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成分的构建块，赋予细胞形状和结构完整性。在细胞的生命周期中，不同的蛋白质根据需要产生，然后在完成工作后被回收。为了完成它们的工作，蛋白质本身可能会经历化学修饰，与其他蛋白质相互作用并采取各种不同的形状。我们对蛋白质形状、结构和功能的理解对于进一步加深我们对生命的分子理解非常有用，从而导致成功的药物发现工作、提高作物产量的方法以及具有经济和社会效益的其他应用。虽然大多数蛋白质采用规则的 3D 形状，但现在人们普遍认为，许多蛋白质的大部分（称为本质无序区域 (IDR)）没有固定的形状。这些“变形”特性使得含有它们的蛋白质能够根据环境动态地采用不同的形状，在不同的时间和细胞的不同部分执行不同的工作。因此，要真正理解“生命的分子规则”，有必要了解这些“变形者”的结构如何随时间变化，这如何影响它们与其他蛋白质相互作用，这如何影响健康/不健康的细胞生命周期以及最终如何使用化学来控制这些特性。在这项研究中，我们将研究一种在细胞生命周期中发挥重要作用的蛋白质（Aurora-A），例如细胞分裂是癌症中出现缺陷的过程，使其成为尚未成功的抗癌药物发现工作的焦点。 Aurora-A 通过与多种不同的“变形”蛋白质相互作用，在不同时间和细胞的不同部位完成不同的工作。我们将使用综合且最先进的化学和生物学方法来表征变形蛋白和 Aurora-A 之间的相互作用何时、何地以及何种相互作用定义了其生物学功能。在此过程中，我们将找到关闭 Aurora-A 和特定变形蛋白之间相互作用的方法，这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。大约三分之一的人类蛋白质被认为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知之甚少的蛋白质的特性和作用。从长远来看，操纵“变形”蛋白质的能力将为开发治疗多种疾病的药物开辟一条新途径。

项目成果

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

在两名肌萎缩侧索硬化症患者中发现，用 β-突触核蛋白中的 Met-38 替换为 Ile 可诱导聚集成淀粉样蛋白

• DOI: http://dx.10.1073/pnas.2309700120
• 发表时间: 2024
• 期刊: Proceedings of the National Academy of Sciences
• 作者: Aubrey L

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: http://dx.10.1002/cbic.202300649
• 发表时间: 2023
• 期刊: a European journal of chemical biology
• 作者: Dawber RS

Peptidomimetic inhibitors of ß-strand mediated protein-protein interactions: tuning binding affinity of intrinsically disordered sequences by covalent backbone modification

β-链介导的蛋白质-蛋白质相互作用的拟肽抑制剂：通过共价主链修饰调节本质上无序序列的结合亲和力

• DOI: http://dx.10.26434/chemrxiv-2023-xglb4-v2
• 发表时间: 2023
• 作者: Cawood E

Proteomic profiling of centrosomes across multiple mammalian cell and tissue types by an affinity capture method

通过亲和捕获方法对多种哺乳动物细胞和组织类型的中心体进行蛋白质组学分析

• DOI: http://dx.10.1016/j.devcel.2023.09.008
• 发表时间: 2023
• 期刊: Developmental Cell
• 影响因子: 11.8
• 作者: Carden S

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: http://dx.10.26434/chemrxiv-2023-xglb4-v3
• 发表时间: 2023
• 作者: Cawood E