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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

基本信息

批准号：
8292197
负责人：
ELIZABETH A CRAIG
金额：
$ 45.7万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
1982
资助国家：
美国
起止时间：
1982-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8292197
关键词：
ATP phosphohydrolase Alzheimer&apos s Disease Amino Acids Amyloid Proteins Binding Biochemical Biogenesis Biological Models Biological Process Cell Nucleus Cell membrane Cell physiology Cells ChIP-on-chip 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 abstracting 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

项目摘要

Project Summary/Abstract 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.

项目摘要/摘要蛋白质如何折叠，即获得其三维结构，是一个基本的生物学问题这一过程对人类健康具有重要影响。错误折叠的蛋白质通常是有毒的，因为被称为“蛋白质折叠疾病”的神经退行性疾病的数量所说明的。分子伴侣在蛋白质结构重塑中的重要作用--辅助从头蛋白质折叠，防止蛋白质聚集和分解蛋白质复合体。基于HSP70的以J-蛋白为必需成分的机器是最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 氨基酸共有的J-结构域。所有的J-蛋白都具有刺激ATPase活性的能力他们的合作伙伴Hsp70，使他们能够捕获客户蛋白质。但正是它们的功能多样性使他们能够协调HSP70？S的能力，以参与广泛的复杂和生物功能多样。这项建议侧重于理解的基础的特殊性 J-蛋白发挥作用。选择酵母胞浆中的两个J-蛋白：Sis1和Zuo1进行了深入的分析。这选择是基于它们的关键重要性和它们高度的序列保守性。他们的人类的同源物能够替代酵母蛋白，因此这项工作的结果将是为理解J-蛋白在其他生物体中的功能提供了一个范例。要了解 Sis1的特异性，它在酵母蛋白繁殖中的作用将被开发，因为它是特别是Pron复合体的碎裂所需要的。因此，结果也将产生重要的这些自我复制的淀粉样蛋白的生物发生和繁殖信息集合体。Zuo1是一种高度保守的核糖体相关伴侣蛋白，可促进相互作用当HSP70离开核糖体时，带有新生多肽的HSP70。核糖体相关伴侣是蛋白质合成和蛋白质折叠之间的纽带，因此是细胞的关键。S 生产功能蛋白质。此外，我们还将研究分子伴侣在核，专注于独立于伴侣的新的调节功能活动。

项目成果

期刊论文数量（24）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Functional interaction of cytosolic hsp70 and a DnaJ-related protein, Ydj1p, in protein translocation in vivo.

胞浆 hsp70 和 DnaJ 相关蛋白 Ydj1p 在体内蛋白质易位中的功能相互作用。

DOI：
10.1128/mcb.16.8.4378
发表时间：
1996
期刊：
Molecular and cellular biology
影响因子：
5.3
作者：
Becker,J;Walter,W;Yan,W;Craig,EA
通讯作者：
Craig,EA

Pathway of Hsp70 interactions at the ribosome.

DOI：
10.1038/s41467-021-25930-8
发表时间：
2021-09-27
期刊：
Nature communications
影响因子：
16.6
作者：
Lee K;Ziegelhoffer T;Delewski W;Berger SE;Sabat G;Craig EA
通讯作者：
Craig EA

The complex evolutionary dynamics of Hsp70s: a genomic and functional perspective.

DOI：
10.1093/gbe/evt192
发表时间：
2013
期刊：
Genome biology and evolution
影响因子：
3.3
作者：
Kominek J;Marszalek J;Neuvéglise C;Craig EA;Williams BL
通讯作者：
Williams BL

Dual interaction of the Hsp70 J-protein cochaperone Zuotin with the 40S and 60S ribosomal subunits.

DOI：
10.1038/nsmb.3299
发表时间：
2016-11
期刊：
NATURE STRUCTURAL & MOLECULAR BIOLOGY
影响因子：
16.8
作者：
Lee, Kanghyun;Sharma, Ruchika;Shrestha, Om Kumar;Bingman, Craig A.;Craig, Elizabeth A.
通讯作者：
Craig, Elizabeth A.

Nucleoid localization of Hsp40 Mdj1 is important for its function in maintenance of mitochondrial DNA.

DOI：
10.1016/j.bbamcr.2013.05.012
发表时间：
2013-10
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
影响因子：
5.1
作者：
Ciesielski, Grzegorz L.;Plotka, Magdalena;Manicki, Mateusz;Schilke, Brenda A.;Dutkiewicz, Rafal;Sahi, Chandan;Marszalek, Jaroslaw;Craig, Elizabeth A.
通讯作者：
Craig, Elizabeth A.