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.
项目总结/文摘
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:
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:
10052806 - 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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