Structure-Function of Nucleo-Cytoplasmic Communication
核-细胞质通讯的结构-功能
基本信息
- 批准号:10793672
- 负责人:
- 金额:$ 9.28万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-01 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AddressCardiacCardiomyopathiesCell NucleusCell physiologyCellsCommunicationComplexCryo-electron tomographyCryoelectron MicroscopyCytoskeletonDrug DesignElementsEmery-Dreifuss Muscular DystrophyEukaryotic CellFunctional disorderGenetic MaterialsGenetic TranscriptionGoalsHumanIndividualLifeMalignant NeoplasmsMapsMembraneMethodsMolecularMuscular DystrophiesMyopathyNuclear EnvelopeNuclear Pore ComplexOrganellesPositioning AttributePremature aging syndromePrimary DystoniasProcessProductivityProteinsResolutionSWP29StructureTechnologyTranslationsX-Ray Crystallographygrasphuman diseaseinnovationmechanotransductionprotein complexskeletalsuccess
项目摘要
PROJECT SUMMARY / ABSTRACT
Eukaryotic cells are defined by their organelles, membrane-enclosed compartments in which specific cellular
processes are carried out. The nucleus is the largest organelle, contains all genetic material, and enables
separation of gene transcription from protein translation. As the nuclear envelope (NE) serves as a tight barrier
enclosing the nucleus, the cell requires machinery to establish and control nucleo-cytoplasmic communication.
There are two principally different components to this machinery. Nuclear pore complexes (NPCs) serve as the
main conduit for molecular exchange across the NE, while universally conserved linker of nucleo- and
cytoskeleton (LINC) complexes serve as physical tethers across the NE. LINCs are necessary for positioning
the nucleus and for mechano-sensing in a diverse set of circumstances. Dysfunction of the machinery is at the
core of important human diseases, including skeletal and cardiac myopathies, premature aging, and cancer. Our
goal is to understand the structure of the protein complexes involved in nucleo-cytoplasmic communication at
high (atomic) resolution. Such information helps to identify and separate the myriad functions this machinery
carries out and that we are still only beginning to fully grasp. High resolution information further provides the
basis for structure-guided drug design to interfere with the salient human diseases, such as Emery-Dreifuss
Muscular Dystrophy (EDMD) and Primary Dystonia, which are still not cured. The structural characterization of
the NPC and the LINC complex are challenging, because of the size and complexity of these multi-MDa
assemblies. Over the past 15 years, we have made significant advances on both problems. For the NPC, we
have chosen a highly productive bottom-up approach, in which we characterized multi-subunit complexes
predominantly by X-ray crystallography, the building blocks of the massive, 40-100 MDa NPC. Those structures
have now been used in combination with cryo-electron tomographic (cryo-ET) maps of assembled NPCs to
generate composite structures that can tentatively position the roughly 500 individual proteins within one NPC.
For the LINC complex, we solved the universally conserved core component and have started to untangle the
diverse network of its components, the Sad1/UNC-84 (SUN) and Klarsicht/ANC1/Syne-Homology (KASH)
proteins. Going forward, the challenge is the structural characterization of large and dynamic assemblies, which
is true for both, the NPC and the LINC complex, for the latter particularly when including the connection to the
nucleo- and cytoskeletal components. The dramatic advances in cryo-electron microscopy (cryo-EM) over the
recent past make this technology particularly important for our studies. We anticipate combining X-ray
crystallography and cryo-EM for studying the most relevant structures going forward. The success of this will
depend upon innovative methods to address the particular challenges that come with each project. We have
repeatedly shown how to successfully approach such challenges and have devised methods to meet them.
项目总结/摘要
真核细胞由它们的细胞器定义,细胞器是膜封闭的隔室,其中特定的细胞
过程进行。细胞核是最大的细胞器,包含所有遗传物质,
基因转录与蛋白质翻译的分离。由于核被膜(NE)是一个紧密的屏障,
包围细胞核的细胞需要机制来建立和控制核质通讯。
这一机制有两个主要不同的组成部分。核孔复合物(NPC)作为
跨NE分子交换的主要管道,而普遍保守的核-和
细胞骨架(LINC)复合物充当穿过NE的物理系链。LINC是定位所必需的
在不同的环境下,细胞核和机械感应。机器的故障是在
核心的重要人类疾病,包括骨骼和心脏肌病,过早衰老和癌症。我们
目的是了解参与核质通讯的蛋白质复合物的结构,
高(原子)分辨率。这些信息有助于识别和分离这一机制的无数功能
这一点,我们才刚刚开始全面了解。高分辨率信息进一步提供了
结构导向药物设计的基础,以干扰突出的人类疾病,如Emery-Dreifuss
肌营养不良症(EDMD)和原发性肌张力障碍,这仍然没有治愈。的结构表征
由于这些多个多学科设计领域(multi-MDa)的规模和复杂性,NPC和LINC复合体是具有挑战性的
组件.过去15年来,我们在这两个问题上都取得了重大进展。对于NPC,我们
我选择了一种高效的自下而上的方法,在这种方法中,我们描述了多亚基复合物的特征,
主要是通过X射线晶体学,巨大的,40-100 MDa NPC的构建块。这些结构
现在已经与组装NPC的低温电子断层扫描(cryo-ET)图结合使用,
生成复合结构,可以在一个NPC中暂时定位大约500个蛋白质。
对于LINC复合体,我们解决了普遍保守的核心组件,并开始解开
其组成部分的多样化网络,Sad 1/ANC-84(SUN)和Klarsicht/ANC 1/Syne-Homology(KASH)
proteins.展望未来,挑战是大型动态组件的结构表征,
对于NPC和LINC复合体两者都是如此,对于后者,特别是当包括到
核和细胞骨架成分。冷冻电子显微镜(cryo-EM)在过去的几年中取得了巨大的进展,
最近的过去使这项技术对我们的研究特别重要。我们预计结合X光
晶体学和冷冻电镜来研究未来最相关的结构。这一举措的成功将
依靠创新的方法来解决每个项目带来的特殊挑战。我们有
我们反复展示了如何成功地应对这些挑战,并设计了应对这些挑战的方法。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Solving the nuclear pore puzzle.
解决核孔之谜。
- DOI:10.1126/science.abq4792
- 发表时间:2022
- 期刊:
- 影响因子:0
- 作者:Schwartz,ThomasU
- 通讯作者:Schwartz,ThomasU
The cellular environment shapes the nuclear pore complex architecture.
- DOI:10.1038/s41586-021-03985-3
- 发表时间:2021-10
- 期刊:
- 影响因子:64.8
- 作者:Schuller AP;Wojtynek M;Mankus D;Tatli M;Kronenberg-Tenga R;Regmi SG;Dip PV;Lytton-Jean AKR;Brignole EJ;Dasso M;Weis K;Medalia O;Schwartz TU
- 通讯作者:Schwartz TU
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Thomas Schwartz其他文献
Thomas Schwartz的其他文献
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{{ truncateString('Thomas Schwartz', 18)}}的其他基金
Mechanism of nuclear pore passage of the HIV-1 capsid
HIV-1衣壳核孔通过机制
- 批准号:
10762097 - 财政年份:2023
- 资助金额:
$ 9.28万 - 项目类别:
Structure-Function of Nucleo-Cytoplasmic Communication
核-细胞质通讯的结构-功能
- 批准号:
10475615 - 财政年份:2021
- 资助金额:
$ 9.28万 - 项目类别:
Structure-Function of Nucleo-Cytoplasmic Communication
核-细胞质通讯的结构-功能
- 批准号:
10693850 - 财政年份:2021
- 资助金额:
$ 9.28万 - 项目类别:
Structure-Function of Nucleo-Cytoplasmic Communication
核-细胞质通讯的结构-功能
- 批准号:
10205329 - 财政年份:2021
- 资助金额:
$ 9.28万 - 项目类别:
Structure-Function of the Nuclear Envelope Bridge and its Role in Laminopathies
核膜桥的结构-功能及其在核纤层蛋白病中的作用
- 批准号:
8816200 - 财政年份:2014
- 资助金额:
$ 9.28万 - 项目类别:
Structure-Function of the Nuclear Envelope Bridge and its Role in Laminopathies
核膜桥的结构-功能及其在核纤层蛋白病中的作用
- 批准号:
8926847 - 财政年份:2014
- 资助金额:
$ 9.28万 - 项目类别:
Structure-Function of the Nuclear Envelope Bridge and its Role in Laminopathies
核膜桥的结构-功能及其在核纤层蛋白病中的作用
- 批准号:
9119762 - 财政年份:2014
- 资助金额:
$ 9.28万 - 项目类别:
Structure-Function of the Nuclear Envelope Bridge and its Role in Laminopathies
核膜桥的结构-功能及其在核纤层蛋白病中的作用
- 批准号:
9325433 - 财政年份:2014
- 资助金额:
$ 9.28万 - 项目类别:
Structure-Function of the Nuclear Envelope Bridge and its Role in Laminopathies
核膜桥的结构-功能及其在核纤层蛋白病中的作用
- 批准号:
8261891 - 财政年份:2011
- 资助金额:
$ 9.28万 - 项目类别:
Structure-Function of the Nuclear Envelope Bridge and its Role in Laminopathies
核膜桥的结构-功能及其在核纤层蛋白病中的作用
- 批准号:
8174164 - 财政年份:2011
- 资助金额:
$ 9.28万 - 项目类别:
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