Defining the Mechanisms Underlying Tandem Repeat Protein Functions

据估计，人类基因组中编码的蛋白质中有近20%含有串联重复多次的小结构单元。许多所谓的？串联重复序列蛋白？在癌症和神经退行性疾病中失调，这是我们老龄化人口面临的两个最大的医疗问题。它们还涉及大量其他疾病，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。重复的蛋白质结构不同于更常见的研究？球状的？（球形）蛋白质。重复蛋白质的各个模块以线性方式堆叠，以产生高度伸长的超螺旋结构，从而为分子识别提供延伸的支架。术语？脚手架？意味着刚性结构;然而，正如它们的弹簧状形状所暗示的，重复阵列可能利用更动态和弹性的作用模式。举例来说：拉伸和收缩运动来调节结合酶的活性;可逆的纳米弹簧来操作离子通道;蛋白质包裹它们的货物，将它们运送到细胞核中。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，并解决以下关键问题，其独特的架构：（1）如何做的属性的各个模块有助于作为一个整体的阵列的行为？在生理条件下，重复蛋白质的运动是什么？这些运动如何使它发挥功能？(2)重复蛋白质具有高度对称的结构，这意味着它们以非均匀的方式表现;我们可以量化和表征这种异质混合物中的每个物种吗？(3)重复蛋白质的机械特性是什么？它们如何控制功能？(4)重复蛋白识别其结合伴侣的途径是什么？(5)最后，我们将利用我们所了解的，然后问蛋白质的稳定性是如何在细胞中调节？蛋白质的具体特征是什么？的结构决定了它对细胞的敏感性？的蛋白质降解机制称为？蛋白酶体？一旦它们完成了它们的功能，就可以去除不需要的蛋白质？我们的研究结果将为未来开发药物样分子铺平道路，我们的目标是操纵串联重复蛋白的行为以获得治疗益处。

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.