Defining the Mechanisms Underlying Tandem Repeat Protein Functions

定义串联重复蛋白功能的机制

• 批准号: G1002329/1
• 负责人: Laura Itzhaki
• 金额: $ 104.1万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G1002329%2F1
• 关键词: Defining; Mechanisms; Underlying; Tandem; Repeat

Almost 20% of the proteins estimated to be encoded in the human genome contain small structural units repeated multiple times in tandem. Many of these so-called ?tandem repeat proteins? are dys-regulated in cancers and neurodegenerative diseases, two of the biggest medical problems facing our ageing population. They are also implicated in a plethora of other disorders including inflammatory, cardiovascular and respiratory diseases. In order to find new ways to treat these diseases we need to understand the basic mechanisms underlying repeat protein functions. Repeat protein structures are distinct from the more commonly studied ?globular? (spherical-shaped) proteins. The individual modules of a repeat protein stack in a linear fashion to produce highly elongated, superhelical structures, thereby presenting an extended scaffold for molecular recognition. The term ?scaffold? implies a rigid structure; however, as suggested by their Slinky spring-like shapes, it is likely that repeat arrays utilise much more dynamic and elastic modes of action. For example: stretching and contraction motions to regulate the activity of a bound enzyme; reversible nanosprings to operate ion channels; proteins that wrap around their cargoes to transport them into the nucleus of the cell. We propose to assemble a new toolbox of biophysical and single molecule techniques to overcome the challenges specific to these proteins and to address the following key questions about their unique architectures: (1) How do the properties of the individual modules contribute to the behaviour of the array as a whole? What are the motions of a repeat protein under physiological conditions and how do these motions enable it to carry out its function? (2) Repeat proteins have highly symmetrical structures and this means that they behave in a non-homogeneous way; can we quantify and characterize each species within this heterogeneous mix? (3) What are the mechanical properties of repeat proteins and how do they control function? (4) What is the pathway by which a repeat protein recognises its binding partner? (5) Finally, we will exploit what we learn to then ask how protein stability is regulated in the cell ? specifically what features of a protein?s structure determine its susceptibility to the cell?s protein degradation machinery known as the ?proteasome? which removes unwanted proteins once they have carried out their functions? The findings of our research will pave the way for future development of drug-like molecules with which we aim to manipulate the behaviour of tandem repeat proteins for therapeutic benefit.

据估计，在人类基因组中编码的蛋白质中，几乎有20%含有重复多次的小结构单位。这些所谓的串联重复蛋白有很多吗？癌症和神经退行性疾病是我们老龄化人口面临的两个最大的医疗问题。他们还牵涉到许多其他疾病，包括炎症、心血管和呼吸系统疾病。为了找到治疗这些疾病的新方法，我们需要了解重复蛋白功能的基本机制。重复蛋白结构与更普遍研究的球状蛋白结构不同。(球形)蛋白质。重复蛋白质的各个模块以线性方式堆叠，产生高度拉长的超螺旋结构，从而为分子识别提供了一个延伸的支架。术语？脚手架？这意味着一种刚性结构；然而，正如其细长的弹簧形状所暗示的那样，重复阵列很可能使用更动态和更有弹性的动作模式。例如：伸展和收缩运动调节结合酶的活性；可逆纳米弹簧操作离子通道；包裹货物的蛋白质将货物运送到细胞核。我们建议组装一个新的生物物理和单分子技术工具箱，以克服这些蛋白质特有的挑战，并解决关于其独特结构的以下关键问题：(1)单个模块的属性如何影响整个阵列的行为？重复蛋白在生理条件下的运动是什么？这些运动如何使其发挥功能？(2)重复蛋白具有高度对称的结构，这意味着它们的行为方式不同；我们能量化和描述这种异质混合物中的每一种物种吗？(3)重复蛋白的机械性质是什么，它们如何控制功能？(4)重复蛋白识别其结合伙伴的途径是什么？(5)最后，我们将利用所学知识来研究蛋白质稳定性在细胞中是如何调节的？具体地说，一种蛋白质的什么特征？S的结构决定了它对细胞的敏感性？S蛋白质的降解机制被称为？蛋白酶体？一旦它们完成了它们的功能，它会移除不需要的蛋白质吗？我们的研究结果将为未来开发类药物分子铺平道路，我们的目标是利用这些分子来操纵串联重复蛋白的行为，从而达到治疗的目的。