Deciphering the function of intrinsically disordered protein regions in a cellular context

破译细胞环境中本质上无序的蛋白质区域的功能

• 批准号: BB/V003577/1
• 负责人: Andrew Wilson
• 金额: $ 543.74万
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FV003577%2F1
• 关键词: Deciphering; function; intrinsically; disordered; protein

Proteins carry out the chemical reactions necessary for life, and are used as building blocks to assemble key components of cells, giving them shape and structural integrity. During a cell's life cycle, different proteins are produced as needed and then recycled when they have finished their work. To perform their jobs, proteins may themselves undergo chemical modifications, interact with other proteins and adopt a variety of different shapes. Our understanding of protein shape, structure and function has been enormously useful in furthering our molecular understanding of life, leading to successful drug-discovery efforts, methods to improve crop production and other applications with economic and societal benefits. While most proteins adopt a regular 3D shape, it is now accepted that large sections of many proteins termed intrinsically disordered regions (IDRs) have no fixed shape. These "shape-shifting" properties allow the proteins that contain them to perform different jobs at different times and in different parts of the cell by dynamically adopting different shapes in response to their environment. To truly understand the "molecular rules of life", it is therefore necessary to understand how the structures of these "shape-shifters" changes with time, how this influences what other proteins they interact with, how this impacts on the healthy/unhealthy cells life-cycle and ultimately how to control these properties using chemistry. In this research we will study a protein that plays an essential role in the cells life-cycle (Aurora-A) e.g. in cell-division, a process that becomes defective in cancer making it a focus of anticancer drug discovery efforts that have not yet been successful. Aurora-A fulfils different jobs at different times and in different parts of the cell by interacting with multiple different "shape-shifting" proteins. We will use an integrated and state-of-the-art chemical and biological approach to characterise when, where and which interactions between shape-shifting proteins and Aurora-A define its biological function. In doing so, we will identify methods to switch off the interactions between Aurora-A and specific shape-shifters, which can be used to further understand the functional role of these proteins and provide starting points for drug discovery. About a third of human proteins are thought to have an intrinsically disordered region, and our study will help biologists to investigate the properties and roles of these poorly-understood proteins. In the longer term, the ability to manipulate "shape-shifting" proteins will open up a new route to developing medicines to treat a wide range of diseases.

蛋白质进行生命所需的化学反应，并用作组装细胞关键组成部分的构件，从而使它们形成和结构完整性。在细胞的生命周期中，根据需要产生不同的蛋白质，然后在完成工作后进行回收。为了履行工作，蛋白质本身可以进行化学修饰，与其他蛋白质相互作用并采用各种不同形状。我们对蛋白质形状，结构和功能的理解在进一步的分子理解中非常有用，导致成功的药物发现努力，改善作物生产的方法以及具有经济和社会利益的其他应用。尽管大多数蛋白质都采用常规的3D形状，但现在可以接受的是，许多称为本质上无序区域（IDR）的蛋白质的大部分没有固定形状。这些“形状转移”属性允许包含它们的蛋白质在不同时间和单元的不同部分通过动态采用不同形状来响应其环境，从而在细胞的不同部分中执行不同的作业。为了真正理解“生命的分子规则”，有必要了解这些“形状变速器”的结构如何随着时间而变化，这如何影响与他们相互作用的其他蛋白质，这如何影响健康/不健康的细胞生命周期，最终如何使用化学控制这些特性。在这项研究中，我们将研究一种在细胞生命周期（Aurora-A）中起着至关重要作用的蛋白质，例如在细胞划分中，在癌症中变得有缺陷的过程使其成为尚未成功的抗癌药物发现工作的重点。 Aurora-A通过与多种不同的“形状转化”蛋白质相互作用，在不同时间和细胞的不同部分中履行不同的作业。我们将使用综合和最先进的化学和生物学方法来表征何时，何地和哪些相互作用在形状转化蛋白和Aurora-A之间定义其生物学功能。在此过程中，我们将确定关闭Aurora-A与特定变形器之间相互作用的方法，这些方法可用于进一步了解这些蛋白质的功能作用并为药物发现提供起点。人们认为，大约三分之一的人蛋白具有本质上无序的区域，我们的研究将帮助生物学家研究这些不良蛋白质的特性和作用。从长远来看，操纵“形状转化”蛋白的能力将为开发用于治疗多种疾病的药物的新途径。

项目成果

Substitution of Met-38 to Ile in γ-synuclein found in two patients with amyotrophic lateral sclerosis induces aggregation into amyloid.

• DOI: 10.1073/pnas.2309700120
• 发表时间: 2024-01-09
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Aubrey, Liam D.;Ninkina, Natalia;Ulamec, Sabine M.;Abramycheva, Natalia Y.;Vasili, Eftychia;Devine, Oliver M.;Wilkinson, Martin;Mackinnon, Eilish;Limorenko, Galina;Walko, Martin;Muwanga, Sarah;Amadio, Leonardo;Peters, Owen M.;Illarioshkin, Sergey N.;Outeiro, Tiago F.;Ranson, Neil A.;Brockwell, David J.;Buchman, Vladimir L.;Radford, Sheena E.
• 通讯作者: Radford, Sheena E.

a-Helix stabilization by co-operative side chain charge-reinforced interactions to phosphoserine in a basic kinase-substrate motif

通过与碱性激酶底物基序中的磷酸丝氨酸的协同侧链电荷增强相互作用来稳定α螺旋

• DOI: 10.1101/2021.11.27.470016
• 发表时间: 2021
• 作者: Batchelor M

Structural features of the protein kinase domain and targeted binding by small-molecule inhibitors.

• DOI: 10.1016/j.jbc.2022.102247
• 发表时间: 2022-08
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Arter, Chris;Trask, Luke;Ward, Sarah;Yeoh, Sharon;Bayliss, Richard
• 通讯作者: Bayliss, Richard

Understanding ß-strand mediated protein-protein interactions using peptidomimetics: tuning binding affinity of intrinsically disordered sequences by covalent backbone modification

使用肽模拟物了解α链介导的蛋白质-蛋白质相互作用：通过共价主链修饰调节本质无序序列的结合亲和力

• DOI: 10.26434/chemrxiv-2023-xglb4-v3
• 发表时间: 2023
• 作者: Cawood E

Inhibition of Aurora-A/N-Myc protein-protein interaction using peptidomimetics: Understanding the role of peptide cyclization

使用肽模拟物抑制 Aurora-A/N-Myc 蛋白质-蛋白质相互作用：了解肽环化的作用

• DOI: 10.26434/chemrxiv-2023-g7sbd
• 发表时间: 2023
• 作者: Dawber R