何释放铁。其中之一来自大肠杆菌——几十年来，这种细菌一直是理解细胞过程的主力，但它也可能是致病性的。另一种铁蛋白是最近在浮游植物中发现的。这些生物负责海洋中二氧化碳有机分子的大部分初级生产。此外，它们还会在暂时营养充足的地区形成壮观的花朵。在许多地区，限制生长的营养物质是铁，现在人们知道，这些浮游植物体内铁蛋白的存在对它们利用暂时可用铁的能力至关重要。这项研究将使我们对铁循环过程以及铁蛋白的结构和功能特性之间的关系的理解取得重大进展。这也将对理解铁蛋白的反应性和蛋白质驱动的生物矿化过程产生更广泛的影响。