Contributions of protein aggregation to gene regulation and phenotypic diversity

蛋白质聚集对基因调控和表型多样性的贡献

基本信息

批准号：
9104516
负责人：
Randal Arthur Halfmann
金额：
$ 33万
依托单位：
STOWERS INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9104516
关键词：
Age Aging Bacteria Behavior Biological Biological Assay Biological Process Biology Buffers Cell physiology Cells Characteristics Data Disease Elements Environment Epigenetic Process Eukaryota Future Gene Expression Regulation Goals Growth Hand Health Heterogeneity Human Individual Investigation Life Microscopy Modeling Molecular Mutation Nature Nutrient Open Reading Frames Organism Phenotype Physiological Play Population Prions Process Protein Kinase Proteins RNA-Binding Proteins Regulation Reporter Role Saccharomyces cerevisiae Saccharomycetales Testing Time Work Yeasts base biological systems design environmental change genetic regulatory protein human disease in vivo loss of function mutation mutant non-prion novel novel strategies prion-like protein aggregate protein aggregation protein expression protein function transcription factor

项目摘要

ABSTRACT The aggregation of proteins is deeply associated with human diseases, including dozens of familial and age-associated disorders that together comprise a major emerging health threat to our aging populace. However, recent discoveries indicate that protein aggregation can also have a wide range of structural and regulatory functions. The breadth and pervasiveness of such non-pathological aggregation is largely unexplored. In the budding yeast, Saccharomyces cerevisiae, multiple intrinsically disordered proteins (IDPs), including transcription factors, RNA- binding proteins, and kinases, have a tendency to aggregate under physiological conditions. One such protein, the transcription factor Mot3, is one of only a handful of proteins known to form self-propagating aggregates that act as protein-based elements of inheritance, or prions. By switching to and from its aggregated state, Mot3 broadens the range of phenotypes accessible to clonal yeast populations. The goals of this work are to 1) develop a quantitative flow cytometric reporter for intracellular aggregation by IDPs, 2) investigate the consequences of aggregation on the regulatory activities of IDPs, and 3) test whether aggregation by these proteins, and by Mot3 in particular, is an adaptive biological process. This work will advance our understanding of non-pathological protein aggregation, while establishing a platform for future interrogations of both functional and disease-associated aggregation in living cells.

抽象的蛋白质的聚集与人类疾病密切相关，包括数十种疾病家族性疾病和与年龄相关的疾病共同构成了新出现的主要健康威胁我们的老龄化人口。然而，最近的发现表明蛋白质聚集也可以具有广泛的结构和监管职能。的广度和普遍性这种非病理性聚集在很大程度上尚未被探索。在芽殖酵母中，酿酒酵母酿酒酵母，多种内在无序蛋白（IDP），包括转录因子、RNA- 结合蛋白和激酶在生理条件下有聚集的倾向。其中一种蛋白质，转录因子 Mot3，是已知的少数蛋白质之一。形成自我繁殖的聚集体，充当基于蛋白质的遗传元件或朊病毒。通过在聚合状态之间切换，Mot3 拓宽了表型范围可用于克隆酵母群体。这项工作的目标是 1）开发一个定量的 IDP 细胞内聚集的流式细胞报告仪，2) 研究后果国内流离失所者监管活动的汇总，以及 3) 测试这些汇总是否蛋白质，尤其是 Mot3，是一种适应性生物过程。这项工作将推动我们了解非病理性蛋白质聚集，同时为未来建立平台对活细胞中功能性和疾病相关聚集的询问。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The UBR-1 ubiquitin ligase regulates glutamate metabolism to generate coordinated motor pattern in Caenorhabditis elegans.

DOI：
10.1371/journal.pgen.1007303
发表时间：
2018-04
期刊：
PLoS genetics
影响因子：
4.5
作者：
Chitturi J;Hung W;Rahman AMA;Wu M;Lim MA;Calarco J;Baran R;Huang X;Dennis JW;Zhen M
通讯作者：
Zhen M

Heritable remodeling of yeast multicellularity by an environmentally responsive prion.

DOI：
10.1016/j.cell.2013.02.026
发表时间：
2013-03-28
期刊：
Cell
影响因子：
64.5
作者：
Holmes DL;Lancaster AK;Lindquist S;Halfmann R
通讯作者：
Halfmann R

A self-perpetuating repressive state of a viral replication protein blocks superinfection by the same virus.

DOI：
10.1371/journal.ppat.1006253
发表时间：
2017-03
期刊：
PLoS pathogens
影响因子：
6.7
作者：
Zhang XF;Sun R;Guo Q;Zhang S;Meulia T;Halfmann R;Li D;Qu F
通讯作者：
Qu F

Quantifying Nucleation In Vivo Reveals the Physical Basis of Prion-like Phase Behavior.

DOI：
10.1016/j.molcel.2018.06.016
发表时间：
2018-07-05
期刊：
Molecular cell
影响因子：
16
作者：
Khan T;Kandola TS;Wu J;Venkatesan S;Ketter E;Lange JJ;Rodríguez Gama A;Box A;Unruh JR;Cook M;Halfmann R
通讯作者：
Halfmann R

Detecting and Characterizing Protein Self-Assembly In Vivo by Flow Cytometry.

通过流式细胞术检测和表征体内蛋白质自组装。

DOI：
10.3791/59577
发表时间：
2019
期刊：
Journal of visualized experiments : JoVE
影响因子：
0
作者：
Venkatesan,Shriram;Kandola,TejbirS;Rodríguez-Gama,Alejandro;Box,Andrew;Halfmann,Randal
通讯作者：
Halfmann,Randal