Role of Myosin Binding Protein-C in the Regulation of Myocardial Contraction

肌球蛋白结合蛋白-C 在心肌收缩调节中的作用

基本信息

批准号：
8792856
负责人：
Samantha P Harris
金额：
$ 37.16万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-01 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8792856
关键词：
Actins Actomyosin Adolescent Affect Alanine Algorithms Award Binding Boxing Cardiac Cardiac Myosins Clinical Conserved Sequence DAG/PE-Binding Domain Data Devices Disease Goals Grant Head Health Heart Heart failure Human Hypertrophic Cardiomyopathy In Vitro Incidence Kinetics Ligand Binding Ligands Maps Mechanics Mediating Missense Mutation Molecular Muscle Muscle Contraction Mutation Myocardial Contraction Myocardium Myosin ATPase N-terminal Older Population Oranges Peptides Phosphorylation Positioning Attribute Proline Property Protein Isoforms Proteins Recombinants Regulation Role Sarcomeres Serine Speed Structure Testing Thick Filament Thin Filament Transgenic Mice Transgenic Organisms Troponin I Work alanylproline base disease diagnosis disease-causing mutation hemodynamics improved in vivo insight molecular recognition myosin-binding protein C novel outcome forecast protein protein interaction research study single molecule sudden cardiac death

项目摘要

ABSTRACT The long-range goal of the proposed experiments is to understand the function of cardiac myosin binding protein-C (cMyBP-C) in the regulation of myocardial contraction. Mutations in cMyBP-C cause hypertrophic cardiomyopathy and heart failure in millions of people worldwide and under normal conditions cMyBP-C regulates contraction on a beat-to- beat basis. However, neither the mechanisms by which cMyBP-C mutations cause disease nor the mechanisms by which cMyBP-C affects contraction are completely understood. Until now the prevailing hypothesis has been that MyBP-C reversibly limits the speed of contraction by binding to myosin and restricting the ability of myosin heads to extend away from thick filaments and to undergo cycles of interaction with actin on the thin filaments. However, discoveries made by our lab during the first period of this grant challenged this idea and suggest that cMyBP-C itself can bind to actin or other ligands to influence contraction. Aims here will test the role of ligand binding interactions mediated by cMyBP-C by probing the functional significance of novel Molecular Recognition Features (MoRFs) in the regulatory M- domain of cMyBP-C that confer specific binding of the cMyBP-C N-terminus to actin or that mediate other functional effects of the N-terminus in vitro. Understanding the function of the MoRF segment will further provide new insights into disease since HCM missense mutations are clustered within this segment. Specific Aims will 1) map residues in the M-domain MoRFs that mediate actin binding and other functional effects of the M-domain in vitro and in vivo using novel transgenic mice; 2) determine whether the proline-alanine and C1 domains of cMyBP-C outside the M-domain contribute the function of cMyBP-C in vivo using new and existing transgenic mice; and 3) define structural interactions of cMyBP-C with thin and thick filaments. Results from the proposed experiments will provide new insights into the function of MyBP-C and regulatory mechanisms of myocardial contraction in health and disease.

抽象的所提出的实验的长期目标是了解心肌肌球蛋白结合蛋白-C (cMyBP-C) 在心肌收缩调节中的作用。 cMyBP-C 突变导致数百万人肥厚型心肌病和心力衰竭世界各地的人们在正常情况下 cMyBP-C 按节拍调节收缩击败基础。然而，cMyBP-C 突变导致疾病的机制和 cMyBP-C 影响收缩的机制已完全了解。到目前为止普遍的假设是 MyBP-C 通过以下方式可逆地限制收缩速度与肌球蛋白结合并限制肌球蛋白头延伸远离厚层的能力丝并经历与细丝上肌动蛋白相互作用的循环。然而，我们实验室在这笔资助的第一阶段所取得的发现挑战了这一想法，并且表明 cMyBP-C 本身可以与肌动蛋白或其他配体结合以影响收缩。目标这里将通过探测 cMyBP-C 介导的配体结合相互作用来测试其作用新型分子识别特征（MoRF）在调节M-中的功能意义 cMyBP-C 的结构域，赋予 cMyBP-C N 末端与肌动蛋白的特异性结合，或者在体外介导 N 末端的其他功能作用。了解其功能 MoRF 片段将进一步提供对 HCM 错义突变后疾病的新见解都聚集在这个细分市场中。具体目标将 1) 映射 M 结构域 MoRF 中的残基在体外和体内介导肌动蛋白结合和 M 结构域的其他功能效应使用新型转基因小鼠； 2) 确定脯氨酸-丙氨酸和C1结构域是否 M 结构域外的 cMyBP-C 使用新的和现有的转基因小鼠； 3) 定义 cMyBP-C 与薄层和厚层的结构相互作用细丝。所提出的实验结果将为我们的功能提供新的见解 MyBP-C 以及健康和疾病中心肌收缩的调节机制。