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: 7728962
• 负责人: ELIZABETH A CRAIG
• 金额: $ 45.35万
• 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/7728962
• 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; Hand; 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 association study; 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; public health relevance; 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，即获得三维结构，是一个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，被称为“蛋白质折叠疾病”的神经退行性疾病的数量说明了这一点。分子伴侣在重塑蛋白质结构中起着至关重要的作用——帮助蛋白质从头折叠，防止蛋白质聚集和分解蛋白质复合物。以hsp70为基础的机器，具有j蛋白作为专性成分，是最高度保守的分子伴侣系统之一。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j蛋白都具有刺激其伴侣hsp70的atp酶活性的能力，从而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Hsp70的能力，参与广泛的复杂和多样化的生物功能。本研究的重点是了解j蛋白功能特异性的基础。选取酵母胞浆中的两个j蛋白Sis1和Zuo1进行深入分析。这种选择是基于它们的重要性和高度的序列保守性。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j蛋白在其他生物中的功能的范例。为了了解Sis1的特异性，我们将利用它在酵母朊病毒繁殖中的功能，因为它是朊病毒复合物断裂所必需的。因此，研究结果也将提供有关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。Zuo1是一种高度保守的核糖体相关伴侣，当新生多肽离开核糖体时，它促进Hsp70与它们相互作用。核糖体相关伴侣是蛋白质合成和蛋白质折叠之间的纽带，因此是细胞产生功能蛋白的关键。此外，我们将研究分子伴侣在细胞核中的作用，重点关注与伴侣活性无关或可分离的新调控功能。公共卫生相关性：本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。蛋白质折叠对正常细胞功能至关重要；蛋白质错误折叠是许多人类疾病的主要原因，包括囊性纤维化和神经退行性疾病，如阿尔茨海默病。