Functional Diversity of J-protein Components of Hsp70 Chaperone Machinery

Hsp70 伴侣机械 J 蛋白成分的功能多样性

• 批准号: 8098692
• 负责人: ELIZABETH A CRAIG
• 金额: $ 45.65万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1982
• 资助国家: 美国
• 起止时间: 1982-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8098692
• 关键词: ATP phosphohydrolase; Alzheimer' s Disease; Amino Acids; Amyloid Proteins; Binding; Biochemical; Biogenesis; Biological Models; Biological Process; Cell Nucleus; Cell membrane; Cell physiology; Cells; Client; Complex; Coupling; Cystic Fibrosis; Cytosol; Enzymes; Eukaryota; Gene Expression; Gene Expression Regulation; Genes; Genetic; Goals; Grant; Health; Homeostasis; Homologous Gene; Human; Integral Membrane Protein; Life; Link; Mediating; Membrane Transport Proteins; Molecular Chaperones; Neurodegenerative Disorders; Normal Cell; Organism; Orthologous Gene; Outcome; Phospholipids; Physiological Processes; Play; Prions; Process; Production; Progress Reports; Property; Protein Binding; Protein Biosynthesis; Protein Dynamics; Protein-Folding Disease; Proteins; Regulation; Research; Ribosomes; Role; Saccharomyces cerevisiae; Set protein; Signal Transduction Pathway; Site; Specificity; System; Test Result; Testing; Work; Yeasts; base; chaperone machinery; chromatin immunoprecipitation; follow-up; genome-wide analysis; human disease; macromolecule; mutant; novel; polypeptide; prevent; protein aggregate; protein aggregation; protein complex; protein folding; protein function; protein misfolding; protein protein interaction; protein structure; three dimensional structure; transcription factor; yeast prion; yeast protein

DESCRIPTION (provided by applicant): How proteins fold, that is attain their three-dimensional structure, is a fundamental biological process with important implications for human health. Misfolded proteins are often toxic, as illustrated by the number of neurodegenerative diseases referred to as "protein folding diseases". Molecular chaperones play vital roles in remodeling protein structure -- assisting de novo protein folding, preventing protein aggregation and disassembling protein complexes. Hsp70-based machineries, having J-proteins as obligate components, are amongst the most highly conserved molecular chaperone systems. J-proteins are a very diverse set of proteins, having only the 70 amino acid J-domain in common. All J-proteins share the ability to stimulate the ATPase activity of their partner Hsp70s, allowing them to capture client proteins. But it is their functional diversity that enables them to orchestrate Hsp70's capacity to participate in a wide array of complex and diverse biological functions. This proposal focuses on understanding the basis of the specificity of J-proteins function. Two J-proteins of the yeast cytosol have been chosen for in depth analysis: Sis1 and Zuo1. This choice is based on their critical importance and their high degree of sequence conservation. Their human homologs are able to substitute for the yeast proteins, thus the outcome of this work will serve as a paradigm for understanding J-protein function in other organisms. To understand the specificity of Sis1, its function in the propagation of yeast prions will be exploited, as it is specifically required for fragmentation of prion complexes. Thus, results will also yield important information about the biogenesis and propagation of these self-replicating amyloid protein aggregates. Zuo1 is a highly conserved ribosome-associated chaperone that facilitates interaction of Hsp70 with nascent polypeptides as they exit the ribosome. Ribosome-associated chaperones serve as a link between protein synthesis and protein folding and are thus a key to the cell<s production of functional proteins. In addition, we will investigate roles of molecular chaperones in the nucleus, focusing on novel regulatory functions independent of and separable from chaperone activity. PUBLIC HEALTH RELEVANCE: The research described in this proposal focuses on understanding the processes of protein folding and maturation within living cells and the important roles of molecular chaperones in them. Productive protein folding is critical to normal cell function; protein misfolding is the primary cause of many human diseases, including cystic fibrosis and neurodegenerative diseases such as Alzheimer's disease.

描述（由申请人提供）：蛋白质如何折叠，即获得其三维结构，是对人类健康具有重要意义的基本生物学过程。错误折叠的蛋白质通常是有毒的，如被称为“蛋白质折叠疾病”的神经退行性疾病的数量所示。分子伴侣在重塑蛋白质结构中起着至关重要的作用--帮助蛋白质重新折叠，防止蛋白质聚集和分解蛋白质复合物。Hsp 70为基础的机器，具有J-蛋白作为专性组件，是其中最高度保守的分子伴侣系统。J-蛋白是一组非常多样化的蛋白质，只有70个氨基酸的J-结构域是共同的。所有的J蛋白都具有刺激其伴侣Hsp 70的ATP酶活性的能力，使它们能够捕获客户蛋白。但正是它们的功能多样性使它们能够协调Hsp 70参与各种复杂多样的生物功能的能力。该提案的重点是了解J蛋白功能特异性的基础。酵母细胞质中的两个J蛋白被选择用于深入分析：Sis 1和Zuo 1。这种选择是基于它们的关键重要性和它们的高度序列保守性。它们的人类同源物能够替代酵母蛋白，因此这项工作的结果将作为理解其他生物中J蛋白功能的范例。为了理解Sis 1的特异性，将利用其在酵母朊病毒繁殖中的功能，因为它是朊病毒复合物片段化所特别需要的。因此，这些结果也将产生关于这些自我复制的淀粉样蛋白聚集体的生物发生和繁殖的重要信息。Zuo 1是一种高度保守的核糖体相关分子伴侣，它促进Hsp 70与新生多肽在离开核糖体时的相互作用。核糖体伴侣蛋白是连接蛋白质合成和蛋白质折叠的纽带，是细胞合成功能蛋白的关键。此外，我们将调查分子伴侣在细胞核中的作用，专注于新的监管功能的独立和分离的伴侣活性。公共卫生相关性：该提案中描述的研究重点是了解活细胞内蛋白质折叠和成熟的过程以及分子伴侣在其中的重要作用。高效的蛋白质折叠对于正常的细胞功能至关重要;蛋白质错误折叠是许多人类疾病的主要原因，包括囊性纤维化和阿尔茨海默病等神经退行性疾病。