Regulation of Cytoplasmic Dynein
细胞质动力蛋白的调节
基本信息
- 批准号:8630495
- 负责人:
- 金额:$ 48.66万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-06-10 至 2018-02-28
- 项目状态:已结题
- 来源:
- 关键词:ATP HydrolysisAddressAffectAffinityBerylliumBindingBiochemistryBiological AssayBiophysicsCell physiologyCellsCellular biologyComplexCryoelectron MicroscopyDefectDevelopmentDiseaseDynein ATPaseElementsFluorescence MicroscopyGoalsGrantHumanIn VitroKinesinLaboratoriesLeadMechanicsMediatingMessenger RNAMethodsMicrotubulesMitotic spindleModelingMolecularMolecular MotorsMotorMotor ActivityMovementMutateMutationMyosin ATPaseNerve DegenerationNeurodegenerative DisordersNeuronsPropertyProteinsRegulationResearchResearch Project GrantsResolutionRoleStructureTestingWalkingbasecell motilitydimerdynactinin vivoinsightmacromoleculemonomermutantpolarized cellprotein complexpublic health relevanceresearch studysingle moleculethree dimensional structure
项目摘要
PROJECT SUMMARY
The long-term goal of this research project is to understand how the microtubule (MT)-based motor
cytoplasmic dynein ("dynein") is regulated. Dynein is the largest and most complex of all cytoskeletal motors;
this >1 MDa dimeric complex contains numerous mechanical elements whose movements must be
coordinated over strikingly long molecular distances to achieve processive motility along MTs. In addition to its
enormous size, dynein is also the most versatile of the molecular motors; in sharp contrast to the 45 kinesins
and 39 myosins present in humans, a single dynein gene product is responsible for transporting
macromolecules within neurons, constructing the mitotic spindle, polarizing cells, and anchoring mRNAs during
development. To give dynein the functional plasticity necessary for carrying out its many roles, several
ubiquitous co-factors interact with dynein, including Lis1 and the dynactin complex. This project will apply our
combined expertise in biochemistry, single-molecule biophysics and cryo-electron microscopy to address the
structural and mechanistic bases of dynein's interaction with MTs and its regulation by Lis1 and dynactin.
We recently showed that binding of dynein to MTs is accompanied by conformational changes in its MT-
binding domain and that Lis1 acts as a "clutch" to uncouple MT binding and release from ATP hydrolysis,
promoting a strongly MT-attached state. Dynactin, a 1.2 MDa complex, enhances dynein's processivity and is
required for nearly all dynein functions in cells, but its mechanism of action is poorly understood. This grant will
address major mechanistic questions about dynein and its regulation. What are the structural and mechanistic
bases of MT binding (Aim 1), and of regulation by Lis1 (Aim 2) and dynactin (Aim 3)?
项目摘要
该研究项目的长期目标是了解微管(MT)为基础的运动是如何
细胞质动力蛋白(“动力蛋白”)受到调节。动力蛋白是所有细胞骨架马达中最大和最复杂的;
这种>1 MDa的二聚体复合物含有许多机械元件,其运动必须是
在惊人的长分子距离上协调以实现沿沿着MT的进行性运动。除了其
动力蛋白体积巨大,也是最通用的分子马达;与45个驱动蛋白形成鲜明对比。
和39肌球蛋白存在于人类,一个单一的动力蛋白基因产物负责运输
大分子在神经元内,构建有丝分裂纺锤体,极化细胞,并锚定mRNA,
发展为了赋予动力蛋白发挥其多种作用所必需的功能可塑性,
普遍存在的辅因子与动力蛋白相互作用,包括Lis 1和动力蛋白复合物。该项目将应用我们的
结合生物化学,单分子生物物理学和冷冻电子显微镜的专业知识,
动力蛋白与MTs相互作用的结构和机制基础及其受Lis 1和dynactin的调节。
我们最近发现,动力蛋白与MT的结合伴随着MT构象的变化,
结合结构域,并且Lis 1作为“离合器”解偶联MT结合并从ATP水解中释放,
促进一个强烈的MT附着状态。Dynactin是一种1.2MDa的复合物,它增强了动力蛋白的持续合成能力,
细胞中几乎所有的动力蛋白功能都需要它,但其作用机制知之甚少。这笔赠款将
解决关于动力蛋白及其调节的主要机制问题。什么是结构和机械
MT结合的基础(目标1),以及由Lis 1(目标2)和dynactin(目标3)调节的基础?
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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Andres Leschziner其他文献
Andres Leschziner的其他文献
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{{ truncateString('Andres Leschziner', 18)}}的其他基金
Mechanism of cytoskeletal transport and transcription-coupled DNA repair
细胞骨架运输和转录偶联DNA修复机制
- 批准号:
10405228 - 财政年份:2022
- 资助金额:
$ 48.66万 - 项目类别:
Mechanism of cytoskeletal transport and transcription-coupled DNA repair
细胞骨架运输和转录偶联DNA修复机制
- 批准号:
10669570 - 财政年份:2022
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Chameleon Sample Preparation Device for Cryo-EM
用于冷冻电镜的变色龙样品制备装置
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10440804 - 财政年份:2022
- 资助金额:
$ 48.66万 - 项目类别:
Mechanism of cytoskeletal transport and transcription-coupled DNA repair
细胞骨架运输和转录偶联DNA修复机制
- 批准号:
10795265 - 财政年份:2022
- 资助金额:
$ 48.66万 - 项目类别:
A comparative structural study of ATP-dependent chromatin remodeling complexes
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- 资助金额:
$ 48.66万 - 项目类别:
A comparative structural study of ATP-dependent chromatin remodeling complexes
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10220986 - 财政年份:2011
- 资助金额:
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