Structure and Function of Arr4 in G-protein signalling and Tail-Anchored Membrane Protein Insertion

Arr4 在 G 蛋白信号传导和尾锚定膜蛋白插入中的结构和功能

• 批准号: G0900936/2
• 负责人: Rivka Isaacson
• 金额: $ 19.15万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0900936%2F2
• 关键词: Structure; Function; Arr4; protein; signalling

Since the completion of the Human Genome Project the field of ?genomics? has fast been augmented by its natural successor, ?proteomics?. Solving the proteome, however, is far more daunting than sequencing long lengths of DNA code, since it entails collecting numerous different pieces of information including protein structure, function, interactions, location, modification, regulation, etc. While genes only come in one shape, the famous ?double helix?, proteins fold up their linear sequence into complicated mechanical machines that perform vital functions in the body. Knowing a protein?s sequence is not enough - to understand the way they work and design drugs to improve or disrupt their function we need to know their precise structures. Proteins are too small to see so we measure their shapes in indirect ways by interpreting their behaviour when we bounce X-rays off them, put them in strong magnetic fields or combine numerous low-resolution images from an electron microscope to generate 3-dimensional reconstructions. Each of these techniques has its strengths and weaknesses but a combined approach can yield complementary information filling in the gaps left by using just one of the methods. Research has shown that living a long and healthy life depends on our ability to handle stress both on a human, psychological level and in the way that our proteins respond to toxins, heat and other extreme conditions that interfere with their mechanical functions. Intuitively, ageing seem to have a large genetic component but, while there are many known gene mutations which have a negative effect on lifespan, very few human genes have, so far, been proven to confer longevity. Our bodies are equipped with layers of protein-driven quality-control mechanisms and recycling systems which respond to the daily gamut of stresses to which we subject our cells, through the things we eat and the natural course of living. It is thought that keeping these stress-response proteins in good working order is the key to remaining healthy. Genetics experiments in yeast have connected several previously uncharacterised genes with the regulation of stress resistance. Since we lack structural information on the proteins encoded by these genes we cannot yet understand their modes of action, how they interact with other molecules and how they fit into the complete physiological picture. In this project I propose to use an interdisciplinary biophysics approach, using the techniques described above, to investigate the shapes of some of the proteins involved in helping us to beat stress and solve the jigsaw puzzle of how they fit together. This information will cast light on their mechanisms of action and aid the design of drugs that fit neatly into their reactive crevices to manipulate their mechanisms for disease therapies.

自人类基因组计划完成以来，基因组学领域？FAST是否得到了它的天然继承者蛋白质组学的增强？然而，解决蛋白质组远比对长长的DNA代码进行测序更令人望而生畏，因为它需要收集大量不同的信息，包括蛋白质结构、功能、相互作用、位置、修饰、调节等。虽然基因只有一种形状，但著名的？双螺旋？蛋白质将其线性序列折叠成复杂的机械机器，在人体内执行重要功能。了解一种蛋白质？S的序列是不够的--要了解它们的工作方式，并设计药物来改善或破坏它们的功能，我们需要知道它们的精确结构。蛋白质太小，看不见，所以我们通过解释它们的行为来间接测量它们的形状，当我们从它们身上反射X射线，将它们置于强磁场中，或者结合电子显微镜的大量低分辨率图像来生成三维重建。这些技术各有长处和短处，但组合起来的方法可以产生补充信息，填补仅使用其中一种方法留下的空白。研究表明，健康长寿取决于我们处理压力的能力，无论是在人的心理层面上，还是在我们的蛋白质对毒素、高温和其他干扰其机械功能的极端条件做出反应的方式上。直觉上，衰老似乎有很大的遗传成分，但是，尽管有许多已知的基因突变对寿命有负面影响，但到目前为止，很少有人类基因被证明能延长寿命。我们的身体配备了一层由蛋白质驱动的质量控制机制和循环系统，通过我们吃的东西和自然的生活过程，对我们细胞每天承受的各种压力做出反应。人们认为，保持这些应激反应蛋白处于良好的工作状态是保持健康的关键。在酵母中的遗传学实验已经将几个以前没有特征的基因与抗逆性的调节联系在一起。由于我们缺乏这些基因编码的蛋白质的结构信息，我们还不能理解它们的作用模式，它们如何与其他分子相互作用，以及它们如何适应完整的生理图景。在这个项目中，我建议使用一种跨学科的生物物理学方法，使用上述技术来研究一些蛋白质的形状，这些蛋白质参与帮助我们战胜压力，并解决它们如何组合在一起的拼图游戏。这些信息将揭示它们的作用机制，并帮助设计适合于它们的反应性缝隙的药物，以操纵它们的疾病治疗机制。