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：
10395991
负责人：
Angeline Marie Lyon
金额：
$ 37.85万
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10395991
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 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.

抽象的磷脂酶C（PLC）酶，特别是PLCEPSILON，对于正常细胞功能至关重要在心血管系统中。在那里，它们会产生第二信使，以应对细胞外提高钙水平并激活蛋白激酶的信号C。高度有害，可能导致心脏收缩性，细胞重塑和肥大。因此，plcepsilon在其活性和亚细胞中都受到严格调节本土化。在基础条件下，酶驻留在细胞质中，表现出低活性。在激活G蛋白偶联受体和/或受体酪氨酸激酶之后，酶通过与直接相互作用与小分子量GTPase。小的GTPase Rap1a激活并易位到达核周膜，它刺激参与心脏的蛋白激酶级联肥大。但是，对基础变构的分子机制知之甚少 Plcepsilon及其本地化的激活。该提议的目的是使用一系列结构，功能和基于细胞的研究，以提供有关分子机制的见解 plcepsilon的正常和病理功能的基础。将来，我们的实验将有助于在鉴定该酶的选择性化学探针时，并促进了治疗心血管疾病的新型治疗方法，这是死亡的主要原因美国和全球迅速增长的问题。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Structure of phospholipase Cε reveals an integrated RA1 domain and previously unidentified regulatory elements.

磷脂酶 Cβ 的结构揭示了集成的 RA1 结构域和以前未识别的调节元件。

DOI：
10.1038/s42003-020-01178-8
发表时间：
2020
期刊：
Communications biology
影响因子：
5.9
作者：
Rugema,NgangoY;Garland-Kuntz,ElisabethE;Sieng,Monita;Muralidharan,Kaushik;VanCamp,MichelleM;O'Neill,Hannah;Mbongo,William;Selvia,ArielleF;Marti,AndreaT;Everly,Amanda;McKenzie,Emmanda;Lyon,AngelineM
通讯作者：
Lyon,AngelineM

Structure and regulation of phospholipase Cβ and ε at the membrane.