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J-Protein Regulation of Yeast Prion Propagation

J 蛋白对酵母朊病毒传播的调节

基本信息

批准号：
10277234
负责人：
Justin Keith Hines
金额：
$ 44.27万
依托单位：
LAFAYETTE COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10277234
关键词：
Alzheimer&apos s Disease Amino Acid Sequence Amino Acids Amyloid Amyloid Proteins Behavior Binding Biochemical Biochemical Phenomena Biological Assay Biological Models Biology Buffers Collection Complex Cytosol Data Disease Elements Evaluation Genetic Glycine Goals Hand Heritability Human Intervention Knowledge Laboratories Life Literature Maintenance Mediating Methods Mission Mitosis Molecular Molecular Chaperones National Institute of General Medical Sciences Neurodegenerative Disorders Orthologous Gene Outcome Parkinson Disease Pattern Peptides Pharmacology Prion Diseases Prions Process Progress Reports Proteins Public Health Regulation Research Role Saccharomyces cerevisiae Saccharomycetales Specificity Structure System Testing United States National Institutes of Health Variant Viral Proteins Virus Replication Work Yeasts amyloid structure base chaperone machinery conformer genetic manipulation in vivo innovation protein aggregation protein function protein misfolding therapy development transmission process yeast genetics yeast prion

项目摘要

A critical barrier to advancing the understanding of chaperone function in prion biology is that the fundamental chaperone requirements for most yeast prions remain unidentified. Existing knowledge is disjointed due to a lack of systematic evaluation that controls for variation in yeast strain background and prion structure. The continued existence of this barrier is an important problem because, until it is overcome, an understanding of how protein sequences give rise to amyloids with distinct patterns of chaperone interaction cannot be fully realized. The long- term goal is to utilize the highly tractable budding yeast, S. cerevisiae, to systematically decipher the complex relationships between amyloid-forming yeast prions and molecular chaperone proteins with a goal of better un- derstanding J-protein chaperone function and prion behavior. The objective of this particular application is to utilize genetic systems and biochemical assays to determine the functional elements involved in specific prion- chaperone interactions. The central hypothesis is that differences in amyloid structure, arising primarily from amino acid composition, create distinct challenges for prion transmission which are overcome by specific J- protein functions that buffer prions against loss during mitosis. The hypothesis has been formulated on the basis of data produced in the applicant's laboratory. The rationale for the proposed research is that unambiguous determinations of J-protein functional requirements are a necessary step toward understanding the mechanisms of J-protein function in amyloid biology. Using our own collection of well-studied, naturally-occurring prions, and the yeast cytosol as model systems, this hypothesis will be tested by pursuing two specific aims: 1) Determine the role of the Apj1 QS region in Hsp104-mediated prion elimination, and 2) Identify elements of higher eukaryotic Sis1 orthologs responsible for amyloid conformer-specific propagation. Proven yeast genetic manipulations, which have been established as feasible in the applicant's hands, will be the primary methods used to accomplish these aims. The approach is innovative because it represents a substantive departure from the status quo by placing emphasis on the ability to draw distinctions and make comparisons among multiple J-proteins and yeast prions as a way to broadly understand J-protein function. The contribution of the proposed research is expected to be the elucidation of the roles of distinct J-proteins in prion propagation and prion elimination. This contribution is significant because it is the next step in a continuum of research which is expected to contribute to the under- standing of the biochemical basis of J-protein·amyloid interactions. A molecular understanding of prion-chaper- one interactions has the potential to inform the development of interventions for protein misfolding disorders, including the increasing prevalent neurodegenerative disorders Alzheimer's and Parkinson's.

推进对朊病毒生物学中伴侣蛋白功能的理解的一个关键障碍是，大多数酵母朊病毒的伴侣蛋白需求仍然没有确定。现有的知识是脱节的，由于缺乏控制酵母菌株背景和朊病毒结构变异的系统评价。继续这一障碍的存在是一个重要的问题，因为，直到它被克服，了解蛋白质如何序列产生具有不同伴侣相互作用模式的淀粉样蛋白无法完全实现。很长的- 长期的目标是利用高度易处理的芽殖酵母，S。酿酒酵母，系统地破译复杂的淀粉样蛋白形成酵母朊病毒和分子伴侣蛋白之间的关系，了解J蛋白伴侣蛋白功能和朊病毒行为。本申请的目的是利用遗传系统和生物化学测定来确定参与特定朊病毒的功能元件，伴侣互动中心假设是淀粉样蛋白结构的差异，主要是由氨基酸组成，为朊病毒传播带来了独特的挑战，这些挑战被特异性J- 在有丝分裂过程中缓冲朊病毒损失的蛋白质功能。这一假设是基于申请人实验室产生的数据。拟议研究的基本原理是，确定J蛋白的功能要求是了解其机制的必要步骤 J蛋白在淀粉样蛋白生物学中的功能。使用我们自己收集的经过充分研究的自然产生的朊病毒，酵母胞质溶胶作为模型系统，这一假设将通过追求两个具体目标进行测试：1）确定 Apj 1 QS区在Hsp 104介导的朊病毒清除中的作用; 2）鉴定高等真核生物的元件负责淀粉样蛋白适形体特异性繁殖的sis 1直系同源物。酵母基因操作，这些方法在申请人手中已经确立为可行的，将是用于实现的主要方法。这些目标。这一方法是创新的，因为它代表了对现状的实质性改变，强调在多种J蛋白和酵母之间进行区分和比较的能力朊病毒作为广泛了解J蛋白功能的一种方式。预计拟议研究的贡献阐明不同J蛋白在朊病毒增殖和朊病毒消除中的作用。这一贡献是重要的，因为它是一个连续的研究，预计将有助于下- 站在J蛋白·淀粉样蛋白相互作用的生化基础上。对朊病毒伴侣的分子理解- 一种相互作用有可能为蛋白质错误折叠疾病的干预措施的发展提供信息，包括日益流行的神经退行性疾病阿尔茨海默氏症和帕金森氏症。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Hsp40 function in yeast prion propagation: Amyloid diversity necessitates chaperone functional complexity.

DOI：
10.1080/19336896.2015.1020268
发表时间：
2015
期刊：
Prion
影响因子：
2.3
作者：
Sporn ZA;Hines JK
通讯作者：
Hines JK

Determination of Growth-Phase Dependent Influences Exerted by Prions on Yeast Lipid Content Using HPTLC-Densitometry.

使用 HPTLC 密度测定法测定朊病毒对酵母脂质含量的生长阶段依赖性影响。

DOI：
10.1556/1326.2016.28.3.7
发表时间：
2016
期刊：
Acta chromatographica
影响因子：
1.9
作者：
Bui,Q;Sherma,J;Fried,B;Hines,JK
通讯作者：
Hines,JK

Structural Elements of 'Anti-prion J protein 1' (Apj1) Required for Efficient Curing of the [PSI+] Prion by Hsp104 Overexpression.

通过 Hsp104 过表达有效治愈 [PSI] 朊病毒所需的“抗朊病毒 J 蛋白 1”(Apj1) 的结构元件。

DOI：
发表时间：
2022
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Ganser,SamanthaJ;McNish,BridgetA;Corpus,BridgetA;Hines,JustinK
通讯作者：
Hines,JustinK

Prion-specific Hsp40 function: The role of the auxilin homolog Swa2.