Analysis of the proteostasis network and the thermostability of the proteome

蛋白质稳态网络和蛋白质组热稳定性分析

• 批准号: RGPIN-2016-04248
• 负责人: Mayor, Thibault
• 金额: $ 3.93万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=659108
• 关键词: Analysis; proteostasis; network; thermostability; proteome

Proteins are central components of our cells. Each protein typically folds or adopts a specific three-dimensional structure, also called native state, that is required for the protein to be functional and stable. The protein folding field witnessed tremendous advances in the past 50 years. Notably, it first became clear that the information required for folding is contained within the protein sequence. It was then discovered that folding is often assisted by chaperones that are specialized molecular machines. A major challenge is now to determine how the combination of these two actions leads to a stable proteome, which is the ensemble of all proteins in the cell. While chaperone proteins can be assessed on an individual basis, thanks to a myriad of elegant and sophisticated biochemical assays, it remains difficult to translate this knowledge into the cellular context, in which millions of different proteins cohabit in a very confined environment. We therefore need to develop new systems-wide approaches and tools to determine how the individual chaperones contribute to the overall stability of the proteome. ***In this research program, we propose to employ several complementary approaches to probe which proteins are destabilized upon stresses due to the loss of their three-dimensional structures. Our hypothesis is that destabilization is caused by both intrinsic features that make the proteins more vulnerable and the inability of specific chaperones to prevent their destabilization under the stress situations. To test this idea, we will employ the well characterized Saccharomyces cerevisiae yeast model organism that is less complex and more malleable than human cells. We will first determine which proteins in the proteome are more often destabilized and identify which characteristics are shared among those proteins using computational biology approaches. We will then selectively remove specific chaperones from cells to determine which proteins are further destabilized in these conditions. Our goal is to unveil some of the fundamental rules that govern proteome stability. A better knowledge of how the proteome can be maintained stable has wide implications from our understanding of cellular aging to industrial applications that rely on recombinant protein production. **

蛋白质是我们细胞的核心组成部分。每种蛋白质通常折叠或采用特定的三维结构，也称为天然状态，这是蛋白质具有功能和稳定所必需的。蛋白质折叠领域在过去的50年里取得了巨大的进步。值得注意的是，首先变得清楚的是，折叠所需的信息包含在蛋白质序列中。然后发现折叠通常由分子伴侣辅助，分子伴侣是专门的分子机器。现在的一个主要挑战是确定这两种作用的组合如何导致稳定的蛋白质组，这是细胞中所有蛋白质的集合。虽然伴侣蛋白可以在个体的基础上进行评估，但由于无数优雅而复杂的生化测定，仍然难以将这些知识转化为细胞环境，其中数百万种不同的蛋白质共存于非常有限的环境中。因此，我们需要开发新的系统范围的方法和工具，以确定如何个别分子伴侣有助于蛋白质组的整体稳定性。* 在这项研究计划中，我们建议采用几种互补的方法来探测哪些蛋白质由于失去三维结构而在应力下不稳定。 我们的假设是，不稳定是由两个内在的功能，使蛋白质更脆弱和特定的伴侣蛋白，以防止他们的不稳定的压力情况下的能力。为了验证这一想法，我们将使用特征良好的酿酒酵母模型生物，它比人类细胞更简单，更具可塑性。我们将首先确定蛋白质组中哪些蛋白质更经常不稳定，并使用计算生物学方法确定这些蛋白质之间共享哪些特征。然后，我们将选择性地从细胞中去除特定的分子伴侣，以确定哪些蛋白质在这些条件下进一步不稳定。我们的目标是揭示一些管理蛋白质组稳定性的基本规则。更好地了解蛋白质组如何保持稳定具有广泛的意义，从我们对细胞衰老的理解到依赖重组蛋白生产的工业应用。**