Understanding the molecular mechanism of iron sulfur cluster biogenesis
了解铁硫簇生物发生的分子机制
基本信息
- 批准号:BB/S001832/1
- 负责人:
- 金额:$ 43.76万
- 依托单位:
- 依托单位国家:英国
- 项目类别:Research Grant
- 财政年份:2018
- 资助国家:英国
- 起止时间:2018 至 无数据
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Cells work thanks to 'fuel' which is absorbed from the environment. Small molecules made of iron and sulfur (called iron-sulfur clusters), which are attached to proteins, play key roles in the process by which energy stored in food (or light) is converted to a useable form in respiration (and photosynthesis). These iron-sulfur cluster molecules do not form spontaneously, however, and need to be assembled directly in the cell. This process poses an important problem: iron and sulfur are elements which are essential for life but, at the same time, also intrinsically toxic. Nature has thus engineered very complex and tightly regulated molecular machines, evolutionarily conserved across the kingdoms of life and all discovered within the past 15-20 years, to synthesise iron-sulfur cluster molecules and attach them to proteins in a very orderly and regulated way, making sure to minimise waste and the potential for harm to the cell. The importance of these machines for human life is illustrated by the number of diseases which increasingly appear to be linked to impairment of iron-sulfur cluster proteins and their formation. When any of the parts of these machines break down, disease occurs.We have in the past focused a major part of our research efforts on understanding this important problem and on iron-sulfur cluster biochemistry in general, resulting in several seminal papers which have substantially advanced the field. An increasingly sophisticated understanding of the iron-sulfur cluster assembly machines of humans and bacteria is slowly emerging. However, we are still far from having the full picture, and understanding the steps involved in formation of the cluster is limited by the lack of detailed information on the precise sequence of events and nature of intermediates, which interactions are formed and how they regulate this process.We propose a project aimed at understanding in unprecedented detail the mechanism by which the cluster is formed from iron and cysteine (the source of sulfur). Specifically, the experimental programme will address crucial outstanding questions including: the precise mechanism by which iron and sulfur are delivered, the steps that lead to cluster formation, the precise role of frataxin (a protein linked to the genetic disease Friedreich's ataxia in humans and know to be an important component of iron-sulfur cluster assembly), the process of cluster transfer to carrier and/or target proteins that require a cluster for function. We will use a powerful combination of different biophysical, structural and biochemical techniques which will allow us to reconstruct the whole mechanism. We have already developed all the necessary know-how and expertise in all the proposed techniques. Of particular novelty is the application of mass spectrometry to iron-sulfur cluster proteins under conditions in which the protein remains folded. This has the tremendous advantage that iron-sulfur clusters, and fragments thereof, remain bound to the folded protein so that by measuring accurately the mass of the protein with cofactors bound, the identity of the cofactor can be deduced. This has recently provided unprecedented insight into iron-sulfur cluster conversion and degradation in other systems, and is an extremely promising, novel methodology to elucidate the steps of de novo cluster assembly.Overall, our research has important implications for our basic comprehension of these cellular processes in bacteria, which is to a large extent conserved in humans, with potential longer term medical benefits.
细胞工作要归功于从环境中吸收的“燃料”。由铁和硫组成的小分子(称为铁硫簇)附着在蛋白质上,在将储存在食物(或光)中的能量转化为呼吸(和光合作用)中可用的形式的过程中发挥关键作用。然而,这些铁-硫簇分子不是自发形成的,需要直接在细胞中组装。这一过程带来了一个重要的问题:铁和硫是生命所必需的元素,但同时也具有本质上的毒性。因此,大自然设计了非常复杂且受到严格控制的分子机器,在进化上保守地存在于生命王国中,所有这些机器都是在过去15-20年内被发现的,以合成铁-硫簇分子并以非常有序和受监管的方式将它们连接到蛋白质上,确保将浪费和对细胞的潜在损害降至最低。这些机器对人类生活的重要性从疾病的数量上得到了说明,这些疾病越来越多地似乎与铁-硫簇蛋白及其形成的损害有关。当这些机器的任何一个部件发生故障时,疾病就会发生。过去,我们将主要研究努力集中在了解这个重要问题和一般的铁-硫团簇生物化学上,从而产生了几篇开创性的论文,大大推动了该领域的发展。对人类和细菌的铁-硫簇组装机器的日益复杂的理解正在慢慢形成。然而,我们仍然远未有完整的图景,由于缺乏关于事件的确切顺序和中间体的性质、哪些相互作用是形成的以及它们如何调节这一过程的详细信息,我们对形成该簇的步骤的了解受到限制。我们提出了一个项目,旨在以前所未有的详细方式了解该簇是由铁和半胱氨酸(硫的来源)形成的机制。具体而言,实验方案将解决尚未解决的关键问题,包括:铁和硫输送的确切机制,导致簇形成的步骤,Frataxin(一种与人类遗传病Friedreich‘s共济失调有关的蛋白质,已知是铁硫簇组装的重要组成部分)的确切作用,簇转移到载体和/或需要簇才能发挥功能的靶蛋白的过程。我们将使用不同的生物物理、结构和生化技术的强大组合,这将使我们能够重建整个机制。我们已经在所有拟议的技术中开发了所有必要的技术诀窍和专业知识。特别新奇的是,在蛋白质保持折叠的条件下,将质谱学应用于铁-硫簇蛋白质。这有一个巨大的优点,即铁-硫簇及其片段仍然与折叠的蛋白质结合,因此通过准确地测量结合了辅因子的蛋白质的质量,可以推断辅因子的同一性。这提供了对其他系统中铁-硫团簇转化和降解的前所未有的洞察力,是一种非常有前途的新方法,可以阐明从头组装簇的步骤。总体而言,我们的研究对我们基本理解细菌中的这些细胞过程具有重要意义,这些过程在很大程度上保存在人类身上,具有潜在的长期医学益处。
项目成果
期刊论文数量(9)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Adding a temporal dimension to the study of Friedreich's ataxia: the effect of frataxin overexpression in a human cell model.
- DOI:10.1242/dmm.032706
- 发表时间:2018-06-25
- 期刊:
- 影响因子:4.3
- 作者:Vannocci T;Notario Manzano R;Beccalli O;Bettegazzi B;Grohovaz F;Cinque G;de Riso A;Quaroni L;Codazzi F;Pastore A
- 通讯作者:Pastore A
A Guide to Native Mass Spectrometry to determine complex interactomes of molecular machines.
天然质谱指南,以确定分子机的复杂相互作用。
- DOI:10.1111/febs.15281
- 发表时间:2020-06
- 期刊:
- 影响因子:0
- 作者:Puglisi R;Boeri Erba E;Pastore A
- 通讯作者:Pastore A
Chemical shift assignment of a thermophile frataxin.
- DOI:10.1007/s12104-017-9790-3
- 发表时间:2018-04
- 期刊:
- 影响因子:0.9
- 作者:Rasheed M;Yan R;Kelly G;Pastore A
- 通讯作者:Pastore A
The role of chaperones in iron-sulfur cluster biogenesis.
伴侣在铁硫簇生物发生中的作用。
- DOI:10.1002/1873-3468.13245
- 发表时间:2018-12
- 期刊:
- 影响因子:3.5
- 作者:Puglisi R;Pastore A
- 通讯作者:Pastore A
The role of oxidative stress in Friedreich's ataxia.
- DOI:10.1002/1873-3468.12928
- 发表时间:2018-03
- 期刊:
- 影响因子:3.5
- 作者:Lupoli F;Vannocci T;Longo G;Niccolai N;Pastore A
- 通讯作者:Pastore A
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Annalisa Pastore其他文献
Letter to the Editor: Assignment of the 1H, 13C, and 15N Resonances of Holo Isoform 4 of Lethocerus Indicus Troponin C
- DOI:
10.1023/b:jnmr.0000032558.31512.c8 - 发表时间:
2004-07-01 - 期刊:
- 影响因子:1.900
- 作者:
GianFelice De Nicola;Rolf Biekofsky;Geoff Kelly;Bogos Agianian;Feng Qiu;Belinda Bullard;Annalisa Pastore - 通讯作者:
Annalisa Pastore
Regulating Insect Flight Muscle with Troponin
- DOI:
10.1016/j.bpj.2011.11.1261 - 发表时间:
2012-01-31 - 期刊:
- 影响因子:
- 作者:
Anja R. Katzemich;Gian-Felice De Nicola;Kevin R. Leonard;Annalisa Pastore;Belinda Bullard - 通讯作者:
Belinda Bullard
The C-terminal domain of alpha-spectrin is structurally related to calmodulin.
α-血影蛋白的 C 末端结构域在结构上与钙调蛋白相关。
- DOI:
- 发表时间:
1995 - 期刊:
- 影响因子:0
- 作者:
Gilles Travé;Annalisa Pastore;Marko Hyvönen;M. Saraste - 通讯作者:
M. Saraste
Troponin Isoforms and Stretch-activation of Insect Flight Muscle
- DOI:
10.1016/j.bpj.2008.12.1140 - 发表时间:
2009-02-01 - 期刊:
- 影响因子:
- 作者:
Uros Krzic;Gian De Nicola;Vladimir Rybin;Annalisa Pastore;Kevin Leonard;Wolfgang Linke;Belinda Bullard - 通讯作者:
Belinda Bullard
A survey of the primary structure and the interspecies conservation of I-band titin's elastic elements in vertebrates.
脊椎动物I带肌联弹性元件的一级结构和种间保守性调查。
- DOI:
- 发表时间:
1998 - 期刊:
- 影响因子:3
- 作者:
C. Witt;N. Olivieri;T. Centner;B. Kolmerer;Stefania Millevoi;Jane Morell;D. Labeit;Siegfried Labeit;Harald Jockusch;Annalisa Pastore - 通讯作者:
Annalisa Pastore
Annalisa Pastore的其他文献
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{{ truncateString('Annalisa Pastore', 18)}}的其他基金
The mechanism of stretch activation in muscle: a multidisciplinary approach
肌肉拉伸激活机制:多学科方法
- 批准号:
BB/M006824/1 - 财政年份:2015
- 资助金额:
$ 43.76万 - 项目类别:
Research Grant
Structural studies of proteins involved in neurodegenerative and muscular diseases 2
参与神经退行性疾病和肌肉疾病的蛋白质的结构研究 2
- 批准号:
MC_PC_13054 - 财政年份:2013
- 资助金额:
$ 43.76万 - 项目类别:
Intramural
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上皮细胞黏着结构半桥粒在热激保护中的作用机制研究
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