Analysis of the structure function and regulation of the Rho1-specific GTP-exchange proteins of the yeast cell wall integrity pathway

构成每一种有机体的细胞都是精细复杂的机器，它们必须执行许多复杂的任务才能维持生命。单细胞真菌，发芽酵母，虽然大小不大，但与我们的细胞分享了许多这些复杂的机制。在科学研究方面，酵母比人类有巨大的优势：它相对容易和廉价地进行研究。对酵母细胞如何工作的许多见解都以这样或那样的形式适用于其他生物体，包括我们自己。酵母菌和人类细胞共有的关键任务之一是能够变得更大而不破裂。另一种是在直接环境中威胁裂解(破裂)的变化中幸存下来，例如温度变化或有害的化学物质。酵母拥有一个主要的系统，它可以感知细胞完整性的各种威胁并做出反应，从而维持细胞的完整性(从而保持细胞的存活)-细胞壁完整性(CWI)途径。这个系统的许多组件与人类共享，但有些不是--后者可能是一种真菌的“阿喀琉斯”之踵，可以开发出药物，导致真菌细胞(许多致病细胞)爆炸(死亡)，而人类细胞不受干扰。CWI途径是值得理解的。此外，CWI途径提出了一些科学难题，挑战了我们对生命系统如何工作的理解。多个信号输入这条通路，而这条通路可以激活各种不同的反应：一条途径如何整合许多输入并‘决定’做出合理的反应？CWI途径的关键调节因子是称为GEF的蛋白质。CWI-GEF似乎有两种不同的味道，似乎在激活该途径方面发挥着不同的作用。在这项提案中，我们试图更好地了解这些全球环境基金是如何管理的，它们在结构和功能上是如何相互区别的，以及这些全球环境基金如何处理信息，以适当的方式影响CWI的产出。我们希望更好地了解复杂而重要的CWI途径是如何调控的。

The cells that make up every organism are delicate and intricate machines that must carry out many complex tasks to stay alive. The single celled fungus, the budding yeast, although modest in size, shares with our cells many of these intricate mechanisms. Yeast has the huge advantage over humans in scientific research: it is relatively easy and cheap to study. Many of the insights gained into how yeast cells work apply, in one form or another, to other organisms, including ourselves. Among the key tasks shared between yeast and human cells is the ability to grow bigger without bursting. Another is to survive changes in the immediate environment that threaten lysis (bursting), such as changes in temperature or nasty chemicals. Yeast possesses one main system that senses a variety of threats to the cell's integrity and responds so as to maintain that integrity (and thereby keep the cell alive) - the cell wall integrity (CWI) pathway. Many of the components of this system are shared with humans but some are not - these latter may be a fungus' Achilles' heel, to which drugs could be developed that cause fungal cells (many pathogenic) to blow up (die) leaving human cells undisturbed. The CWI pathway is worth understanding. In addition, the CWI pathway presents scientific puzzles that challenge our understanding of how living systems work. Multiple signals feed into this pathway, and the pathway can activate a variety of distinct responses: how can one pathway integrate many inputs and 'decide' to make a sensible response? Key regulators of the CWI pathway are proteins called GEFs. CWI-GEFs appear to come in two distinct flavours that appear to perform distinct roles in activating the pathway. In this proposal, we seek to better understand how these GEFs are regulated, how they differ from each other both structurally and functionally and how information is processed by these GEFs to affect CWI outputs in the appropriate way. We hope to better understand how the complex and important CWI pathway is regulated.