Functional diversity of Hsp70 and J-protein chaperone systems

Hsp70 和 J 蛋白伴侣系统的功能多样性

• 批准号: 10473676
• 负责人: ELIZABETH A CRAIG
• 金额: $ 38.25万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10473676
• 关键词: Automobile Driving; Binding; Biochemical; Biogenesis; Biological; Biological Process; Cell physiology; Cells; Complex; Equilibrium; Genetic; Goals; Homeostasis; Knowledge; Maintenance; Modeling; Molecular Chaperones; Monitor; Organism; Pattern; Peptides; Play; Proteins; Ribosomes; Role; Site; Structure; System; Therapeutic; Touch sensation; Translation Process; Work; experimental analysis; polypeptide; portability; protein degradation; protein folding; proteostasis; trafficking

PROJECT SUMMARY/ABSTRACT Maintenance of cellular homeostasis requires a fine-tuned balance of many biological processes. Protein homeostasis is particularly intricate, because it requires maintaining balance amongst biogenesis, folding, trafficking and degradation of all cellular proteins. A group of ubiquitous proteins, referred to collectively as molecular chaperones, play active roles in maintaining protein homeostasis by transiently binding to many different polypeptides. Of these, the Hsp70 chaperone/J-protein co-chaperone systems, which are present in all major cellular compartments, are the most versatile. They play key roles not only in general homeostasis networks of protein folding and degradation, but also in core biological processes, often by driving assembly and disassembly of multimeric complexes. The overarching goal of this proposal is to understand the attributes of Hsp70, and its J-protein co- chaperones, that drive their ability to carry out diverse biological roles. To do so we will use well-developed Hsp70/J-protein systems that are exceptionally amenable to both genetic and biochemical analysis. Knowledge generated using these systems will be portable to other organisms, as the Hsp70 and J-proteins being studied are highly conserved. It will also inform other Hsp70/J-protein systems that are less amenable to experimental analysis than those we employ as models. We are focusing on two major knowledge gaps. First, how Hsp70s interact with biologically relevant substrates. In the cell, polypeptides with substantial secondary and tertiary structure are Hsp70s' natural substrates. However, most work dissecting Hsp70's cycle of interaction with substrates has been done using peptide, because of the difficulty in working with partially folded proteins. Thus, understanding of how Hsp70s interact with these natural substrates is limited. Second, tethering to sites of action is a major means by which J-proteins drive Hsp70 function. But, that such tethering has evolved into complex and nuanced modes of functionality has only recently become evident. We will continue analysis of the eukaryotic ribosome associated J-protein/Hsp70 system. This system is fundamentally important. It not only plays a first-line role in de novo protein folding, it has been implicated in monitoring and modulating the translation process itself.

项目摘要/摘要 维持细胞动态平衡需要许多生物过程的微调平衡。蛋白 动态平衡是特别复杂的，因为它需要在生物发生、折叠、 所有细胞蛋白质的运输和降解。一组普遍存在的蛋白质，统称为 分子伴侣通过瞬时与许多分子结合，在维持蛋白质动态平衡方面发挥积极作用。 不同的多肽。其中，Hsp70分子伴侣/J蛋白共分子伴侣系统存在于 主要的细胞室是最多才多艺的。它们不仅在整体动态平衡中起着关键作用 蛋白质折叠和降解的网络，但也在核心生物过程中，通常通过驱动组装和 多聚体复合体的拆解。 这项提议的首要目标是了解Hsp70的属性及其J-蛋白协同作用。 监护人，驱动他们执行不同的生物角色的能力。为此，我们将使用开发良好的 HSP70/J-蛋白质系统，特别适合进行遗传和生化分析。知识 使用这些系统产生的蛋白质将可移植到其他生物体，因为正在研究Hsp70和J-蛋白质 是高度保守的。它还将通知其他不太适合实验的Hsp70/J-蛋白质系统 而不是我们用来做模型的分析。 我们正在关注两个主要的知识差距。首先，Hsp70是如何与生物相关的 底物。在细胞内，具有丰富的二级和三级结构的多肽是Hsp70的天然产物 底物。然而，大多数工作是用来解剖热休克蛋白70与底物相互作用的S循环的 多肽，因为处理部分折叠的蛋白质很困难。因此，理解Hsp70是如何 与这些天然底物的相互作用是有限的。其次，与行动地点捆绑是一种主要手段，通过 J-蛋白驱动Hsp70的功能。但是，这种束缚已经演变成复杂和细微差别的模式 功能只是在最近才变得明显。我们将继续分析真核细胞的核糖体 相关的J-蛋白/Hsp70系统。这个系统从根本上说是重要的。它不仅在以下方面发挥了第一线作用 从头开始蛋白质折叠，它被认为参与了对翻译过程本身的监测和调节。

项目成果

Two-step mechanism of J-domain action in driving Hsp70 function.

J 域驱动 Hsp70 功能的两步机制。

• DOI: 10.1371/journal.pcbi.1007913
• 发表时间: 2020
• 期刊: PLoS computational biology
• 影响因子: 4.3
• 作者: Tomiczek,Bartlomiej;Delewski,Wojciech;Nierzwicki,Lukasz;Stolarska,Milena;Grochowina,Igor;Schilke,Brenda;Dutkiewicz,Rafal;Uzarska,MartaA;Ciesielski,SzymonJ;Czub,Jacek;Craig,ElizabethA;Marszalek,Jaroslaw
• 通讯作者: Marszalek,Jaroslaw

NAC and Zuotin/Hsp70 chaperone systems coexist at the ribosome tunnel exit in vivo.

NAC 和 Zuotin/Hsp70 伴侣系统在体内共存于核糖体隧道出口处。

• DOI: 10.1093/nar/gkae005
• 发表时间: 2024
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Ziegelhoffer,Thomas;Verma,AmitK;Delewski,Wojciech;Schilke,BrendaA;Hill,PaigeM;Pitek,Marcin;Marszalek,Jaroslaw;Craig,ElizabethA
• 通讯作者: Craig,ElizabethA

During FeS cluster biogenesis, ferredoxin and frataxin use overlapping binding sites on yeast cysteine desulfurase Nfs1.

• DOI: 10.1016/j.jbc.2022.101570
• 发表时间: 2022-03
• 期刊: The Journal of biological chemistry
• 作者: Uzarska MA;Grochowina I;Soldek J;Jelen M;Schilke B;Marszalek J;Craig EA;Dutkiewicz R
• 通讯作者: Dutkiewicz R

Interaction of client-the scaffold on which FeS clusters are build-with J-domain protein Hsc20 and its evolving Hsp70 partners.

• DOI: 10.3389/fmolb.2022.1034453
• 发表时间: 2022
• 期刊: Frontiers in molecular biosciences
• 影响因子: 5

Essentiality of Sis1, a J-domain protein Hsp70 cochaperone, can be overcome by Tti1, a specialized PIKK chaperone.

• DOI: 10.1091/mbc.e21-10-0493
• 发表时间: 2022-03-01
• 期刊: MOLECULAR BIOLOGY OF THE CELL
• 影响因子: 3.3
• 作者: Schilke, Brenda A.;Craig, Elizabeth A.
• 通讯作者: Craig, Elizabeth A.