Structural and Functional Characterization of the Chd1 Chromatin Remodeler
Chd1 染色质重塑剂的结构和功能表征
基本信息
- 批准号:10798558
- 负责人:
- 金额:$ 19.33万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-04-01 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:ATP phosphohydrolaseAddressAffectBindingBinding SitesBiological ModelsCHD1 geneChromatinCoupledDNADNA Binding DomainDNA SequenceDefectElementsEnzymesExperimental DesignsGenesGenomeGrowth and Development functionHealthHumanKineticsLinkMalignant NeoplasmsMolecular ConformationMotorMutationNucleosomesNucleotidesPhysical shapePositioning AttributeProcessRegulationRoleSideSlideStructureTestingabsorptioncancer typecell growthchromatin remodelingdevelopmental diseasehuman diseaseinsightpreferencetranslocase
项目摘要
ABSTRACT
Chromatin remodelers are ATP-dependent DNA translocases that catalyze disassembly, reassembly, and
repositioning of nucleosomes throughout eukaryotic genomes. As evidenced from multiple types of cancer and
developmental disorders associated with remodeler mutations, chromatin remodeling is essential for normal
growth and development. This proposal aims to address core mechanistic questions of remodeler action and
regulation, using the Chd1 chromatin remodeler as a model system. Recent studies revealed that chromatin
remodelers shift nucleosomes using a twist defect mechanism. In this process, remodelers couple distinct
nucleotide-dependent conformations of the ATPase motor to create and then eliminate DNA distortions (twist
defects) that stimulate the nucleosome to transiently absorb and then release an extra bp at the remodeler
binding site. Currently, it is unknown how remodelers create twist defects. Aim 1 of this proposal seeks to
identify key residues and elements of Chd1 necessary for distorting DNA into twist defects, which should allow
for a mechanistic understanding of this central process. Another question addressed by this proposal is how
remodeler ATPases are regulated. For Chd1, nucleosome sliding activity is coupled to DNA outside the
nucleosome, with a requirement for flanking DNA on the “entry” side and preference for little or no DNA on the
“exit” side. For Chd1, flanking DNA controls sliding activity through a DNA-binding domain that is coupled to
autoinhibitory elements. A central question addressed by Aim 2 of this proposal is how stability and interactions
of autoinhibitory elements are controlled by distinct domain arrangements on the nucleosome. Experiments are
designed to reveal kinetic transitions of remodeler rearrangements on the nucleosome. Finally, a major
unanswered question is how two remodelers bound to the same nucleosome affect activity of each other. Chd1
has been shown to bind to nucleosomes in a 2:1 ratio, with the DNA-binding domain interacting in trans with
the chromo-ATPase, yet the significance of these interactions is unknown. Aim 3 tests the hypothesis that two
opposing remodelers bound to the same nucleosome antagonize each other. Together, these studies will
provide new mechanistic insights into how remodelers alter nucleosome structure, autoregulate action of their
central ATPase motor, and coordinate and potentially control other remodelers on the nucleosome.
抽象的
染色质重塑是ATP依赖性的DNA易位酶,可催化拆卸,重新组装
核糖体的重新定位是癌症的多裂。
与重塑突变相关的发育障碍,染色质重塑对于正常
增长和发展。
调节,使用CHD1染色质重塑作为模型系统。
在此过程中,使用扭曲缺陷机制进行重塑。
ATPase电动机的核苷酸深度构象会产生和裂变(扭曲)
刺激核小体瞬时吸收的缺陷),然后在重塑器处释放额外的BP
绑定站点。
确定将DNA变成扭曲缺陷所必需的CHD1的关键残基和元素,这应允许
为了理解此项目的另一个问题。
改建机适用于CHD1。
核小体,需要在“入口”侧侧翼DNA,并且偏爱很少或没有DNA
“出口”一侧。
自动抑制元素。
自抑制元件由核小体上的不同域排列控制
旨在揭示核小体上重塑的动力学转变
未解决的问题是如何与相同的核小体相互影响的两个重塑
已显示以2:1的比例与核小体结合,而DNA结合结构域则与Trans相互作用
铬atpase,但固定相互作用的意义尚不清楚。
相对的重塑与同一核小体结合在一起,这些研究将相互拮抗。
提供有关重塑如何改变核小体结构,自动调节作用的新机械洞察力
中央ATPase电动机,并在核小体上协调并可能控制其他重塑剂。
项目成果
期刊论文数量(37)
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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GREGORY DEAN BOWMAN其他文献
GREGORY DEAN BOWMAN的其他文献
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Structural Studies of the Tumor M2 Isoform of Pyruvate Kinase
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- 批准号:
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- 资助金额:
$ 19.33万 - 项目类别:
STRUCTURE DETERMINATION OF THE DNA BINDING DOMAIN OF S CEREVISIAE CHD1 IN COMPL
完整的酿酒酵母CHD1 DNA结合域的结构测定
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$ 19.33万 - 项目类别:
STRUCTURE DETERMINATION OF THE CHD1 DNA-BINDING DOMAIN
CHD1 DNA 结合域的结构测定
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8363383 - 财政年份:2011
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$ 19.33万 - 项目类别:
STRUCTURAL CHARACTERIZATION OF THE NUCLEOSOME-CHD1 COMPLEX
核小体-CHD1 复合物的结构表征
- 批准号:
8363549 - 财政年份:2011
- 资助金额:
$ 19.33万 - 项目类别:
Structural and Functional Analysis of the CHD1 Chromatin Remodeler
CHD1 染色质重塑蛋白的结构和功能分析
- 批准号:
7931254 - 财政年份:2009
- 资助金额:
$ 19.33万 - 项目类别:
Structural and Functional Analysis of the CHD1 Chromatin Remodeler
CHD1 染色质重塑蛋白的结构和功能分析
- 批准号:
8248770 - 财政年份:2008
- 资助金额:
$ 19.33万 - 项目类别:
Structural and Functional Analysis of the Chd1 Chromatin Remodeler
Chd1 染色质重塑剂的结构和功能分析
- 批准号:
8579226 - 财政年份:2008
- 资助金额:
$ 19.33万 - 项目类别:
Structural and Functional Analysis of the Chd1 Chromatin Remodeler
Chd1 染色质重塑剂的结构和功能分析
- 批准号:
8727583 - 财政年份:2008
- 资助金额:
$ 19.33万 - 项目类别:
Structural and Functional Analysis of the Chd1 Chromatin Remodeler
Chd1 染色质重塑剂的结构和功能分析
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9912780 - 财政年份:2008
- 资助金额:
$ 19.33万 - 项目类别:
Structural and Functional Analysis of the CHD1 Chromatin Remodeler
CHD1 染色质重塑蛋白的结构和功能分析
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8043586 - 财政年份:2008
- 资助金额:
$ 19.33万 - 项目类别:
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