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Hsp110 protein chaperone function in yeast

Hsp110 蛋白伴侣在酵母中的功能

基本信息

批准号：
7591629
负责人：
KEVIN ANTHONY MORANO
金额：
$ 30.63万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7591629
关键词：
ATP phosphohydrolase ATPase Domain Address Bacteria Binding Biochemical Biogenesis Biological Assay Cells Cellular biology Client Collaborations Complement Complex Coupling Eukaryota Family Genes Glucocorticoid Receptor Growth Heat shock proteins Heat-Shock Response Homologous Gene Human Hydrolysis In Vitro Investigation Ischemia Mammalian Cell Mediating Mitogen-Activated Protein Kinases Modeling Molecular Molecular Chaperones Nucleotides Oncogene Proteins Pathway interactions Peptides Play Process Protein Isoforms Protein p53 Proteins Regulation Regulatory Pathway Relative (related person)Role Saccharomyces cerevisiae Signal Pathway Signal Transduction Site Staging Stress System Testing Tissues Yeasts base cytotoxic heat-shock proteins 110 in vivo novel protein folding receptor expression research study src-Family Kinases structure-specific endonuclease I tumorigenesis v-src Oncogenes

项目摘要

Heat shock proteins (Hsps) play dual roles in cellular biology; they are the first line of defense against cytotoxic stresses, and are tightly integrated into signaling and regulatory pathways under normal growth conditions. A subset of Hsps, including Hsp70 and HspQO, act as molecular chaperones, and may be required at multiple stages during a substrate protein's lifetime, ranging from biogenesis, localization, and stability, to activation and degradation. Protein chaperones are induced during numerous pathophysiological conditions including ischemia and tumorigenesis, and are known to facilitate stability and activity of oncoproteins such as v-src kinase and the p53 tumor suppressor. The Hsp110 class of chaperones is a poorly understood Hsp70 relative and is present in all eukaryotes, with tissue-specific isoforms of unknown function in humans. Our long-term objective is to elucidate the cellular roles of this chaperone family. The baker's yeast Hsp110 homolog is encoded by the SSE1 and SSE2 genes, and little is known about their function. We have discovered that Sse1 exists as a heterodimer in vivo with the cytosolic Hsp70s Ssa and Ssb, and that Sse1 is required for signal transduction activity of the Hsp90 chaperone system. Wetherefore hypothesize that Sse1, and by extension the mammalian Hsp110 chaperone, may function primarily as a modulator of Hsp70 activity. This proposal seeks to gain a mechanistic understanding of the cellular roles of Hsp110 chaperones by asking two specific questions: 1) How does Sse1 operate in partnership with the yeast Hsp70 Ssa1 and 2) How does Sse1 participate in signal transduction with Hsp90? In the first aim we will determine interaction sites and regulation of Hsp70 by Sse1 using purified chaperones, ultimately deciphering effects of Sse1 on protein folding in vitro. We will complement these experiments with in vivo assays to determine the contribution of Sse1 to Ssa1-dependent processes. In the second aim, we will determine both the stage at which Sse1 acts in the Hsp90 substrate folding cycle, and specific effects on substrate maturation using the model client protein glucocorticoid receptor. Finally we will apply these findings to understand how Sse1 in collaboration with Hsp90 is required for heat shock survival by modulating signaling through the Slt2 MAP kinase in the cell integrity pathway. These lines of investigation in yeast will serve as a model for predicting which processes Hsp110 may facilitate in mammalian cells.

热休克蛋白（Hsps）在细胞生物学中具有双重作用；他们是第一道防线