Cardiac Myosin-Binding Protein C: Molecular Modulation of Actomyosin Function.
心肌肌球蛋白结合蛋白 C:肌动球蛋白功能的分子调节。
基本信息
- 批准号:8860500
- 负责人:
- 金额:$ 47.18万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-09-01 至 2019-05-31
- 项目状态:已结题
- 来源:
- 关键词:ActinsActivities of Daily LivingActomyosinAdrenergic AgentsAffectAffinityAlanineAspartic AcidAtomic Force MicroscopyBindingBinding SitesBiological AssayBiological ModelsCalciumCalcium BindingCardiacCardiac Muscle ContractionCardiac MyosinsCircular DichroismComplexCoupledCyclic AMP-Dependent Protein KinasesDNA Sequence AlterationDefectDevelopmentDiastoleDiseaseEventFiberFunctional disorderGenerationsGenesHeadHeartHeart failureHumanHypertrophic CardiomyopathyImaging TechniquesIn SituIn VitroIndividualKnowledgeLabelLightLinkLiteratureMeasuresMicroscopicMicroscopyMolecularMolecular StructureMonitorMotionMusMutagenesisMutateMutationMyofibrilsMyosin ATPaseN-terminalPerformancePhosphorylationPhosphorylation SiteProteinsResolutionSarcomeresSerineSiteStructureSudden DeathSystoleTestingThick FilamentThin FilamentTimeTissuesTransgenic MiceTropomyosinTroponinUncertaintyVertebral columnactivated Protein Cadrenergicbasebiophysical techniquescell motilityimprovedin vitro Modelin vivoinnovationlight scatteringmolecular mechanicsmutantmyosin-binding protein Cpublic health relevanceresponsesingle-molecule FRETtargeted treatmentyoung adult
项目摘要
DESCRIPTION (provided by applicant): Cardiac myosin-binding protein C (cMyBP-C) is a sarcomeric thick filament associated protein that is critically important to normal cardiac structure and function. The importance of cMyBP-C is emphasized by mutations to cMyBP-C being a leading cause of hypertrophic cardiomyopathy. Despite being a key regulator of cardiac contractility, the molecular mechanism by which cMyBP-C modulates actomyosin force and motion generation is far from certain. Although cMyBP-C's N-terminal domains can bind to actin and the myosin head region, it is not known which of these binding partners is physiologically relevant and whether these binding partner interactions modulate cardiac contractility by directly affecting actomyosin power generation or indirectly by altering Ca2+-dependent thin filament activation. With phosphorylation of cMyBP-C's N terminus occurring in response to ß-adrenergic stimulation, phosphorylation may offer a measure of cMyBP-C functional tunability in order to enhance cardiac contractility. We propose the following three specific aims. Aim 1 tests the hypothesis that cMyBP-C's thin filament activation and actomyosin power inhibition are independent mechanisms associated with a specific binding partner. Thus, cMyBP-C binding partner interactions will be determined using state-of-the-art molecular biophysical approaches in simplified in vitro model systems (e.g. single molecule FRET) and in situ within myofibrils (super-resolution STORM microscopy). Structural mutagenesis of cMyBP-C to ablate binding partner sites of interaction in both expressed N-terminal fragments and in mutant cMyBP-C from transgenic mice will help link cMyBP-C's functional capacities to its interaction with either the thin filament or the myosin head region. Aim 2 tests the hypothesis that cMyBP-C activates the thin filament directly through a mechanism similar to calcium activation. Thus, we have developed an in vitro single thin filament activation assay to monitor the molecular sequence of events by which expressed fluorescently-labeled N-terminal fragments of cMyBP-C initiate the cooperative recruitment of fluorescently- labeled myosin molecules to the thin filament. Aim 3 tests the hypothesis that phosphorylation of cMyBP-C tunes cMyBP-C's modulation of contractility through alterations in cMyBP-C's molecular mechanics, which in turn alters its binding partner interactions. Cardiac tissue and native thick filaments from transgenic mice expressing mutant cMyBP-C as well as expressed N-terminal fragments with one or more serines replaced by non-phosphorylatable alanines or aspartic acids (phosphomimetics) will be used in assays described in Aims 1 and 2 to characterize the effect of site-specific phosphorylation. Using atomic force microscopy, we will characterize possible mechanisms by which phosphorylation affects M-domain molecular mechanics and structure, thus modulating cMyBP-C function. With the knowledge and understanding of cMyBP-C function derived from these collective studies, targeted therapies directed at cMyBP-C binding partner interactions may be developed to help modulate and to improve cardiac performance in the failing heart.
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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David M Warshaw其他文献
David M Warshaw的其他文献
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{{ truncateString('David M Warshaw', 18)}}的其他基金
Cargo Transport by Myosin Va and Kinesin-1 Molecular Motors: In Vitro Model Systems that Build Complexity in 3-Dimensions.
Myosin Va 和 Kinesin-1 分子马达的货物运输:构建 3 维复杂性的体外模型系统。
- 批准号:
10393000 - 财政年份:2021
- 资助金额:
$ 47.18万 - 项目类别:
Cargo Transport by Myosin Va and Kinesin-1 Molecular Motors: In Vitro Model Systems that Build Complexity in 3-Dimensions.
Myosin Va 和 Kinesin-1 分子马达的货物运输:构建 3 维复杂性的体外模型系统。
- 批准号:
10204620 - 财政年份:2021
- 资助金额:
$ 47.18万 - 项目类别:
Equipment supplement - Refeyn TwoMP iSCAT microscope
设备补充 - Refeyn TwoMP iSCAT 显微镜
- 批准号:
10784112 - 财政年份:2021
- 资助金额:
$ 47.18万 - 项目类别:
Cargo Transport by Myosin Va and Kinesin-1 Molecular Motors: In Vitro Model Systems that Build Complexity in 3-Dimensions.
Myosin Va 和 Kinesin-1 分子马达的货物运输:构建 3 维复杂性的体外模型系统。
- 批准号:
10605333 - 财政年份:2021
- 资助金额:
$ 47.18万 - 项目类别:
Cardiac Myosin-Binding Protein C: Molecular Modulation of Actomyosin Function.
心肌肌球蛋白结合蛋白 C:肌动球蛋白功能的分子调节。
- 批准号:
9128036 - 财政年份:2015
- 资助金额:
$ 47.18万 - 项目类别:
Cardiac Myosin-Binding Protein C: Molecular Modulation of Actomyosin Function.
心肌肌球蛋白结合蛋白 C:肌动球蛋白功能的分子调节。
- 批准号:
9282730 - 财政年份:2015
- 资助金额:
$ 47.18万 - 项目类别:
Myosin Va and VI Cargo Transport: In Vitro Model Systems
肌球蛋白 Va 和 VI 货物运输:体外模型系统
- 批准号:
8103714 - 财政年份:2011
- 资助金额:
$ 47.18万 - 项目类别:
cMyBP-C: Molecular Mechanisms of Actomyosin Modulation
cMyBP-C:肌动球蛋白调节的分子机制
- 批准号:
8215309 - 财政年份:2011
- 资助金额:
$ 47.18万 - 项目类别:
Myosin Va and VI Cargo Transport: In Vitro Model Systems
肌球蛋白 Va 和 VI 货物运输:体外模型系统
- 批准号:
8248783 - 财政年份:2011
- 资助金额:
$ 47.18万 - 项目类别:
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