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Cytoplasmic Organization by phase transitions

通过相变进行细胞质组织

基本信息

批准号：
10914345
负责人：
Amy Susanne Gladfelter
金额：
$ 31.84万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-07 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10914345
关键词：
Address Amino Acid Sequence Architecture Base Pairing Binding Biochemical Reaction Biochemistry Biophysics Cell Cycle Cell Death Cell Polarity Cell Shape Cell division Cell membrane Cell physiology Cells Cellular biology Cyclins Cytoplasm Data Diffusion Disease Elements Genetic Goals Health Human Human Pathology Image In Vitro Link Lipid Bilayers Location Malignant Neoplasms Mediating Membrane Messenger RNA Modeling Molds Molecular Molecular Genetics Neurodegenerative Disorders Normal Cell Nucleic Acids Output Pathologic Pathology Pattern Phase Phase Transition Physical condensation Physiological Porosity Property Proteins Publishing RNA RNA Sequences RNA-Binding Proteins Reaction Role Site Specific qualifier value Specificity Structure Surface Tension System Tertiary Protein Structure Time Translations Viscosity Work cell growth experimental study high resolution imaging human disease molecular dynamics nanoscale nuclear division physical property physical state polyglutamine protein protein interaction protein structure reconstitution scaffold

项目摘要

Project Summary/Abstract (PI Gladfelter, AS) Cells must compartmentalize biochemistry in time and space. A newly appreciated mechanism of organization is biomolecular condensation. In many cases, condensates form via weak, multivalent interactions among disordered proteins and nucleic acids. These interactions determine the material states of condensates such as viscosity, surface tension and porosity, which in turn impact the concentrations, reaction and transport rates in, out and within condensates of key constituents. There are major gaps in understanding how cells control where condensates form, which molecules coassemble, and how condensate material state contributes to function. We discovered a physiological function for condensates in controlling nuclear division and cell polarity in the filamentous fungus, Ashbya gossypii. These condensates can control translation and are formed by an RNA-binding protein called Whi3 binding to target RNAs important for nuclear division (cyclins) and cell polarity (formins). The power of this cell system is that we can link physical properties and locations of condensates to functional outputs of protein translation, cell shape and nuclear division. The goals of the proposed work are to determine how structured elements in proteins, RNAs and cell membranes control the material state, location and function of condensates in the cell. We will determine how nanometer scale features of protein and RNA sequences promote mesoscale physical states of condensates to spatially pattern protein translation. We use an interdisciplinary suite of advanced imaging, genetic, biophysical and modeling approaches to tackle these fundamental open problems that not yet understood for any phase-separating system. Specifically, we will: Aim 1: Determine roles of hidden structured domains of proteins. We hypothesize that transiently ordered states promote specific protein-protein interactions and condensate material properties. Aim 2. Establish the architecture and function of RNA-based scaffolds. We hypothesize that mRNA forms a higher-order network using base-pairing that determines condensate properties. Aim 3: Delineate how membrane platforms control condensate assemblies. We hypothesize that endomembranes provide sites of assembly to specify the location of condensates. The proposed work will define how protein structure, RNA scaffolds and cell membranes are harnessed to control the properties, functions and locations of condensates in cells. The importance of condesates is underscored by numerous findings that link aberrant formation of condensates to multiple human diseases, including cancer and neurodegenerative diseases. While it is clear condensates undoubtably impact biochemistry, we do not yet understand how condensates actually contribute to normal cell function which is critical to understand how their malfunction leads to human pathologies.

项目摘要/摘要（PI Gladfelter， AS）

项目成果

期刊论文数量（38）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Design considerations for analyzing protein translation regulation by condensates.

DOI：
10.1261/rna.079002.121
发表时间：
2022-01
期刊：
RNA (New York, N.Y.)
影响因子：
0
作者：
Roden CA;Gladfelter AS
通讯作者：
Gladfelter AS

RNA contributions to the form and function of biomolecular condensates.

DOI：
10.1038/s41580-020-0264-6
发表时间：
2021-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
0
作者：
Roden C;Gladfelter AS
通讯作者：
Gladfelter AS

Double-stranded RNA drives SARS-CoV-2 nucleocapsid protein to undergo phase separation at specific temperatures.

DOI：
10.1093/nar/gkac596
发表时间：
2022-08-12
期刊：
NUCLEIC ACIDS RESEARCH
影响因子：
14.9
作者：
Roden, Christine A.;Dai, Yifan;Giannetti, Catherine A.;Seim, Ian;Lee, Myungwoon;Sealfon, Rachel;McLaughlin, Grace A.;Boerneke, Mark A.;Iserman, Christiane;Wey, Samuel A.;Ekena, Joanne L.;Troyanskaya, Olga G.;Weeks, Kevin M.;You, Lingchong;Chilkoti, Ashutosh;Gladfelter, Amy S.
通讯作者：
Gladfelter, Amy S.

Genomic RNA Elements Drive Phase Separation of the SARS-CoV-2 Nucleocapsid.

DOI：
10.1016/j.molcel.2020.11.041
发表时间：
2020-12-17
期刊：
Molecular cell
影响因子：
16
作者：
Iserman C;Roden CA;Boerneke MA;Sealfon RSG;McLaughlin GA;Jungreis I;Fritch EJ;Hou YJ;Ekena J;Weidmann CA;Theesfeld CL;Kellis M;Troyanskaya OG;Baric RS;Sheahan TP;Weeks KM;Gladfelter AS
通讯作者：
Gladfelter AS

What your PI forgot to tell you: why you actually might want a job running a research lab.

您的 PI 忘记告诉您的事情：为什么您实际上可能想要一份管理研究实验室的工作。