Interrogating the molecular basis of aggregation inhibition by molecular chaperones

探究分子伴侣抑制聚集的分子基础

• 批准号: BB/J014346/1
• 负责人: Andrew Baldwin
• 金额: $ 143.54万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Fellowship
• 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%2FJ014346%2F1
• 关键词: Interrogating; molecular; basis; aggregation; inhibition

Proteins are the basic building blocks of all organisms. Over 100,000 different types are responsible for various functions such as moving muscles, digesting food, defending against infections or sending signals between different cells or other parts of the organism. They are all composed of only 20 different building blocks, called amino-acids, arranged in a sequential chain. The exact sequence of the protein is stored in our genes, and can be many hundreds or even thousands of blocks long, and they are produced inside cells as linear chains. In order for protein molecules to function, they must adopt a well defined 3D structure. The process by which the newly synthesised chain finds its 3D structure is called 'protein folding'. A family of proteins known as 'molecular chaperones' are present to facilitate the folding process. Biological organisms need correctly folded proteins in order to function optimally. Rather than always adopting their correct fold, protein chains however have an intrinsic tendency to cluster together and aggregate. The build up of aggregates in tissues together with the loss of function of the aggregating protein can lead to a set of diseases known as 'mis-folding diseases'. A wide range of pathologic human conditions, including neurodegenerative disorders Alzheimer's and Parkinson's diseases as well as type II diabetes and the prion diseases are mis-folding diseases. Such diseases as well as being some of the most feared in old age, place a larger financial burden on society than cancer and heart disease combined. At present, the fundamental roots of mis-folding disease are poorly understood.A particular family of molecular chaperones, the sHSPs are found bound to aggregates removed post-mortem from Alzheimer's disease. Strikingly, they are able to stop proteins from aggregating in vitro, but we know very little about how they are able to do this. sHSPs naturally exist in an aggregated state that makes them intrinsically very hard to study. My proposed research is aimed at determining how they are able to prevent protein aggregation. To do this, I will take advantage of recent technological advances in three state-of-the-art methodologies - nuclear magnetic resonance spectroscopy, mass spectrometry and electron microscopy. Each is able to look at very different aspects of sHSPs, and the combination will make a powerful toolkit that I anticipate will lead to new insights into how sHSPs can prevent protein aggregation. By doing so, I hope to find new ways to look at developing therapeutic treatments for those suffering from mis-folding diseases.The potential for these techniques to provide insights into biological systems is immense. A BBSRC David Phillips Fellowship will enable me bring the necessary expertise to conduct such studies in the UK. The research will be performed at the University of Oxford, a world leading centre of research. I am very excited to have the opportunity to enter this uniquely stimulating environment at the next stage of my career.

蛋白质是所有生物的基本基础。超过100,000种不同类型的原因是各种功能，例如移动肌肉，消化食物，防御感染或在不同细胞或生物体其他部位之间发送信号。它们全部仅由20个不同的构件组成，称为氨基酸，在连续链中排列。蛋白质的确切序列存储在我们的基因中，并且可以长数百甚至数千个块，并且它们以线性链的形式在细胞内产生。为了使蛋白质分子起作用，它们必须采用定义明确的3D结构。新合成链发现其3D结构的过程称为“蛋白质折叠”。存在称为“分子伴侣”的蛋白质家族，以促进折叠过程。生物生物需要正确折叠的蛋白质才能发挥最佳作用。蛋白质链并非总是采用正确的折叠，而是具有将聚集和聚集的固有趋势。组织中的聚集体的积聚以及聚集蛋白功能的功能丧失会导致一组被称为“折叠疾病”的疾病。各种各样的病理性人类疾病，包括神经退行性疾病，阿尔茨海默氏症和帕金森氏症的疾病以及II型糖尿病和prion疾病是错误的疾病。这些疾病也是老年最担心的疾病，比癌症和心脏病加在一起给社会带来更大的经济负担。目前，错误折叠疾病的基本根源很熟悉。一个特定的分子伴侣家族，发现SHSP被认为是从阿尔茨海默氏病后彻底去除的骨料。令人惊讶的是，他们能够阻止蛋白质在体外汇总，但我们对如何做到这一点了解一无所知。 SHSP自然存在于汇总状态，使它们本质上很难研究。我提出的研究旨在确定它们如何能够防止蛋白质聚集。为此，我将利用三种最新方法论的最新技术进步 - 核磁共振光谱，质谱和电子显微镜。每个人都可以研究SHSP的非常不同的方面，并且该组合将制造出一个强大的工具包，我期望这将导致对SHSP如何防止蛋白质聚集的新见解。通过这样做，我希望找到新的方法来研究为患有错误折叠疾病的人开发治疗性治疗方法。这些技术提供对生物系统的见解的潜力是巨大的。 BBSRC戴维·菲利普斯（David Phillips）奖学金将使我带来必要的专业知识，以在英国进行此类研究。该研究将在世界领先的研究中心牛津大学进行。我很高兴有机会在我职业生涯的下一阶段进入这个独特的刺激环境。

项目成果

Quantifying the stabilizing effects of protein-ligand interactions in the gas phase.

• DOI: 10.1038/ncomms9551
• 发表时间: 2015-10-06
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Allison TM;Reading E;Liko I;Baldwin AJ;Laganowsky A;Robinson CV
• 通讯作者: Robinson CV

Dysregulated interactions triggered by a neuropathy-causing mutation in the IPV motif of HSP27

HSP27 IPV 基序中引起神经病变的突变引发的相互作用失调

• DOI: 10.1101/708180
• 发表时间: 2019
• 作者: Alderson T

Investigating the mechanisms of amylolysis of starch granules by solution-state NMR.

• DOI: 10.1021/acs.biomac.5b00190
• 发表时间: 2015-05-11
• 期刊: BIOMACROMOLECULES
• 影响因子: 6.2
• 作者: Baldwin, Andrew J.;Egan, Danielle L.;Warren, Fredrick J.;Barker, Paul D.;Dobson, Christopher M.;Butterworth, Peter J.;Ellis, Peter R.
• 通讯作者: Ellis, Peter R.

Proline isomerization in the C-terminal region of HSP27.

• DOI: 10.1007/s12192-017-0791-z
• 发表时间: 2017-07
• 期刊: Cell stress & chaperones
• 影响因子: 3.8
• 作者: Alderson TR;Benesch JLP;Baldwin AJ
• 通讯作者: Baldwin AJ

A weakened interface in the P182L variant of HSP27 associated with severe Charcot-Marie-Tooth neuropathy causes aberrant binding to interacting proteins.

• DOI: 10.15252/embj.2019103811
• 发表时间: 2021-04-15
• 期刊: The EMBO journal
• 作者: Alderson TR;Adriaenssens E;Asselbergh B;Pritišanac I;Van Lent J;Gastall HY;Wälti MA;Louis JM;Timmerman V;Baldwin AJ;Lp Benesch J
• 通讯作者: Lp Benesch J