The landscape of NFκB transcription dynamics
NFκB 转录动力学景观
基本信息
- 批准号:10686820
- 负责人:
- 金额:$ 56.54万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-08-19 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAcquired Immunodeficiency SyndromeAffinityApoptoticArthritisAsthmaAtomic Force MicroscopyAutoimmune DiseasesBehaviorBindingBiochemicalBiophysicsCell NucleusCellsCessation of lifeChIP-seqCodeCollaborationsComplexComputer ModelsCouplingDNADNA BindingDNA Binding DomainDNA SequenceDataDiabetes MellitusDiseaseElementsEndowmentEventExcisionExhibitsFamilyFloodsGene ExpressionGenesGenetic Enhancer ElementGenetic TranscriptionGoalsGrowthI Kappa B-AlphaImmuneImmune responseIn VitroInflammatoryInvadedKineticsLaboratoriesLengthMalignant NeoplasmsMeasuresMediatingMicro Array DataMolecularMonitorMutagenesisNuclearNuclear ExportNuclear ProteinsNucleosomesPlayProcessPromoter RegionsProteinsPublishingRPS3 geneRegulationRelaxationResearch PersonnelRoleSeriesSiteSlideSpeedStressStructureSystemSystems BiologyTNF geneTNFRSF5 geneTestingTherapeuticThermodynamicsTimeTransactivationTranscription CoactivatorTranscription InitiationTranscriptional ActivationTranscriptional RegulationViralVirus DiseasesWorkbiological adaptation to stressbiophysical techniquescell growthdesignexperimental studyflexibilityin vivomolecular recognitionmutantprotein complexprotein foldingrecruitresponsesimulationsingle-molecule FRETstoichiometrytheoriestranscription factortranscriptome sequencing
项目摘要
Summary/Abstract
The mechanism by which transcription factors assemble active transcription complexes on specific DNA
sequences does not appear to follow a simple recognition code. Direct readout, wherein specific residues in
the transcription factor “read” the specific DNA sequence through direct interactions is most often assumed to
apply due to an oversimplified view of DNA as a rigid molecule. However, subtle, and not-so-subtle, structural
changes occur when DNA binds to transcription factors. In addition, the DNA binding domains of transcription
factors exhibit a large range of flexibility and often contain intrinsically disordered regions. These elements of
flexibility endow the problem of transcription factor-DNA molecular recognition with many of the features of the
protein folding problem. Our overall hypothesis is that transcription factor-DNA binding would instead be better
described by similar principles as have been elucidated for the protein folding problem. Here, we will focus on
the stress-response transcription factor, nuclear factor κB (NFκB), which activates hundreds of genes involved
in growth regulation and the immune response. We will combine rigorous theory with molecular biophysical
experiments to study the assembly kinetics of NFκB transcriptosome complexes. We will investigate coupling
between DNA and NFκB as it relates to tandem κB sites, nucleosomal DNA, and the DNA-binding co-activator,
RPS3. We predict that NFκB and additional nuclear proteins assemble into specific NFκB transcriptosomes on
κB-DNA sites via a cooperative assembly process. We will test this hypothesis with the following aims: Aim 1
Determine the role of DNA context in NFκB binding. We will test the hypothesis that DNA context plays a key
role in determining which NFκB binding events result in transcription activation by studying the binding of NFκB
to a series of bona fide NFκB promoter and enhancer sequences both theoretically and experimentally. Aim 2
Explore how NFκB interacts with nucleosomal DNA and can invade or unwind nucleosomal DNA. We will test
the hypothesis that NFκB is capable of disrupting nucleosome stability in a manner dependent on NFκB
concentration and the sequence of DNA that is wrapped by the nucleosome, thereby exposing DNA for the
initiation of transcription. Atomic force microscopy and computational modeling of the NFκB interaction with
nucleosomes will be pursued. Aim 3 Determine how the ternary interaction between DNA, NFκB and the
transcription co-activator, RPS3 forms. The NFκB coactivator, RPS3, associates with, and activates, subsets of
NFκB transcription activation sites forming higher-order NFκB transcriptosome complexes. We will use the
AWSEM-Suite code to predict the structures of these larger protein complexes and will verify the predicted
long-range contacts between proteins and domains by NMR paramagnetic relaxation, SAXS, and HDX-MS
experiments.
摘要/摘要
转录因子在特定DNA上组装活性转录复合体的机制
序列似乎并不遵循简单的识别码。直接读出,其中特定残留物在
转录因子通过直接相互作用“读取”特定的DNA序列,通常被认为是
适用于将DNA视为刚性分子的过于简单化的观点。然而,微妙和不那么微妙的结构性
当DNA与转录因子结合时,就会发生变化。此外,转录的DNA结合域
因素表现出很大范围的灵活性,往往包含本质上无序的区域。这些要素
灵活性使转录因子-DNA分子识别问题具有许多
蛋白质折叠问题。我们的总体假设是转录因子与DNA的结合会更好
用与蛋白质折叠问题已阐明的原理类似的原理描述。在这里,我们将重点关注
应激反应转录因子核因子κB(NFκB),激活数百个相关基因
在生长调节和免疫反应方面。我们将把严谨的理论与分子生物物理学结合起来
研究核因子κB转录体复合体组装动力学的实验。我们将研究耦合
核糖核酸和核因子κB之间的关系,因为它与串联的κB位点、核小体DNA和DNA结合共激活因子有关,
RPS3。我们预测,核因子κB和额外的核蛋白组装成特定的核因子κB转录体。
通过合作组装过程的κB-dna位点。我们将通过以下目标来检验这一假设:目标1
确定DNA上下文在核因子κB结合中的作用。我们将检验DNA背景起关键作用的假设
通过研究核因子κB的结合在确定哪些核因子κB结合事件导致转录激活中的作用
从理论上和实验上都得到了一系列真实的NFκB启动子和增强子序列。目标2
探索核因子κB如何与核小体脱氧核糖核酸相互作用,以及如何入侵或解离核小体脱氧核糖核酸。我们将测试
关于核因子κB能够以依赖于核因子κB的方式破坏核小体稳定性的假设
浓度和被核小体包裹的DNA序列,从而暴露DNA
启动转录。原子力显微镜与核因子κB相互作用的计算模拟
将对核小体进行追踪。目的3确定脱氧核糖核酸、核因子κB和细胞因子之间的三元相互作用
转录共激活因子,RPS3形式。核因子κB辅活化子rps 3与其亚群结合并激活
核因子κB转录激活位点形成更高顺序的核因子κB转录体复合体。我们将使用
AWSEM-Suite代码来预测这些较大的蛋白质复合体的结构,并将验证预测
核磁共振顺磁驰豫、SAXS和HDX-MS研究蛋白质与结构域之间的远程接触
实验。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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ELIZABETH A. KOMIVES其他文献
ELIZABETH A. KOMIVES的其他文献
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{{ truncateString('ELIZABETH A. KOMIVES', 18)}}的其他基金
Administrative Supplement for Flow Quench Instrument
流动淬火仪行政补充
- 批准号:
10799448 - 财政年份:2022
- 资助金额:
$ 56.54万 - 项目类别:
Molecular Biophysics Training Grant at UC San Diego
加州大学圣地亚哥分校分子生物物理学培训补助金
- 批准号:
10418781 - 财政年份:2021
- 资助金额:
$ 56.54万 - 项目类别:
Molecular Biophysics Training Grant at UC San Diego
加州大学圣地亚哥分校分子生物物理学培训补助金
- 批准号:
10269570 - 财政年份:2021
- 资助金额:
$ 56.54万 - 项目类别:
Molecular Biophysics Training Grant at UC San Diego
加州大学圣地亚哥分校分子生物物理学培训补助金
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10615137 - 财政年份:2021
- 资助金额:
$ 56.54万 - 项目类别:
Synapt G2-S System with HXMS Automation
具有 HXMS 自动化功能的 Synapt G2-S 系统
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BACKBONE DYNAMICS OF THROMBIN AND THROMBIN-THROMBOMODULIN COMPLEXES
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8361179 - 财政年份:2011
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$ 56.54万 - 项目类别:
BACKBONE DYNAMICS OF THROMBIN AND THROMBIN-THROMBOMODULIN COMPLEXES
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7924964 - 财政年份:2009
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