Conformational Control of Heterochromatin Formation by the HP-1 Protein from Fission Yeast
裂殖酵母 HP-1 蛋白对异染色质形成的构象控制
基本信息
- 批准号:9568786
- 负责人:
- 金额:$ 39.24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-09-30 至 2021-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAffinityAnimal ModelArchitectureBindingBiochemicalBiochemical GeneticsBiologicalBiological AssayCellsChromatinChromatin StructureChromosome SegregationComplexComputer-Assisted Image AnalysisCryoelectron MicroscopyCrystallizationDNADataDimerizationDockingEssential GenesEuchromatinFission YeastFoundationsGene SilencingGenomeGenome StabilityGoalsHematopoietic NeoplasmsHeritabilityHeterochromatinHistone H3HistonesHumanIn VitroKnowledgeLinkLysineMass Spectrum AnalysisMediatingModelingMolecular ConformationNMR SpectroscopyNatureNormal CellNucleosome Core ParticleNucleosomesPathologyPlayPolymersProtein FamilyProteinsReportingResolutionRestRoentgen RaysRoleSchizosaccharomyces pombe ProteinsStructural ModelsStructureTailTelomere MaintenanceTestingWorkX-Ray Crystallographybiophysical techniquescancer cellconformational conversioncrosslinkgenetic analysisheterochromatin-specific nonhistone chromosomal protein HP-1in vivoinsightmutantpolymerizationrecruitrestraint
项目摘要
Project Summary
Eukaryotic genomes are organized into active and inactive domains referred to euchromatin and
heterochromatin. This functional organization plays an important role in chromosome segregation, telomere
maintenance and genome stability. A key component of heterochromatin are the HP-1 family of proteins, which
bind to a histone 3 lysine-9 methyl mark and act as a platform for diverse regulators. A biochemical activity
thought to be important for the spread of heterochromatin is the ability of HP-1 proteins to polymerize. Recent
work on the fission yeast HP-1 protein, Swi6, reveals that polymerization is regulated by autoinhibition. A
critical and poorly understood question is the extent of the conformational transition between closed, inactive
and open, active forms of Swi6 that drive heterochromatin spread. This gap in knowledge derives from the fact
that HP-1 proteins and their complexes with nucleosomes are conformationally dynamic in solution and difficult
to crystallize. Here we will define the structural dynamics of the Swi6-chromatin complex and link the structural
states to function. In Aim 1 we will determine the structure of the autoinhibited form of Swi6 using an integrated
modeling approach that employs restraints NMR spectroscopy and small-angle x-ray scattering in solution
(SAXS). The biological significance of the structural models will be tested in gene silencing assays in the
fission yeast S. pombe. In Aim 2, we will determine the degree of conformational rearrangements of
chromatin when Swi6 engages the nucleosome to form a spreading competent state. The structure and
dynamics of the nucleosome-Swi6 complex will be interrogated by a combination of biophysical methods,
such as Methyl-TROSY NMR and HD-exchange mass-spectrometry (MS), that can provide residue specific
structural information in solution. Cross-linking mass-spectrometry in conjunction with cryoEM will be employed
to obtain models of the spreading competent form if Swi6 bound to nucleosomes. This approach will shed
insights into conformational control of heterochromatin formation by Swi6 in fission yeast and provide a
conceptual foundation for how heterochromatin is regulated in human cells.
项目总结
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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John D Gross其他文献
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{{ truncateString('John D Gross', 18)}}的其他基金
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10577994 - 财政年份:2023
- 资助金额:
$ 39.24万 - 项目类别:
Conformational Control of Heterochromatin Formation by the HP-1 Protein from Fission Yeast
裂殖酵母 HP-1 蛋白对异染色质形成的构象控制
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DOMAIN MAPPING HIV VIF COMPLEXES BY LIMITED PROTEOLYSIS AND MASS-SPECTROMETRY
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Structure and Function of the Decapping Enzyme Complex
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8387778 - 财政年份:2008
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Structure and Function of the Decapping Enzyme Complex
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