Cardiac Myosin-Binding Protein C: Molecular Mechanisms Governing Cardiac Contractility
心肌肌球蛋白结合蛋白 C:控制心脏收缩力的分子机制
基本信息
- 批准号:10624275
- 负责人:
- 金额:$ 54.49万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-06-01 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:AblationActinsActomyosinAddressAdrenergic AgentsAffectAtomic Force MicroscopyBindingCardiacCardiac MyosinsCollaborationsContractile ProteinsDNADNA Sequence AlterationDefectDevelopmentEquilibriumFilamentGenerationsHeadHeartHeart failureHumanHypertrophic CardiomyopathyKnowledgeLasersLocationMass Spectrum AnalysisMeasuresModelingMolecularMolecular ConformationMolecular StructureMossesMotionMutagenesisMutationMyocardiumMyofibrilsMyosin ATPaseN-terminalNanotubesPerformancePeriodicityPhosphorylationPhysiologicalPositioning AttributePreparationProteinsPumpRegulationRelaxationRoleSarcomeresStructureSudden DeathSurfaceTechniquesTestingThickThick FilamentThin FilamentThinnessTimeTransgenic MiceVertebral columnbeta-Myosinbiophysical techniquescell motilitycitrate carrierflexibilityimprovedin vivomolecular mechanicsmutantmyosin-binding protein Cnanometernanoscalenovelnovel strategiesoperationrecruitresponsesingle moleculespatial relationshipsuperresolution imagingtargeted treatmentyoung adult
项目摘要
Cardiac myosin-binding protein C (cMyBP-C) is a sarcomeric thick filament associated protein that is essential
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 β-
adrenergic stimulation, phosphorylation may offer a measure of cMyBP-C functional tunability in order to
enhance cardiac contractility. To address these questions, we propose two specific aims. Aim 1 will test the
hypothesis that phosphorylation modulates cMyBP-C's N-terminal domain structure to influence its binding
partner interactions (i.e. thin filament and myosin head region). We will use a novel mass-spectrometry
technique and atomic force microscopy to characterize the molecular mechanics of cMyBP-C's N terminus that
has been structurally altered due to phosphorylation or mutagenesis. The functional impact of these structural
perturbations will be characterized in the context of cardiac myofibrils and native thick filaments to determine if
cMyBP-C operates only where it exist in the thick filament and whether it can sequester cardiac myosin into a
reserve pool of super-relaxed myosin heads. Thus, we will measure the location and time course of
fluorescent-ATP turnover in single cardiac myofibrils and the force generated by native thick filaments in the
laser trap in preparations from transgenic mice expressing phosphorylation and binding partner ablated mutant
cMyBP-C. In Aim 2 we will create DNA-based “designer” thick filament nanotubes to define how the spatial
relationships that normally exist in the thick filament between cMyBP-C and its myosin and actin binding
partners are critical determinants of cMyBP-C's modes of operation. These DNA-nanotubes will allow exquisite
nanometer spatial positioning of expressed cMyBP-C and human β-cardiac myosin on the nanotube surface
relative to each other. By this novel approach we can assign cMyBP C's modulation of actomyosin motility to
binding of the myosin head and/or thin filament, as assessed by both thin filament motility and force generation
using the laser trap. 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.
心脏肌球蛋白结合蛋白C(CMYBP-C)是肌肉厚的细丝相关的蛋白,是必不可少的
达到正常的心脏结构和功能。 CMYBP-C的重要性通过突变对CMYBP-C的强调
是肥厚性心肌病的主要原因。尽管是心脏收缩性的关键调节器,但
CMYBP-C调节肌动球蛋白力和运动产生的分子机制远非
尽管CMYBP-C的N末端结构域可以与肌动蛋白和肌球蛋白头部区域结合,但尚不清楚
这些约束伙伴中的哪一个在身体上是相关的,以及这些约束伙伴的互动是否
通过直接影响肌动球蛋白发电或通过改变Ca2+ - 来调节心脏收缩性。
依赖性细丝激活。随着CMYBP-C的N末端的磷酸化,响应于β-
肾上腺素模拟,磷酸化可能提供CMYBP-C功能可鼠的量度,以便为了
增强心脏收缩。为了解决这些问题,我们提出了两个具体目标。 AIM 1将测试
假设磷酸化调节CMYBP-C的N末端结构结构以影响其结合
伴侣互动(即细丝和肌球蛋白头部区域)。我们将使用一种新颖的质谱法
技术和原子力显微镜表征了CMYBP-C的N末端的分子机制
由于磷酸化或诱变,已在结构上改变了。这些结构的功能影响
扰动将在心脏肌原纤维和天然厚细丝的背景下进行表征
CMYBP-C仅在厚丝中存在的地方运行,是否可以将心脏肌球蛋白隔离到
保留超级磁头肌球蛋白头的池。那我们将测量的位置和时间课程
单个心脏肌原纤维中的荧光-ATP周转率,以及由天然厚细丝产生的力
来自表达磷酸化和结合伴侣消融突变体的转基因小鼠制剂的激光陷阱
CMYBP-C。在AIM 2中,我们将创建基于DNA的“设计师”厚丝纳米管,以定义空间如何
CMYBP-C及其肌球蛋白和肌动蛋白结合之间通常存在的关系
合作伙伴是CMYBP-C操作模式的关键决定者。这些DNA纳米管将允许独家
纳米型CMYBP-C和纳米管表面上表达的CMYBP-C和人β-心肌球蛋白的空间位置
相对于彼此。通过这种新颖的方法,我们可以将CMYBP C的Actomyosin运动调节调节
肌球蛋白头和/或细丝的结合,如薄细丝运动和力产生所评估
使用激光陷阱。借助从这些集体得出的CMYBP-C功能的知识和理解
可以开发针对CMYBP-C结合伴侣相互作用的针对针对性的疗法来帮助
调节并改善心脏失败的心脏表现。
项目成果
期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Dilated cardiomyopathy mutation in beta-cardiac myosin enhances actin activation of the power stroke and phosphate release.
扩张型心肌病β-心肌肌球蛋白突变增强了动力冲程的肌动蛋白激活和磷酸盐释放。
- DOI:10.1101/2023.11.10.566646
- 发表时间:2023
- 期刊:
- 影响因子:0
- 作者:Bodt,SkylarML;Ge,Jinghua;Ma,Wen;Rasicci,DavidV;Desetty,Rohini;McCammon,JAndrew;Yengo,ChristopherM
- 通讯作者:Yengo,ChristopherM
Cardiac myosin binding protein-C phosphorylation accelerates β-cardiac myosin detachment rate in mouse myocardium
心肌肌球蛋白结合蛋白-C 磷酸化加速小鼠心肌中β-心肌肌球蛋白脱离率
- DOI:10.1152/ajpheart.00673.2020
- 发表时间:2021
- 期刊:
- 影响因子:4.8
- 作者:Tanner, Bertrand C.;Previs, Michael J.;Wang, Yuan;Robbins, Jeffrey;Palmer, Bradley M.
- 通讯作者:Palmer, Bradley M.
Nanosurfer assay dissects β-cardiac myosin and cardiac myosin-binding protein C interactions.
- DOI:10.1016/j.bpj.2022.05.013
- 发表时间:2022-06-21
- 期刊:
- 影响因子:3.4
- 作者:Touma, Anja M.;Tang, Wanjian;Rasicci, David, V;Vang, Duha;Rai, Ashim;Previs, Samantha B.;Warshaw, David M.;Yengo, Christopher M.;Sivaramakrishnan, Sivaraj
- 通讯作者:Sivaramakrishnan, Sivaraj
A dynamic Dab2 keeps myosin VI stably on track.
- DOI:10.1016/j.jbc.2021.100640
- 发表时间:2021-01
- 期刊:
- 影响因子:0
- 作者:Cirilo JA Jr;Yengo CM
- 通讯作者:Yengo CM
Dilated cardiomyopathy mutation E525K in human beta-cardiac myosin stabilizes the interacting-heads motif and super-relaxed state of myosin.
- DOI:10.7554/elife.77415
- 发表时间:2022-11-24
- 期刊:
- 影响因子:7.7
- 作者:Rasicci DV;Tiwari P;Bodt SML;Desetty R;Sadler FR;Sivaramakrishnan S;Craig R;Yengo CM
- 通讯作者:Yengo CM
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Sivaraj Sivaramakrishnan其他文献
Sivaraj Sivaramakrishnan的其他文献
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{{ truncateString('Sivaraj Sivaramakrishnan', 18)}}的其他基金
Impact of dilated cardiomyopathy mutations on cardiac myosin structure and function
扩张型心肌病突变对心肌肌球蛋白结构和功能的影响
- 批准号:
10595237 - 财政年份:2022
- 资助金额:
$ 54.49万 - 项目类别:
Cardiac Myosin-Binding Protein C: Molecular Mechanisms Governing Cardiac Contractility
心肌肌球蛋白结合蛋白 C:控制心脏收缩力的分子机制
- 批准号:
10425753 - 财政年份:2020
- 资助金额:
$ 54.49万 - 项目类别:
Research Supplement to Promote Diversity in Health-Related Research
促进健康相关研究多样性的研究补充
- 批准号:
10615955 - 财政年份:2020
- 资助金额:
$ 54.49万 - 项目类别:
Cardiac Myosin-Binding Protein C: Molecular Mechanisms Governing Cardiac Contractility
心肌肌球蛋白结合蛋白 C:控制心脏收缩力的分子机制
- 批准号:
10427318 - 财政年份:2020
- 资助金额:
$ 54.49万 - 项目类别:
Cardiac Myosin-Binding Protein C: Molecular Mechanisms Governing Cardiac Contractility
心肌肌球蛋白结合蛋白 C:控制心脏收缩力的分子机制
- 批准号:
9907191 - 财政年份:2020
- 资助金额:
$ 54.49万 - 项目类别:
Cardiac Myosin-Binding Protein C: Molecular Mechanisms Governing Cardiac Contractility
心肌肌球蛋白结合蛋白 C:控制心脏收缩力的分子机制
- 批准号:
10171616 - 财政年份:2020
- 资助金额:
$ 54.49万 - 项目类别:
Research supplement to promote diversity in Heath-related research
研究补充以促进健康相关研究的多样性
- 批准号:
10221154 - 财政年份:2020
- 资助金额:
$ 54.49万 - 项目类别:
Cardiac Myosin-Binding Protein C: Molecular Mechanisms Governing Cardiac Contractility
心肌肌球蛋白结合蛋白 C:控制心脏收缩力的分子机制
- 批准号:
10618511 - 财政年份:2020
- 资助金额:
$ 54.49万 - 项目类别:
Emergent cellular functions of GPCRs and myosins
GPCR 和肌球蛋白的新兴细胞功能
- 批准号:
9919584 - 财政年份:2018
- 资助金额:
$ 54.49万 - 项目类别:
Emergent cellular functions of GPCRs and myosins
GPCR 和肌球蛋白的新兴细胞功能
- 批准号:
10550541 - 财政年份:2018
- 资助金额:
$ 54.49万 - 项目类别:
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