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.
项目摘要/摘要
肌动蛋白细胞骨架的显著功能多功能性源于它能够组装成各种
由不同的结构组成-分支网络、网状结构和束状结构。这种架构复杂性是经过精心编排的
通过肌动蛋白结合蛋白,其活性受到内部和外部信号的微妙调节。我们的
长期目标是通过促进对肌动蛋白的理解,为人类的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在病理中的作用(例如,先天性
疾病和转移性癌症)。纤毛蛋白/纤毛蛋白家族的细胞骨架组织者是保守的蛋白质,
促进肌动蛋白细丝组装成束,参与细胞迁移、黏附、胞质分裂和形成
内耳、肠和肾上皮的立体纤毛和微绒毛结构。三种人类纤溶酶原
(PLS)亚型,PLS1缺失导致耳聋,PLS2参与免疫系统和
侵袭性转移癌的发展,而PLS3突变导致严重的骨质疏松症
骨脆性和其他结缔组织疾病。尽管世界经济的重要性和长期利益
对于这些蛋白质的研究,了解它们与肌动蛋白的相互作用及其调控是
肤浅的,而已发表的结构和生化数据是不完整的,分散的,有时
自相矛盾。目前提案的总体目标是通过提供全面的
控制Plastins功能的分子和细胞机制的表征和演示
这一改进的理解如何有助于解释与纤溶酶相关的疾病的病理。我们
提出质膜蛋白独特的结构域组织使几种调控模式能够通过
中央变构机制,赋予多方面的贡献,各种肌动蛋白管理的细胞过程。
纤溶酶原异构体的生化特征将揭示其调控和功能的机制。
分子水平(目标1a,b);高分辨率低温电子显微镜(EM)/低温电子断层扫描(ET)
重建将提供血浆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)模拟将生成自动抑制的模型,从而能够预测
先天性突变的功能结果(目标2);而目标3将侧重于了解功能
Plastins的变构自抑制及其与其他肌动蛋白协同作用的意义和意义
结合蛋白。这些方法由单分子散斑(SIMS)支持,全内反射
荧光(TIRF)和体表荧光显微镜将揭示与蛋白质合作的纤溶酶动力学
合作伙伴,以及对活细胞中肌动蛋白依赖过程的贡献。这项提议将取得突破。
在理解由细胞骨架的纤毛蛋白/纤毛蛋白家族控制的肌动蛋白依赖性细胞事件中
组织者,揭示与纤溶酶相关的先天性(耳聋、骨质疏松症和
横隔膜疝气)和获得性(癌症)疾病,为他们的特定治疗提供了机会。
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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