Hsp40 and Stress Protection

Hsp40 和压力保护

• 批准号: 6744186
• 负责人: DOUGLAS M CYR
• 金额: $ 25.37万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6744186
• 关键词: Saccharomyces cerevisiae; binding sites; calorimetry; conformation; cytoprotection; enzyme linked immunosorbent assay; heat shock proteins; molecular chaperones; nuclear magnetic resonance spectroscopy; physiologic stressor; polymerase chain reaction; protein biosynthesis; protein denaturation; protein folding; protein metabolism; protein protein interaction

DESCRIPTION (provided by applicant): The long-term objective of this project is to utilize the yeast S. cerevisiae as a model system to determine the mechanism by which the cytosolic Hsp40s Sis1 and Ydjl act with Hsp70 Ssal (Ssal) to protect cells from denaturing physiological stresses such as heat-shock. The hallmark of the heat-shock response is the rapid induction of chaperone protein expression and the global suppression of protein synthesis. These events occur to prevent the accumulation of non-native proteins and suppress protein aggregation. Hsp40s function to suppress protein aggregation by binding non-native proteins and delivering them to the polypeptide binding site of HspT0. In aim 1, we propose a series of experiments that are designed to determine the mechanism for substrate binding by Hsp40s. In aim 2, we will investigate how denatured proteins that are bound to Hsp40 are delivered to Hsp70 to facilitate protein refolding. An additional feature of Hsp40 family members is that they have evolved to have different domain structures and can target Hsp70 to catalyze different cellular reactions. We have demonstrated that the Ydjl and Sis1 function in the cytosol to direct Ssal to facilitate different aspects of protein metabolism. In Aim 3 and Aim 4 we propose a series of domain swap experiments between Ydjl and Sis1 that are designed to define the rules by which Hsp70s cellular functions are specified.The outcome of these studies will define basic mechanisms by which Hsp40s function with Hsp70 to protect cells from physiological stress.

描述（由申请人提供）： 该项目的长期目标是利用酵母菌酿酒酵母作为模型系统，以确定胞质HSP40S SIS1和YDJL用HSP70 SSAL（SSAL）用来保护细胞的机制，以保护细胞免受变性生理压力（例如热震动）的变性。热震反应的标志是伴侣蛋白表达的快速诱导和蛋白质合成的全球抑制。发生这些事件是为了防止非母蛋白的积累并抑制蛋白质聚集。 HSP40S的功能可通过结合非母蛋白并将其传递到HSPT0的多肽结合位点来抑制蛋白质聚集。在AIM 1中，我们提出了一系列实验，这些实验旨在确定HSP40S底物结合的机制。在AIM 2中，我们将研究如何将与HSP40结合的变性蛋白传递到HSP70，以促进蛋白质的再折叠。 HSP40家庭成员的另一个特征是它们已经演变为具有不同的域结构，并且可以靶向HSP70来催化不同的细胞反应。我们已经证明，YDJL和SIS1在细胞质中的功能指导SSAL以促进蛋白质代谢的不同方面。在AIM 3和AIM 4中，我们提出了YDJL和SIS1之间的一系列域交换实验，这些实验旨在定义指定HSP70S细胞函数的规则。这些研究的结果将定义HSP40S通过HSP70功能与HSP70功能以保护细胞免受生理胁迫的基本机制。