Discovery of human cardiac myosin regulatory sites, modulating cross-bridge kinetics in heart muscle

发现人类心肌肌球蛋白调节位点,调节心肌的跨桥动力学

基本信息

  • 批准号:
    9098891
  • 负责人:
  • 金额:
    $ 44万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-04-05 至 2020-03-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Abstract Healthy human cardiac muscle is composed of two myosin isoforms, alpha and beta, which are significantly different in kinetics of the cross-bridge cycle. The specific myosin isoform composition tunes muscle for maximum performance, force production, power output, and economy. The mechanisms behind this fine muscle's performance tune-up are not known, thus limiting our understanding of a fundamental muscle property. Our long-term goal is to apply insights gained from learning the origin of kinetic differences of cardiac myosin isoforms to help devise ways to restore impaired muscle function. We envision tune-up of failed heart muscle by mimicking the healthy muscle isoform composition. The immediate objective of this proposal is to elucidate the molecular mechanism of kinetic difference of cardiac myosin isoforms. Our central hypothesis is that isoform kinetics i determined by the electrostatic interactions at the regulatory site within myosin head. Our hypothesis is based on a significant body of experimental data, confirming possibility of myosin kinetics modulation. Three specific aims are to validate our hypothesis. The specific aims are focused on potential regulatory sites within different parts of myosin head, Loop1 (Aim 1), upper 50 kDa domain (Aim 2), and the force generating region (Aim 3). According to our working hypothesis, these regulatory sites modulate myosin-nucleotide interaction, including the rate of ADP release from the cross-bridge, which is the rate limiting step of the slow beta myosin isoform. We plan to use site specific mutagenesis, altering electrostatic interactions within proposed regulatory sites. We will prepare mutants of recombinant human cardiac beta myosin and will characterize kinetics of prepared myosin mutants. We will examine our hypothesis on importance of electrostatic interactions within proposed regulatory sites on myosin kinetics modulation. The proposed research is significant because it will provide a detailed understanding of the mechanism by which human cardiac muscle is fine tuned for maximum performance. We will gain new insights into fundamental mechanisms by which produced force and power, and muscle energetics are modulated by muscle isoform composition. Elucidating kinetic tune-up mechanisms may lead to therapeutic ways of restoring or improving muscle function.
 描述(申请人提供):摘要健康的人类心肌由两种肌球蛋白亚型α和β组成,它们在跨桥循环的动力学方面存在显着差异。特定的肌球蛋白异构体组成调整肌肉的最大性能,力的生产,功率输出和经济。这种精细肌肉性能调整背后的机制尚不清楚,因此限制了我们对基本肌肉特性的理解。我们的长期目标是应用从学习心肌肌球蛋白异构体的动力学差异的起源中获得的见解来帮助设计恢复受损肌肉功能的方法。我们设想通过模仿健康的肌肉亚型组成来调整失败的心肌。本研究的近期目标是阐明心肌肌球蛋白异构体动力学差异的分子机制。我们的中心假设是异构体动力学是由肌球蛋白头内调节位点的静电相互作用决定的。我们的假设是基于大量的实验数据,证实了肌球蛋白动力学调制的可能性。三个具体目标是验证我们的假设。具体目标集中在肌球蛋白头部不同部分的潜在调控位点,Loop 1(Aim 1),上50 kDa结构域(Aim 2)和力产生区(Aim 3)。根据我们的工作假设,这些调节位点调节肌球蛋白-核苷酸相互作用,包括ADP从横桥释放的速率,这是慢β肌球蛋白亚型的限速步骤。我们计划使用位点特异性诱变,改变静电相互作用内提出的监管网站。我们将制备重组人心脏β肌球蛋白的突变体,并将表征制备的肌球蛋白突变体的动力学。我们将检查我们的假设的重要性,静电相互作用的建议监管网站肌球蛋白动力学调制。这项拟议中的研究意义重大,因为它将提供对人类心肌微调以获得最大性能的机制的详细了解。我们将获得新的见解的基本机制所产生的力量和权力,肌肉能量是由肌肉亚型组成调制。阐明动力学调整机制可能会导致恢复或改善肌肉功能的治疗方法。

项目成果

期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Electrostatic interactions in the SH1-SH2 helix of human cardiac myosin modulate the time of strong actomyosin binding.
The Local Environment of Loop Switch 1 Modulates the Rate of ATP-Induced Dissociation of Human Cardiac Actomyosin.
Electrostatic interaction of loop 1 and backbone of human cardiac myosin regulates the rate of ATP induced actomyosin dissociation.
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YURI NESMELOV其他文献

YURI NESMELOV的其他文献

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{{ truncateString('YURI NESMELOV', 18)}}的其他基金

Post translational modifications tune cardiac myosin
翻译后修饰调节心肌肌球蛋白
  • 批准号:
    10291447
  • 财政年份:
    2021
  • 资助金额:
    $ 44万
  • 项目类别:
The Mechanism of Myosin ATPase Actin Activation
肌球蛋白 ATP 酶肌动蛋白激活机制
  • 批准号:
    7939094
  • 财政年份:
    2010
  • 资助金额:
    $ 44万
  • 项目类别:
Functional Dynamics of the Myosin Molecular Motor
肌球蛋白分子马达的功能动力学
  • 批准号:
    7920570
  • 财政年份:
    2006
  • 资助金额:
    $ 44万
  • 项目类别:
Functional Dynamics of the Myosin Molecular Motor
肌球蛋白分子马达的功能动力学
  • 批准号:
    7077227
  • 财政年份:
    2006
  • 资助金额:
    $ 44万
  • 项目类别:
Functional Dynamics of the Myosin Molecular Motor
肌球蛋白分子马达的功能动力学
  • 批准号:
    7582431
  • 财政年份:
    2006
  • 资助金额:
    $ 44万
  • 项目类别:
Functional Dynamics of the Myosin Molecular Motor
肌球蛋白分子马达的功能动力学
  • 批准号:
    7391671
  • 财政年份:
    2006
  • 资助金额:
    $ 44万
  • 项目类别:
Functional Dynamics of the Myosin Molecular Motor
肌球蛋白分子马达的功能动力学
  • 批准号:
    7216844
  • 财政年份:
    2006
  • 资助金额:
    $ 44万
  • 项目类别:
Enhanced EPR Sensitivity for Biomedical Research
增强生物医学研究的 EPR 敏感性
  • 批准号:
    6941301
  • 财政年份:
    2003
  • 资助金额:
    $ 44万
  • 项目类别:
Enhanced EPR Sensitivity for Biomedical Research
增强生物医学研究的 EPR 敏感性
  • 批准号:
    6675191
  • 财政年份:
    2003
  • 资助金额:
    $ 44万
  • 项目类别:
Enhanced EPR Sensitivity for Biomedical Research
增强生物医学研究的 EPR 敏感性
  • 批准号:
    6792215
  • 财政年份:
    2003
  • 资助金额:
    $ 44万
  • 项目类别:

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