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Regulatory Mechanisms of Cardiac Muscle

心肌的调节机制

基本信息

批准号：
7426353
负责人：
HERBERT C CHEUNG
金额：
$ 31.04万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-03-01 至 2009-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7426353
关键词：
Actins Address Amino Acid Substitution Attention Back Binding Biochemical C-terminal Calcium Calcium Binding Cardiac Cardiac Muscle Contraction Cations Complex Cyclic AMP-Dependent Protein Kinases Databases Depth Distant Energy Transfer Event Facility Construction Funding Category Feedback Fluorescence Spectroscopy Generations Goals Heart Helix (Snails)Hydrophobic Interactions Kinetics Lead Length Maps Microfilaments Modeling Molecular Monitor Movement Muscle Myocardium Myosin ATPase N Domain N-terminal Neutrons Nucleic Acid Regulatory Sequences Numbers Phosphorylation Physiological Proteins Recombinant Proteins Regulation Resolution Serine Shapes Side Signal Transduction Signaling Protein Site Skeletal Muscle Structure System Testing Thin Filament Troponin Work X-Ray Crystallography base design driving force ear helix feeding follow-up insight member molecular modeling programs protein protein interaction reconstitution response restraint tool troponin-tropomyosin complex

项目摘要

DESCRIPTION (provided by applicant): Contraction of cardiac muscle is initiated by calcium binding to TnC, which is a member of the heterotrimeric troponin complex (TnC, Tnl, TnT). This binding results in structural changes that occur in several proteins that make up the muscle thin filament and alterations of the interactions among these proteins. These molecular changes define the transition of muscle from the inactive to the active state. A calcium switch controls these events during activation/deactivation. A mechanism that regulates cardiac function as a feed back control involves phosphorylation by protein kinase A (PKA) of 2 adjacent serine residues located in the unique N-terminal extension of Tnl. Alteration of the extent of calcium binding and phosphorylation can lead to abnormal cardiac functions. The molecular switch is located in the interface between the 2 subunits Tnl and TnC. How this switch operates in terms of structural alterations and changes in protein-protein interactions remains to be elucidated. A long-term goal of this program is to define these molecular events and changes of these events as related to normal cardiac function, using fluorescence spectroscopy/Forster resonance energy transfer (FRET) and rapid kinetics as major tools. The system to be used is the synthetic thin filament consisting of the troponin complex, tropomyosin and actin. Most of these proteins will be recombinant proteins with specific amino acids substitutions designed for FRET studies. Another long-term goal relates to the mechanisms by which the signal of PKA phosphorylation of Tnl is transmitted to distant parts of the molecule and to the other 2 troponin subunits. The third goal and fourth goals are construction of molecular models for the troponin complex using a large number FRET distances to study structural changes in response to calcium binding, particularly in regions of the complex known to be functionally important, but for which no high-resolution structural information is available. Elucidation of these mechanisms will contribute to the understanding of the structural basis of the diseased state of the heart.

描述（由申请人提供）：心肌收缩由钙与TnC结合引发，TnC是异源三聚体肌钙蛋白复合物（TnC、TnI、TnT）的成员。这种结合导致构成肌肉细丝的几种蛋白质发生结构变化，并改变这些蛋白质之间的相互作用。这些分子变化定义了肌肉从非活动状态到活动状态的转变。钙开关在激活/停用期间控制这些事件。调节心脏功能作为反馈控制的机制涉及通过位于Tnl的独特N-末端延伸中的2个相邻丝氨酸残基的蛋白激酶A（PKA）的磷酸化。钙结合和磷酸化程度的改变可导致心脏功能异常。分子开关位于2个亚基Tnl和TnC之间的界面。这种开关如何在结构改变和蛋白质-蛋白质相互作用的变化方面起作用仍有待阐明。该计划的长期目标是使用荧光光谱/福斯特共振能量转移（FRET）和快速动力学作为主要工具，将这些分子事件和这些事件的变化定义为与正常心脏功能相关。使用的系统是由肌钙蛋白复合物、原肌球蛋白和肌动蛋白组成的合成细丝。这些蛋白质中的大多数将是具有专为FRET研究设计的特定氨基酸取代的重组蛋白质。另一个长期目标涉及Tnl的PKA磷酸化信号传递到分子的远端部分和其他2个肌钙蛋白亚基的机制。第三个目标和第四个目标是使用大量FRET距离构建肌钙蛋白复合物的分子模型，以研究响应钙结合的结构变化，特别是在已知功能重要但没有高分辨率结构信息的复合物区域。阐明这些机制将有助于理解心脏疾病状态的结构基础。