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

自从人类基因组计划完成以来，该领域的？基因组学？很快就被它的自然继承者所增强了蛋白质组学？然而，解决蛋白质组问题比测序长长度的DNA代码要艰巨得多，因为它需要收集许多不同的信息，包括蛋白质结构，功能，相互作用，位置，修饰，调控等。双螺旋？，蛋白质将其线性序列折叠成复杂的机械装置，在体内执行重要功能。了解蛋白质？仅仅知道它们的序列是不够的--要了解它们的工作方式，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。蛋白质太小了，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射线时，把它们放在强磁场中，或者把电子显微镜的许多低分辨率图像联合收割机组合起来产生三维重建。这些技术中的每一种都有其优点和缺点，但一种综合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，健康长寿的生活取决于我们处理压力的能力，无论是在人类心理层面，还是在我们的蛋白质对毒素，热量和其他干扰其机械功能的极端条件的反应方式上。直觉上，衰老似乎有很大的遗传成分，但是，虽然有许多已知的基因突变对寿命有负面影响，但迄今为止，很少有人类基因被证明可以长寿。我们的身体配备了一层层由蛋白质驱动的质量控制机制和回收系统，这些机制和系统通过我们吃的东西和自然的生活过程来应对我们细胞每天承受的各种压力。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。酵母的遗传学实验已经将几个以前未表征的基因与胁迫抗性的调节联系起来。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，以及它们如何融入完整的生理图景。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，研究一些蛋白质的形状，这些蛋白质帮助我们战胜压力，并解决它们如何组合在一起的拼图。这些信息将揭示它们的作用机制，并有助于设计药物，使其巧妙地适应它们的反应裂缝，以操纵它们的疾病治疗机制。

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.