Structure of The Interacting-Heads Motif in Myosin Filaments and Molecules

肌球蛋白丝和分子中相互作用头基序的结构

基本信息

  • 批准号:
    9368275
  • 负责人:
  • 金额:
    $ 43.44万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-07-14 至 2022-05-31
  • 项目状态:
    已结题

项目摘要

The interacting-heads motif (IHM) is a configuration of myosin heads in relaxed thick filaments of muscle, in which ATP turnover and actin binding are inhibited by the interaction of each head with the other. In a dramatic development in the field, this motif has become recognized as a fundamental feature of normal muscle relaxation and contraction, through its regulation of thick filament activity. In addition to its role in thick filaments, the IHM also underlies the structure of single molecules of myosin II in almost all types of animal cell. In this monomeric form, the myosin tail folds up, forming a compact molecule, in which ATPase activity is again inhibited by similar head-head interactions. The IHM appears to play two key roles in the body. In thick filaments, it contributes to energy conservation in the relaxed state of muscle. As a monomer, it functions as a storage form of myosin whose compact form facilitates transport to its site of filament assembly. These critical new findings are the motivation for this application: our goal is to elucidate the structure of this fundamental regulatory motif in skeletal muscle thick filaments and single myosin molecules, thus illuminating how it functions. We will do this using state-of-the-art cryo-EM and 3D reconstruction techniques, studying selected model systems and integrating the information gained from each. In Aim 1 we will determine the 3D structure of the IHM in native thick filaments using novel cryo-EM technology that is currently revolutionizing structural biology. Using tarantula skeletal muscle filaments, the most stable species known, we will determine at better than 10 Å resolution the interactions between the two heads, and between the heads and the tail, that create the IHM. With help from the insights gained, we will determine the structure of frog skeletal thick filaments, the most stable vertebrate filament. And we will build on this information to determine the structure of the IHM in (less stable) mammalian thick filaments. In Aim 2, we will determine the 3D structure of the IHM in isolated myosin molecules, using three complementary systems: smooth muscle myosin as the most stable single molecule, which will provide the highest resolution; tarantula myosin as a direct link to the filament structure in Aim 1, aiding its interpretation; and mammalian myosin, which will reveal the structure in vertebrate skeletal muscle. We will also examine molecules in which putative head interaction sites have been mutated, to test their importance in formation of the IHM. In Aim 3, we will use single molecule EM to test the hypothesis that disease mutations in the head region of skeletal myosin impact the stability of the IHM. The IHM is now recognized as a fundamental motif of normal muscle function. Our proposal will elucidate its interactions, providing new insights into the structural basis of contraction and relaxation, and of the potential impact of disease mutations on these functions.
相互作用头基序(interacting-heads motif,IHM)是肌球蛋白头在松弛的粗肌丝中的构型。 肌肉,其中ATP周转和肌动蛋白结合被每个头部与另一个的相互作用抑制。在 这是该领域的一个戏剧性发展,这一主题已被公认为正常的基本特征。 肌肉松弛和收缩,通过其调节粗丝活动。除了在厚的作用 除了肌丝外,IHM也是几乎所有动物肌球蛋白II单分子结构的基础 cell.在这种单体形式中,肌球蛋白尾部折叠起来,形成一个紧凑的分子,其中ATP酶活性是 又被类似的头-头互动所抑制。IHM似乎在身体中扮演两个关键角色。厚 纤维,它有助于肌肉放松状态下的能量守恒。作为单体,它的功能是 肌球蛋白的储存形式,其紧密的形式便于运输到其细丝装配的位置。这些关键 新的发现是这种应用的动机:我们的目标是阐明这种基本的结构, 调节基序在骨骼肌粗丝和单个肌球蛋白分子,从而阐明了它是如何 功能协调发展的我们将使用最先进的冷冻EM和3D重建技术,研究选定的 模型系统和整合从每个获得的信息。 在目标1中,我们将使用新的冷冻EM确定天然粗丝中IHM的3D结构 这是一项正在革新结构生物学的技术。使用狼蛛骨骼肌细丝, 已知最稳定的物种,我们将以优于10 μ m的分辨率确定两者之间的相互作用。 头和尾之间,创造了IHM。借助所获得的见解,我们将 决定青蛙骨骼结构的粗细丝,是脊椎动物中最稳定的细丝。我们将建立在 这一信息,以确定结构的IHM(不太稳定)哺乳动物厚丝。在目标2中, 将使用三个互补系统确定分离肌球蛋白分子中IHM的3D结构: 平滑肌肌球蛋白作为最稳定的单分子,这将提供最高的分辨率;狼蛛 在Aim 1中,肌球蛋白作为与肌丝结构的直接联系,有助于其解释;以及哺乳动物肌球蛋白, 这将揭示脊椎动物骨骼肌的结构。我们还将检查分子, 头部相互作用位点已经突变,以测试它们在IHM形成中的重要性。在目标3中,我们将使用 单分子EM来检验骨骼肌球蛋白头部区域的疾病突变影响 IHM的稳定性 IHM现在被认为是正常肌肉功能的基本基序。我们的建议将 阐明其相互作用,提供新的见解收缩和放松的结构基础, 疾病突变对这些功能的潜在影响。

项目成果

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ROGER W CRAIG其他文献

ROGER W CRAIG的其他文献

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{{ truncateString('ROGER W CRAIG', 18)}}的其他基金

Mechanism of regulation of cardiac contraction by phosphorylation of myosin binding protein C
肌球蛋白结合蛋白C磷酸化调节心脏收缩的机制
  • 批准号:
    10223413
  • 财政年份:
    2018
  • 资助金额:
    $ 43.44万
  • 项目类别:
Structure of The Interacting-Heads Motif in Myosin Filaments and Molecules
肌球蛋白丝和分子中相互作用头基序的结构
  • 批准号:
    10189521
  • 财政年份:
    2017
  • 资助金额:
    $ 43.44万
  • 项目类别:
Skeletal myosin-binding protein C (MyBP-C): molecular structure and function
骨骼肌球蛋白结合蛋白 C (MyBP-C):分子结构和功能
  • 批准号:
    9116778
  • 财政年份:
    2015
  • 资助金额:
    $ 43.44万
  • 项目类别:
Skeletal myosin-binding protein C (MyBP-C): molecular structure and function
骨骼肌球蛋白结合蛋白 C (MyBP-C):分子结构和功能
  • 批准号:
    9301480
  • 财政年份:
    2015
  • 资助金额:
    $ 43.44万
  • 项目类别:
Skeletal myosin-binding protein C (MyBP-C): molecular structure and function
骨骼肌球蛋白结合蛋白 C (MyBP-C):分子结构和功能
  • 批准号:
    8963227
  • 财政年份:
    2015
  • 资助金额:
    $ 43.44万
  • 项目类别:
cMyBP-C and Native Thick Filament Structure
cMyBP-C 和天然粗丝结构
  • 批准号:
    8215308
  • 财政年份:
    2011
  • 资助金额:
    $ 43.44万
  • 项目类别:
cMyBP-C and Native Thick Filament Structure
cMyBP-C 和天然粗丝结构
  • 批准号:
    7789873
  • 财政年份:
    2010
  • 资助金额:
    $ 43.44万
  • 项目类别:
Transmission Electron Microscope for Core EM Facility
核心 EM 设施的透射电子显微镜
  • 批准号:
    7794260
  • 财政年份:
    2009
  • 资助金额:
    $ 43.44万
  • 项目类别:
Scanning Electron Microscope for Core EM Facility
核心 EM 设施的扫描电子显微镜
  • 批准号:
    7212260
  • 财政年份:
    2007
  • 资助金额:
    $ 43.44万
  • 项目类别:
CCD DIGITAL IMAGING SYSTEM FOR CORE EM FACILITY: NEUROSCIENCES, ALS
用于核心 EM 设施的 CCD 数字成像系统:神经科学、ALS
  • 批准号:
    6973332
  • 财政年份:
    2004
  • 资助金额:
    $ 43.44万
  • 项目类别:

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