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

构成每一个有机体的细胞都是微妙而复杂的机器，它们必须执行许多复杂的任务才能生存。单细胞真菌，芽殖酵母，虽然大小适中，但与我们的细胞共享许多这些复杂的机制。酵母在科学研究中比人类有巨大的优势：它相对容易和便宜的研究。关于酵母细胞如何工作的许多见解以某种形式适用于其他生物，包括我们自己。酵母和人类细胞之间共享的关键任务之一是能够在不破裂的情况下变大。另一个是在威胁溶解（爆裂）的直接环境变化中生存下来，例如温度变化或讨厌的化学物质。酵母有一个主要的系统，可以感知到对细胞完整性的各种威胁，并做出反应，以维持这种完整性（从而保持细胞存活）-细胞壁完整性（CWI）途径。这个系统的许多组成部分与人类共享，但有些不是-后者可能是真菌的“阿喀琉斯之踵”，可以开发药物，导致真菌细胞（许多致病性）爆炸（死亡），而人类细胞不受干扰。CWI路径值得理解。此外，CWI途径提出了科学难题，挑战了我们对生命系统如何工作的理解。多个信号进入这条通路，这条通路可以激活各种不同的反应：一条通路如何整合许多输入并“决定”做出明智的反应？CWI通路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，似乎在激活通路中发挥不同的作用。在本提案中，我们试图更好地了解这些GEF是如何受到监管的，它们在结构和功能上彼此有何不同，以及这些GEF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通路是如何调节的。

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.