cMyBP-C: Phosphorylation-Dependent Regulation In Vivo
cMyBP-C:体内磷酸化依赖性调节
基本信息
- 批准号:7789875
- 负责人:
- 金额:$ 27.18万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-02-01 至 2015-01-31
- 项目状态:已结题
- 来源:
- 关键词:ActinsActomyosinAffectAlanineAnimalsAspartateBindingBinding SitesBiochemical GeneticsCalmodulinCardiacCardiac MyocytesCardiac MyosinsChargeCollaborationsCyclic AMP-Dependent Protein KinasesDataDevelopmentDissectionFailureFamilial Hypertrophic CardiomyopathyFiberFigs - dietaryGene MutationGenerationsGenetic EngineeringHeartHeart DiseasesHeart failureHumanHypertrophyIn VitroIndividualInjuryIschemiaKineticsMechanicsMediatingModelingMolecularMolecular MotorsMotionMusMutateMutationMyosin ATPaseOrganOutcomePathologicPatternPerformancePhenotypePhosphorylationPhosphorylation SitePhosphotransferasesPhysiologicalPopulationPost-Translational Protein ProcessingPreparationProtein IsoformsProtein Kinase CProteinsRegulationRoleSarcomeresSerineSiteStressStructureStructure-Activity RelationshipTechniquesTestingThickThick FilamentThin FilamentTissuesTransgenic MiceTransgenic Organismshuman datain vivomimeticsmyosin-binding protein Cnovel therapeuticsresponseskeletaltherapeutic target
项目摘要
Our objective is to understand the structure-function relationships and the functional consequences of posttranslational modifications of cardiac myosin binding protein C (cMyBP-C). cMyBP-C is critical to normal cardiac performance as evidenced by genetic mutations in cMyBP-C being one of the leading causes of familial hypertrophic cardiomyopathy. Despite its functional importance, the molecular mechanism by which cMyBP-C exerts its effect on the myosin molecular motor as it interacts with actin to generate force and motion remains largely undefined. Additionally, changes in the protein's phosphorylation patterns are tightly
coordinated with the heart's response to stress and failure but the consequences of these changes in terms of the interactions with myosin and actin remain largely unexplored and are critical for the control of contractility. Aim 1 will test the hypothesis that the 3 phosphorylated serines in the cardiac-specific insertion of cMyBP-C (Ser-273, Ser-282 and Ser-302) are not functionally equivalent and that hierarchal patterns of phosphorylation exist for cMyBP-C. A corollary is that these patterns are functionally important. In order to understand the role of each phosphorylation site, Ser-273, Ser-282 and Ser-302 will be mutated to either a nonphosphorylatable residue (alanine) or a charged phosphorylation mimetic (aspartate) singly and in combination. Aim 2 will test
the hypothesis that cMyBP-C has a defined binding site or sites for actin and show, in collaboration with Core B, that this interaction provides an elastic and viscous load on the sarcomere. Although the interactions between cMyBP-C and myosin itself are well defined, cMyBP-C binds to actin but the physiological significance of this binding is obscure and the cMyBP-C residues/regions responsible for this interaction is/are undefined. Using a combination of biochemical and genetic approaches we will first define the regions of cMyBP-C that are responsible for actin binding, mutate them and express those mutations in the cardiomyocyte population via transgenic replacement in order to determine their physiological significance.
我们的目标是了解心肌肌球蛋白结合蛋白C(cMyBP-C)的结构-功能关系和翻译后修饰的功能后果。cMyBP-C对正常心脏性能至关重要,如cMyBP-C中的基因突变所证明的,cMyBP-C是家族性肥厚型心肌病的主要原因之一。尽管其功能的重要性,cMyBP-C发挥其对肌球蛋白分子马达的作用,因为它与肌动蛋白相互作用,产生力和运动的分子机制仍然在很大程度上不确定。此外,蛋白质磷酸化模式的变化与
与心脏对压力和衰竭的反应相协调,但这些变化在与肌球蛋白和肌动蛋白相互作用方面的后果在很大程度上尚未探索,并且对于控制收缩性至关重要。目的1将检验cMyBP-C的心脏特异性插入中的3个磷酸化丝氨酸(Ser-273、Ser-282和Ser-302)在功能上不等同以及cMyBP-C存在磷酸化的分级模式的假设。一个必然的结论是,这些模式在功能上是重要的。为了理解每个磷酸化位点的作用,将Ser-273、Ser-282和Ser-302单独或组合突变为不可磷酸化的残基(丙氨酸)或带电的磷酸化模拟物(天冬氨酸)。目标2将测试
假设cMyBP-C具有确定的肌动蛋白结合位点,并与核心B合作表明,这种相互作用在肌节上提供了弹性和粘性负荷。虽然cMyBP-C和肌球蛋白本身之间的相互作用是明确的,cMyBP-C结合肌动蛋白,但这种结合的生理意义是模糊的,cMyBP-C残基/区域负责这种相互作用是不确定的。使用生物化学和遗传学方法的组合,我们将首先定义负责肌动蛋白结合的cMyBP-C区域,使其突变并通过转基因替代在心肌细胞群体中表达这些突变,以确定其生理意义。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Jeffrey Robbins其他文献
Jeffrey Robbins的其他文献
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{{ truncateString('Jeffrey Robbins', 18)}}的其他基金
Mouse and cMyBP-C Protein Production Core
小鼠和 cMyBP-C 蛋白质生产核心
- 批准号:
8215313 - 财政年份:2011
- 资助金额:
$ 27.18万 - 项目类别:
cMyBP-C: Phosphorylation-Dependent Regulation In Vivo
cMyBP-C:体内磷酸化依赖性调节
- 批准号:
8215310 - 财政年份:2011
- 资助金额:
$ 27.18万 - 项目类别:
Mouse and cMyBP-C Protein Production Core
小鼠和 cMyBP-C 蛋白质生产核心
- 批准号:
7789884 - 财政年份:2010
- 资助金额:
$ 27.18万 - 项目类别:
Cardiomyocyte Toxicity and Heart Failure in Desmin Related Cardiomyopathy
结蛋白相关心肌病中的心肌细胞毒性和心力衰竭
- 批准号:
7364708 - 财政年份:2008
- 资助金额:
$ 27.18万 - 项目类别:
International Society for Heart Research 2008: Cell to Bedside
国际心脏研究学会 2008 年:从细胞到床边
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7530382 - 财政年份:2008
- 资助金额:
$ 27.18万 - 项目类别:
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