Troponin and myosin in regulation of muscle contraction and heart disease
肌钙蛋白和肌球蛋白调节肌肉收缩和心脏病
基本信息
- 批准号:8197235
- 负责人:
- 金额:$ 50.24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-12-15 至 2013-03-01
- 项目状态:已结题
- 来源:
- 关键词:ATP phosphohydrolaseActinsActomyosin AdenosinetriphosphataseAffectAffinityBindingC-terminalCardiacCessation of lifeComplementComplexContractile ProteinsDataDiseaseDisulfidesDivalent CationsDrug DesignEquilibriumFamilial Hypertrophic CardiomyopathyFiberFluorescence Resonance Energy TransferGoalsHeadHeart DiseasesHeart HypertrophyKineticsLabelLeadMeasurementModelingMolecularMuscle ContractionMuscle FibersMuscle functionMutationMyocardiumMyosin ATPasePlayProcessProtein IsoformsProteinsQuality of lifeRegulationRelative (related person)RoleSignal TransductionSkeletal MuscleSolutionsStretchingStructureSystemTechniquesTestingThin FilamentTitrationsTropomyosinTroponinTroponin CTroponin Iactin-S1basecrosslinkgenetic regulatory proteinmutantnovelprematureprotein protein interactionreconstitutionreconstructionresearch studyresponsetool
项目摘要
A number of familial hypertrophic cardiomyopathy (FHC) causing mutations have been
identified in the regulatory proteins, tropomyosin (Tm) and troponin (Tn). Most of these
mutations cause an increase in the Ca2+-sensitivity of muscle contraction, i.e. the onset of force
occurs at lower Ca2+ concentrations. Neither the molecular mechanisms underlying the
increased Ca2+-sensitivity nor its relation to the hypertrophy of the heart are well understood.
Stretch activation is another cardiac phenomenon whose molecular mechanism is not
understood. The long-range goal is to understand the molecular basis of FHC and stretch
activation. The main hypothesis that we will test is that both of these activations involve strongly
bound cross bridges (myosin heads). We plan to:
1. Determine the contribution of the myosin head-induced vs. Ca2+-induced changes in the
interactions of troponin I (TnI) with actin-Tm and with troponin C (TnC) in thin filaments
reconstituted with skeletal and cardiac muscle isoforms of the regulatory proteins. The main
techniques will be solution ATPase and FRET measurements.
2. Determine effects of FHC mutations on occupancy of the 3 thin filament regulatory states
using equilibrium titrations and transient kinetics. Fluorescent labels on selected proteins will be
used to obtain equilibrium constants and rates.
3. Determine effects of selected FHC mutations in TnI and Tm on ATPase in terms of
myosin vs. Ca2+ activation. FRET measurements will be used to obtain structural information.
4. Test the hypothesis that the C-terminal domain of TnC is involved in the myosin head
induced activation of the thin filament. Mutants of TnC having increased affinity for Mg2+ will be
used to assess the role of divalent cation in the C-domain of TnC on thin filament function.
A novel mutant of TnC which reconstitutes into the thin filament and binds Ca2+ but does
not activate ATPase that was developed in this lab will be used. These experiments will lead to
a better understanding of the regulatory mechanism in cardiac and skeletal muscle. In
particular, a better understanding of the relative contribution of the Ca2+/troponin-dependent and
the myosin S1/actin-dependent activation of the thin filament will be obtained. By identifying the
protein-protein interactions that are altered in the disease state it will be possible to suggest
potential targets for drug design for FHC.
一些家族性肥厚型心肌病(FHC)引起的突变已经被发现,
在调节蛋白原肌球蛋白(Tm)和肌钙蛋白(Tn)中鉴定。大多数这些
突变导致肌肉收缩的Ca 2+敏感性增加,即力的开始
发生在较低的Ca 2+浓度下。无论是潜在的分子机制,
Ca 2+敏感性的增加及其与心脏肥大的关系是很好理解的。
牵张激活是另一种心脏现象,其分子机制不是
明白长期目标是了解FHC和拉伸的分子基础
activation.我们将检验的主要假设是,这两种激活都强烈涉及
结合横桥(肌球蛋白头)。我们计划:
1.确定肌球蛋白头诱导的与Ca 2+诱导的变化在心肌细胞中的作用。
肌钙蛋白I(TnI)与肌动蛋白Tm和肌钙蛋白C(TnC)在细丝中的相互作用
用调节蛋白的骨骼肌和心肌同种型重建。主要
技术将是溶液ATP酶和FRET测量。
2.确定FHC突变对3种细丝调节状态占据率的影响
使用平衡滴定和瞬态动力学。在选定的蛋白质上的荧光标记将被
用于获得平衡常数和速率。
3.确定TnI和Tm中选定的FHC突变对ATP酶的影响,
肌球蛋白与Ca 2+激活。FRET测量将用于获得结构信息。
4.检验TnC的C末端结构域参与肌球蛋白头的假设
引起细灯丝的激活。对Mg 2+具有增加的亲和力的TnC突变体将被
用于评估TnC C结构域中二价阳离子对细丝功能的作用。
一种新的TnC突变体,其重组为细丝并结合Ca 2+,但不
将使用本实验室开发的不活化ATP酶。这些实验将导致
更好地了解心肌和骨骼肌的调节机制。在
特别是,更好地了解钙离子/肌钙蛋白依赖性和
将获得肌球蛋白S1/肌动蛋白依赖的细丝激活。通过识别
蛋白质-蛋白质相互作用在疾病状态下发生改变,这将可能表明
FHC药物设计的潜在目标。
项目成果
期刊论文数量(9)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Phosphorylation at Ser²⁶ in the ATP-binding site of Ca²⁺/calmodulin-dependent kinase II as a mechanism for switching off the kinase activity.
- DOI:10.1042/bsr20120116
- 发表时间:2013-02-07
- 期刊:
- 影响因子:4
- 作者:Yilmaz M;Gangopadhyay SS;Leavis P;Grabarek Z;Morgan KG
- 通讯作者:Morgan KG
Insights into modulation of calcium signaling by magnesium in calmodulin, troponin C and related EF-hand proteins.
- DOI:10.1016/j.bbamcr.2011.01.017
- 发表时间:2011-05
- 期刊:
- 影响因子:0
- 作者:Grabarek Z
- 通讯作者:Grabarek Z
X-ray structures of magnesium and manganese complexes with the N-terminal domain of calmodulin: insights into the mechanism and specificity of metal ion binding to an EF-hand.
具有钙调蛋白 N 末端结构域的镁和锰复合物的 X 射线结构:深入了解金属离子与 EF 手结合的机制和特异性。
- DOI:10.1021/bi300698h
- 发表时间:2012-08-07
- 期刊:
- 影响因子:2.9
- 作者:Senguen FT;Grabarek Z
- 通讯作者:Grabarek Z
Differential effects of caldesmon on the intermediate conformational states of polymerizing actin.
卡尔德斯蒙对聚合肌动蛋白中间构象状态的不同影响。
- DOI:10.1074/jbc.m109.065078
- 发表时间:2010
- 期刊:
- 影响因子:0
- 作者:Huang,Renjian;Grabarek,Zenon;Wang,Chih-LuehAlbert
- 通讯作者:Wang,Chih-LuehAlbert
The green tea polyphenol (-)-epigallocatechin-3-gallate inhibits magnesium binding to the C-domain of cardiac troponin C.
- DOI:10.1007/s10974-013-9338-9
- 发表时间:2013-05
- 期刊:
- 影响因子:2.7
- 作者:Fuchs, Franklin;Grabarek, Zenon
- 通讯作者:Grabarek, Zenon
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Zenon Grabarek其他文献
Zenon Grabarek的其他文献
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{{ truncateString('Zenon Grabarek', 18)}}的其他基金
Structure, function, and disease biology of MICU1/MICU2
MICU1/MICU2的结构、功能和疾病生物学
- 批准号:
10197754 - 财政年份:2018
- 资助金额:
$ 50.24万 - 项目类别:
Structure, function, and disease biology of MICU1/MICU2
MICU1/MICU2的结构、功能和疾病生物学
- 批准号:
10450735 - 财政年份:2018
- 资助金额:
$ 50.24万 - 项目类别:
Structure, function, and disease biology of MICU1/MICU2
MICU1/MICU2的结构、功能和疾病生物学
- 批准号:
9768959 - 财政年份:2018
- 资助金额:
$ 50.24万 - 项目类别:
Structure, function, and disease biology of MICU1/MICU2
MICU1/MICU2的结构、功能和疾病生物学
- 批准号:
9980297 - 财政年份:2018
- 资助金额:
$ 50.24万 - 项目类别:
Troponin and myosin in regulation of muscle contraction and heart disease
肌钙蛋白和肌球蛋白调节肌肉收缩和心脏病
- 批准号:
7746421 - 财政年份:2008
- 资助金额:
$ 50.24万 - 项目类别:
Troponin and myosin in regulation of muscle contraction and heart disease
肌钙蛋白和肌球蛋白调节肌肉收缩和心脏病
- 批准号:
7584532 - 财政年份:2008
- 资助金额:
$ 50.24万 - 项目类别:
Troponin and myosin in regulation of muscle contraction and heart disease
肌钙蛋白和肌球蛋白调节肌肉收缩和心脏病
- 批准号:
7994840 - 财政年份:2008
- 资助金额:
$ 50.24万 - 项目类别:
MYOSIN PHOSPHORYLATION BY MYOSIN LIGHT CHAIN KINASE
肌球蛋白轻链激酶磷酸化肌球蛋白
- 批准号:
6434896 - 财政年份:2001
- 资助金额:
$ 50.24万 - 项目类别:
MYOSIN PHOSPHORYLATION BY MYOSIN LIGHT CHAIN KINASE
肌球蛋白轻链激酶磷酸化肌球蛋白
- 批准号:
6571145 - 财政年份:2001
- 资助金额:
$ 50.24万 - 项目类别:
MYOSIN PHOSPHORYLATION BY MYOSIN LIGHT CHAIN KINASE
肌球蛋白轻链激酶磷酸化肌球蛋白
- 批准号:
6570926 - 财政年份:2001
- 资助金额:
$ 50.24万 - 项目类别:
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