Molecular and cellular mechanisms of the actin cytoskeleton organization and function
肌动蛋白细胞骨架组织和功能的分子和细胞机制
基本信息
- 批准号:10419950
- 负责人:
- 金额:$ 36.86万
- 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:2022-09-01 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalActin-Binding ProteinActinsAdhesionsAgeAllosteric RegulationArchitectureAttenuatedAutoimmune DiseasesAutoimmune ProcessBindingBiochemicalBiologicalBloodBundlingCancer InterventionCell AdhesionCell divisionCell physiologyCellsChronic Lymphocytic LeukemiaCommunicationCommunitiesComplexConnective Tissue DiseasesCouplingCrosslinkerCryo-electron tomographyCryoelectron MicroscopyCytokinesisCytoskeletonDataDeletion MutationDiaphragmatic HerniaDiseaseDisseminated Malignant NeoplasmEndocytosisEpithelialEventF-ActinFamilyFiberFilopodiaFimbrinFluorescenceFluorescence MicroscopyFocal AdhesionsFosteringGoalsHealthHumanHuman ActivitiesImmune systemIndividualIntestinesInvestigationKidneyLCP1 geneLabyrinthLeadLibrariesLinkMalignant NeoplasmsMapsMediatingMembraneMetastatic toMicrofilamentsModelingMolecularMolecular ConformationMutationNutrientOsteogenesisOsteoporosisPathologyPerceptionPersonal SatisfactionPost-Translational Protein ProcessingProcessPropertyProtein IsoformsProteinsPublishingRecyclingRegulationRenal dialysisResearchResolutionRoleShapesSignal TransductionSiteStructural ModelsStructureSyndromeSystems DevelopmentTestingTherapeuticTherapeutic InterventionTissuesTranslatingTropomyosinVariantWorkX-Ray Crystallographybone fragilitycalponincancer cellcancer invasivenesscell motilitycellular microvilluscongenital deafnesscongenital hearing losscoronin proteincrosslinkdeafnessflexibilityfunctional outcomeshearing impairmentimmune activationimmunological synapse formationimprovedinterestmembermigrationmolecular dynamicsmutantplastinprotein crosslinkreconstructionrecruitresponsesingle moleculestem
项目摘要
PROJECT SUMMARY/ABSTRACT
The remarkable functional versatility of the actin cytoskeleton stems from its ability to assemble into a variety
of diverse structures – branched networks, meshes, and bundles. This architectural complexity is orchestrated
by actin-binding proteins, whose activity is delicately regulated in response to internal and external signals. Our
long-term goal is to contribute to human health and well-being by advancing the understanding of the actin
cytoskeleton organization by actin-bundling proteins and their contribution to pathologies (e.g., congenital
diseases and metastatic cancers). Plastin/fimbrin family of cytoskeleton organizers are conserved proteins that
promote assembly of actin filaments into bundles involved in cell migration, adhesion, cytokinesis, and formation
of stereocilia and microvilli structures of the inner ear, intestinal and kidney epithelia. Of three human plastin
(PLS) isoforms, PLS1 deletion results in deafness, PLS2 contributes to pathologies of the immune system and
the development of aggressive metastatic cancers, while mutations in PLS3 lead to severe osteoporosis with
bone fragility and other connective tissue disorders. Despite the importance and a long-lasting interest of the
research community to these proteins, understanding of their interaction with actin and their regulation is
superficial, whereas published structural and biochemical data are incomplete, scattered, and sometimes
contradictory. The overall objective of the current proposal is to fill these major gaps by providing a thorough
characterization of the molecular and cellular mechanisms governing the function of plastins and to demonstrate
how this improved understanding can contribute to explaining the pathology of plastin-related diseases. We
propose that the unique domain organization of plastins enables several regulation modes interconnected via a
central allosteric mechanism that confers multifaceted contribution to various actin-governed cellular processes.
Biochemical characterization of plastin isoforms will reveal mechanisms of their regulation and function at the
molecular level (Aim 1a,b); high-resolution cryo-electron microscopy (EM)/cryo-electron tomography (ET)
reconstruction will provide structural details of plastin interaction with actin (Aim 1c); structural analysis and
atomistic molecular dynamics (MD) simulations will generate a model of the auto-inhibition allowing to predict
functional outcomes of congenital mutations (Aim 2); while Aim 3 will focus on understanding functional
significance and implications of the allosteric auto-inhibition of plastins and its role in cooperation with other actin-
binding proteins. These approaches, supported by single-molecule speckle (SiMS), total internal reflection
fluorescence (TIRF), and bulk epi-fluorescence microscopy, will unveil plastin dynamics, cooperation with protein
partners, and contribution to actin-dependent processes in living cells. The proposal will result in a breakthrough
in the understanding of the actin-dependent cellular events controlled by the plastin/fimbrin family of cytoskeleton
organizers, uncover molecular mechanisms behind plastin-linked congenital (deafness, osteoporosis, and
diaphragmatic hernia) and acquired (cancer) diseases, opening opportunities for their specific therapeutics.
项目概要/摘要
肌动蛋白细胞骨架卓越的功能多样性源于其组装成多种细胞的能力
不同的结构——分支网络、网格和束。这种架构的复杂性是精心策划的
由肌动蛋白结合蛋白产生,其活性根据内部和外部信号进行精细调节。我们的
长期目标是通过增进对肌动蛋白的理解来为人类健康和福祉做出贡献
肌动蛋白捆绑蛋白的细胞骨架组织及其对病理学的贡献(例如先天性
疾病和转移性癌症)。细胞骨架组织者的塑性蛋白/纤毛蛋白家族是保守的蛋白质,
促进肌动蛋白丝组装成参与细胞迁移、粘附、胞质分裂和形成的束
内耳、肠和肾上皮细胞的静纤毛和微绒毛结构。三种人类塑性蛋白
(PLS) 同种型,PLS1 缺失会导致耳聋,PLS2 会导致免疫系统病变,
侵袭性转移性癌症的发展,而 PLS3 突变会导致严重的骨质疏松症
骨质脆弱和其他结缔组织疾病。尽管重要性和长期的兴趣
研究界对这些蛋白质的了解,了解它们与肌动蛋白的相互作用及其调节
肤浅,而已发表的结构和生化数据不完整、分散,有时
矛盾的。当前提案的总体目标是通过提供彻底的解决方案来填补这些主要空白
表征控制塑蛋白功能的分子和细胞机制并证明
这种加深的理解如何有助于解释与塑性蛋白相关的疾病的病理学。我们
提出塑料蛋白独特的结构域组织使得多种调节模式通过
中央变构机制,为各种肌动蛋白控制的细胞过程提供多方面的贡献。
塑性蛋白亚型的生化表征将揭示其调节和功能的机制
分子水平(目标 1a、b);高分辨率冷冻电子显微镜 (EM)/冷冻电子断层扫描 (ET)
重建将提供塑性蛋白与肌动蛋白相互作用的结构细节(目标 1c);结构分析和
原子分子动力学(MD)模拟将生成一个自动抑制模型,可以预测
先天性突变的功能结果(目标 2);而目标 3 将侧重于理解功能性
塑蛋白变构自动抑制的意义和含义及其与其他肌动蛋白合作的作用
结合蛋白。这些方法由单分子散斑 (SiMS)、全内反射支持
荧光 (TIRF) 和散装落射荧光显微镜将揭示塑性蛋白动力学以及与蛋白质的合作
合作伙伴,以及对活细胞中肌动蛋白依赖性过程的贡献。该提案将带来突破
理解由细胞骨架的塑性蛋白/纤毛蛋白家族控制的肌动蛋白依赖性细胞事件
组织者,揭示与塑性蛋白相关的先天性疾病(耳聋、骨质疏松症和
膈疝)和获得性(癌症)疾病,为其特定疗法提供了机会。
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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Dmitri Kudryashov其他文献
Dmitri Kudryashov的其他文献
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{{ truncateString('Dmitri Kudryashov', 18)}}的其他基金
Molecular and cellular mechanisms of the actin cytoskeleton organization and function
肌动蛋白细胞骨架组织和功能的分子和细胞机制
- 批准号:
10797753 - 财政年份:2022
- 资助金额:
$ 36.86万 - 项目类别:
Molecular Mechanisms of Bacterial Toxins Targeting the Actin Cytoskeleton
针对肌动蛋白细胞骨架的细菌毒素的分子机制
- 批准号:
10417139 - 财政年份:2015
- 资助金额:
$ 36.86万 - 项目类别:
Molecular Mechanisms of Bacterial Toxins Targeting the Actin Cytoskeleton
针对肌动蛋白细胞骨架的细菌毒素的分子机制
- 批准号:
10224947 - 财政年份:2015
- 资助金额:
$ 36.86万 - 项目类别:
Molecular Mechanisms of Bacterial Toxins Targeting the Actin Cytoskeleton
针对肌动蛋白细胞骨架的细菌毒素的分子机制
- 批准号:
10052806 - 财政年份:2015
- 资助金额:
$ 36.86万 - 项目类别:
Name Molecular mechanisms of bacterial toxins targeting actin cytoskeleton
名称 靶向肌动蛋白细胞骨架的细菌毒素的分子机制
- 批准号:
10632748 - 财政年份:2015
- 资助金额:
$ 36.86万 - 项目类别:
Molecular Mechanisms of Bacterial Toxins Targeting the Actin Cytoskeleton
针对肌动蛋白细胞骨架的细菌毒素的分子机制
- 批准号:
10683078 - 财政年份:2015
- 资助金额:
$ 36.86万 - 项目类别:
Molecular Mechanisms of Bacterial Toxins Targeting the Actin Cytoskeleton
针对肌动蛋白细胞骨架的细菌毒素的分子机制
- 批准号:
10725070 - 财政年份:2015
- 资助金额:
$ 36.86万 - 项目类别:
Actin oligomers as novel toxins targeting key steps of actin dynamics
肌动蛋白寡聚物作为针对肌动蛋白动力学关键步骤的新型毒素
- 批准号:
9134177 - 财政年份:2015
- 资助金额:
$ 36.86万 - 项目类别:
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