Structure and Function of the MEF2 Pathway

MEF2 通路的结构和功能

基本信息

批准号：
7336797
负责人：
LIN CHEN
金额：
$ 26.34万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-12-15 至 2009-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7336797
关键词：
Address Bacteriophages Binding Biochemical Biological Biological Assay Calcium Calcium Signaling Calcium-Binding Proteins Calmodulin Cardiac Cardiac Myocytes Cardiovascular Diseases Cell physiology Cells Class Complement Complex Condition Consensus Sequence DNA Development EP300 gene Engineering Ensure Family Gene Expression Gene Expression Regulation Gene Silencing Genes Genetic Transcription Goals Heart Diseases Heart Hypertrophy Histones Human Immune In Vitro Interphase Cell Ligand Binding Ligands Link Mediating Methods Modeling Molecular Muscle Muscle Cells Mutation Nervous system structure Neurons Pathway interactions Peptides Phage Display Physiological Play Predisposition Protein Family Proteins Recruitment Activity Regulation Repression Research Research Personnel Resolution Role Signal Transduction Solutions Stimulus Stress Structure T-Lymphocyte Testing Transcriptional Activation X-Ray Crystallography base cabin-1 drug development gene repression genetic pedigree in vivo insight interest molecular recognition muscle enhancer factor-2A mutant myocyte-specific enhancer-binding factor 2 programs promoter protein protein interaction protein structure function response small molecule transcription factor

项目摘要

DESCRIPTION (provided by applicant): This proposal focuses on the structure and function of protein complexes participating in the regulation of the myocyte enhancer factor-2 (MEF2) family of transcription factors. MEF2 serves as a molecular switch of specific gene expression in muscle cells, T cells and neuronal cells in response to calcium signals, playing pivotal roles in the development and adaptive responses of the muscle, immune and nervous systems. In heart muscle cells, deregulation of MEF2-controlled genes under stress and a variety of other pathological conditions has been linked to many forms of cardiovascular diseases. The long term goal of the proposed research is to build a high-resolution picture of the MEF2 pathway and analyze its mechanism and function using structure-based approaches. Specifically, X-ray crystallography, biochemical methods and cell-based assays will be used to investigate: (i) How MEF2 recruits transcriptional co-repressors including class II histone deacetylases to specific promoters and ensures proper gene silencing in resting cells (Aim 1); (ii) How MEF2/co-repressor complexes are disassembled by calcium-dependent mechanisms (Aim 2); (iii) How MEF2, upon the release of co-repressors, recruits transcriptional co-activator p300 to turn on specific gene expression (Aim 3). Small peptides that can bind MEF2 specifically and block the recruitment of co-repressors or co-activators will also be developed (Aim 4). The proposed studies in Aims 1-4 are based on the recent structural and biochemical characterization of the Cabin1/MEF2/DNA complex, which suggests that MEF2 possesses a signaling domain capable of binding to a variety of transcriptional co-regulators through related but distinct mechanisms. These studies will not only provide insights into the basic mechanisms of calcium/MEF2-mediated biological responses in a variety of cells but also help drug development in treating human heart diseases.

描述（由申请人提供）：该提案着重于参与调节心肌细胞增强子-2（MEF2）转录因子家族的蛋白质复合物的结构和功能。 MEF2用作肌肉细胞，T细胞和神经元细胞中特定基因表达的分子转换，响应钙信号，在肌肉，免疫和神经系统的发育和适应性反应中发挥关键作用。在心肌细胞中，在压力下对MEF2控制的基因放松管制，并且多种其他病理状况与多种形式的心血管疾病有关。拟议研究的长期目标是建立MEF2途径的高分辨率图片，并使用基于结构的方法分析其机制和功能。具体而言，将使用X射线晶体学，生化方法和基于细胞的测定法来研究：（i）MEF2如何募集包括II类组蛋白脱乙酰基酶在内的转录共抑制剂，并确保在静息细胞中确保适当的基因沉默（AIM 1）；（ii）MEF2/共抑制络合物如何通过钙依赖性机制拆卸（AIM 2）；（iii）MEF2在释放共抑制器后如何募集转录共激活器P300以打开特定的基因表达（AIM 3）。还将开发出可以特异性约束MEF2并阻止共抑制剂或共激活因子的募集的小肽（AIM 4）。 AIM 1-4中提出的研究基于Cabin1/Mef2/DNA复合物的最新结构和生化表征，这表明MEF2具有能够通过相关但不同的机制结合到各种转录共同调节剂的信号域。这些研究不仅将提供有关多种细胞中钙/MEF2介导的生物学反应的基本机制的见解，而且还有助于药物发育治疗人类心脏病。