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Structural Studies of PLCepsilon a regulator of cardiac contractility and hypertrophy.

PLCepsilon 心肌收缩力和肥大调节剂的结构研究。

基本信息

批准号：
9900052
负责人：
Angeline Marie Lyon
金额：
$ 37.88万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9900052
关键词：
Adopted Allosteric Regulation Architecture Binding Biochemical Biological Assay C-terminal Calcium Cardiac Cardiac Myocytes Cardiac development Cardiovascular Diseases Cardiovascular system Catalytic Domain Cause of Death Cell physiology Cells Chemicals Complex Coupled Cryoelectron Microscopy Cytoplasm Data Development Diglycerides Disease Enzymes Exhibits Family Fluorescence Resonance Energy Transfer Future G-Protein-Coupled Receptors Gene Expression Generations Genes Goals Guanine Nucleotide Exchange Factors Guanosine Triphosphate Phosphohydrolases Heart Diseases Heart Hypertrophy Homeostasis Hypertrophy In Vitro Lead Lipase Membrane Molecular Molecular Conformation Molecular Weight Monomeric GTP-Binding Proteins N-terminal Pathologic Pharmaceutical Preparations Phospholipase C Phosphotransferases Physiological Play Protein Kinase Protein Kinase C Receptor Activation Receptor Protein-Tyrosine Kinases Regulation Roentgen Rays Role Second Messenger Systems Signal Transduction Site-Directed Mutagenesis Structure Testing Therapeutic United States Validation Variant X-Ray Crystallography base combat deletion analysis experimental study extracellular in vivo insight member novel therapeutic intervention novel therapeutics particle phosphatidylinositol 4-phosphate protein kinase D recruit response small molecule therapeutic target

项目摘要

ABSTRACT Phospholipase C (PLC) enzymes, in particular PLCepsilon, are essential for normal cellular function in the cardiovascular system. There, they generate second messengers in response to extracellular signals that increase calcium levels and activate protein kinase C. Misregulation of PLCepsilon is highly deleterious and can lead to maladaptive changes in cardiac contractility, cell remodeling, and hypertrophy. Consequently, PLCepsilon is tightly regulated both in its activity and its subcellular localization. Under basal conditions, the enzyme resides in the cytoplasm and exhibits low activity. Following the activation of G protein-coupled receptors and/or receptor tyrosine kinases, the enzyme is allosterically activated and translocated to specific membranes through direct interactions with small molecular weight GTPases. The small GTPase Rap1A activates and translocates PLCepsilon to the perinuclear membrane where it stimulates protein kinase cascades involved in cardiac hypertrophy. However, very little is known about the molecular mechanisms that underlie allosteric activation of PLCepsilon and its localization by Rap1A. The goal of this proposal is to use an array of structural, functional, and cell-based studies to provide insights into the molecular mechanisms underlying the normal and pathological functions of PLCepsilon. In the future, our experiments will aid in the identification of selective chemical probes for this enzyme and facilitate the development of novel therapeutic approaches to treat cardiovascular disease, the leading cause of death in the United States and a rapidly growing problem worldwide.

摘要