The UNC-45 Chaperone as a Modulator of Myosin Biogenesis and Function

UNC-45 伴侣作为肌球蛋白生物发生和功能的调节剂

基本信息

  • 批准号:
    9477067
  • 负责人:
  • 金额:
    $ 30.69万
  • 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:
    2016-05-01 至 2020-04-30
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): In this proposal we aim to elucidate the precise molecular mechanisms by which the chaperones UNC-45 and Hsp90 assist in the folding of the myosin head which is critical for sarcomere assembly during development and repair of stress-induced damage to sarcomeres in mature muscle. Developing an understanding of these mechanisms is a problem at the core of muscle development and function. It is also highly relevant to the folding and repair of the many classes of myosin molecules that are expressed in non-muscle tissues. Our recent discovery that myosin attains a novel conformation, which hydrolyzes ATP at the normal rate but with a greatly reduced ability to translocate actin filaments, in the presence of UNC-45 and is reversed by Hsp90, raises important questions as to the exact roles of these chaperones in myosin folding and repair and myofilament assembly. Guided by our recent published and preliminary studies, we hypothesize that during myosin assembly or repair, UNC-45 assists the myosin head to attain its native conformation and subsequently locks it in a state that prevents premature powerstrokes; this state is relieved by Hsp90 upon successful assembly into the sarcomere or repair of myosin heads. This hypothesis will be tested by using a combination of in vitro and in vivo analyses through a unique collaboration between two expert research labs. In Aim 1 we will use mutagenesis, biochemical and biophysical assays, including myosin-dependent actin filament gliding assays, to establish the UNC-45 domains and key amino acid regions that mediate the different unique functions of UNC-45. In Aims 2 and 3 we will use the power of C. elegans as a model system to examine the functional relationships between mutant UNC-45 proteins and sarcomere assembly (Aim 2), and the dynamics of association of UNC-45 and Hsp90 with themselves and with myosin during repair of damaged myosin heads (Aim 3). Our hypothesis, if confirmed, will represent a new paradigm in the biology of myosins, with potential novel therapeutic approaches not only for striated muscle disorders stemming from mutations in sarcomeric proteins (skeletal myopathies and cardiomyopathies), but also for the problem of tumor invasiveness.
 描述(由申请人提供):在该提案中,我们旨在阐明伴侣蛋白ε 4 -45和Hsp 90协助肌球蛋白头部折叠的精确分子机制,这对于成熟肌肉中肌节的发育和应力诱导损伤的修复过程中的肌节组装至关重要。了解这些机制是肌肉发育和功能的核心问题。它也与非肌肉组织中表达的许多类肌球蛋白分子的折叠和修复高度相关。我们最近的发现,肌球蛋白达到一种新的构象,水解ATP在正常的速度,但大大降低了能力,易位肌动蛋白丝,在存在的β-45和被逆转的热休克蛋白90,提出了重要的问题,这些伴侣蛋白的确切作用,在肌球蛋白折叠和修复和肌丝组装。根据我们最近发表的初步研究,我们假设在肌球蛋白组装或修复过程中,HSP 90 -45帮助肌球蛋白头部达到其天然构象,随后将其锁定在一种防止过早动力中风的状态;这种状态在成功组装成肌节或修复肌球蛋白头部后由HSP 90缓解。这一假设将通过两个专家研究实验室之间的独特合作,使用体外和体内分析的组合进行测试。在目标1中,我们将使用诱变,生物化学和生物物理测定,包括肌球蛋白依赖性肌动蛋白丝滑动测定,以建立介导不同的独特功能的β-45结构域和关键氨基酸区域的β-45。在目标2和3中,我们将使用C的力量。elegans作为一个模型系统,以检查突变的HSP 45蛋白和肌节组装之间的功能关系(目的2),以及HSP 45和HSP 90与自身以及在受损肌球蛋白头修复过程中与肌球蛋白的动态关联(目的3)。我们的假设,如果得到证实,将代表肌球蛋白生物学的一个新的范例,潜在的新的治疗方法,不仅对横纹肌疾病起源于突变的肌节蛋白(骨骼肌病变和心肌病),但也为肿瘤侵袭的问题。

项目成果

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GUY Martin BENIAN其他文献

GUY Martin BENIAN的其他文献

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{{ truncateString('GUY Martin BENIAN', 18)}}的其他基金

A Model Multi-systems Approach for Understanding the Role of the PIX Pathway in Cardiac Muscle and Cardiomyopathy
理解 PIX 通路在心肌和心肌病中作用的模型多系统方法
  • 批准号:
    10532707
  • 财政年份:
    2022
  • 资助金额:
    $ 30.69万
  • 项目类别:
A Model Multi-systems Approach for Understanding the Role of the PIX Pathway in Cardiac Muscle and Cardiomyopathy
理解 PIX 通路在心肌和心肌病中作用的模型多系统方法
  • 批准号:
    10340546
  • 财政年份:
    2022
  • 资助金额:
    $ 30.69万
  • 项目类别:
ApoE4 and C/EBP: Mutually Regulate Each Other in Alzheimer's Disease
ApoE4 和 C/EBP:在阿尔茨海默病中相互调节
  • 批准号:
    10319519
  • 财政年份:
    2020
  • 资助金额:
    $ 30.69万
  • 项目类别:
ApoE4 and C/EBP: Mutually Regulate Each Other in Alzheimer's Disease
ApoE4 和 C/EBP:在阿尔茨海默病中相互调节
  • 批准号:
    10533321
  • 财政年份:
    2020
  • 资助金额:
    $ 30.69万
  • 项目类别:
The UNC-45 Chaperone as a Modulator of Myosin Biogenesis and Function
UNC-45 伴侣作为肌球蛋白生物发生和功能的调节剂
  • 批准号:
    9267166
  • 财政年份:
    2016
  • 资助金额:
    $ 30.69万
  • 项目类别:
The UNC-45 Chaperone as a Modulator of Myosin Biogenesis and Function
UNC-45 伴侣作为肌球蛋白生物合成和功能的调节剂
  • 批准号:
    9789043
  • 财政年份:
    2016
  • 资助金额:
    $ 30.69万
  • 项目类别:
Role of UNC-89 (obscurin) in sarcomere assembly and maintenance.
UNC-89(obscurin)在肌节组装和维护中的作用。
  • 批准号:
    8836489
  • 财政年份:
    2014
  • 资助金额:
    $ 30.69万
  • 项目类别:
Role of UNC-89 (obscurin) in sarcomere assembly and maintenance.
UNC-89(obscurin)在肌节组装和维护中的作用。
  • 批准号:
    8632004
  • 财政年份:
    2014
  • 资助金额:
    $ 30.69万
  • 项目类别:
Using C. elegans to study titin and obscurin (UNC-89)
使用线虫研究 titin 和 obscurin (UNC-89)
  • 批准号:
    7847206
  • 财政年份:
    2009
  • 资助金额:
    $ 30.69万
  • 项目类别:
Nematode UNC-98 functions in focal adhensions and nuclei
线虫 UNC-98 在粘着点和细胞核中发挥作用
  • 批准号:
    6968518
  • 财政年份:
    2005
  • 资助金额:
    $ 30.69万
  • 项目类别:

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