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

摘要 磷脂酶C（PLC）酶，特别是PLC，是正常细胞功能所必需的 在心血管系统中。在那里，它们产生第二信使， 增加钙水平和激活蛋白激酶C的信号。PLC的误调节 高度有害，可导致心脏收缩力、细胞重塑和 肥厚因此，PLC在其活性和亚细胞水平上都受到严格调控。 本地化在基础条件下，该酶存在于细胞质中并表现出低活性。 在G蛋白偶联受体和/或受体酪氨酸激酶活化后， 被别构激活，并通过直接相互作用转移到特定的膜 小分子量GTP酶。小的GTdR Rap 1A激活并转位PLC 到核周膜，在那里它刺激蛋白激酶级联，参与心脏 肥厚然而，关于变构的分子机制知之甚少。 PLC的激活及其通过Rap 1A的定位。这个提议的目标是使用一个数组， 结构，功能和细胞为基础的研究，以提供深入的分子机制 潜在的PLC的正常和病理功能。在未来，我们的实验将有助于 在确定这种酶的选择性化学探针，并促进发展， 治疗心血管疾病的新的治疗方法，心血管疾病是世界上主要的死亡原因， 美国和世界范围内迅速增长的问题。

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.