Phospholipase C Isozymes

摘要 生物膜在细胞内形成隔室，并将细胞内外区分开来。 除了它们作为物理屏障的作用外，脂膜还被用作组织生物学的平台。 对生命至关重要的过程：膜表面具有独特的聚结，组织和 调节细胞间和细胞间传递信息所必需的生物复合物 隔间这些生物复合体中的某些是协调不同输入的核心节点， 保存的输出。一个这样的核心节点是由磷脂酶C γ（PLC-γ）组织和协调的。 应答不同跨膜受体的同工酶，包括受体酪氨酸激酶的宿主， 免疫受体我们将把这个核心节点作为“罗塞塔石碑”来研究， 生物膜上的信号特性。通过系统地、定量地比较 对于不同类型的输入受体， 不同的细胞类型，我们将获得有关细胞和组织如何执行精确的基本和指导原则， 在它们的生物膜的物理化学限制内进行信号传导。这一目标将得以实现 使用高度协作和跨学科的方法：详细的结构，生物物理和生物化学 纯化蛋白质和复合物的研究将指导自我重建节点的补充研究， 组装的脂质双层或在细胞中重新工程化，以用光控制和成像。这些研究的数据 将基于新开发的框架为计算模型提供信息，该框架描述了核心节点在 膜，将用于预测信号动力学，效率和动态响应的变化， 核心部件、输入和反馈调节。总之，这些研究将揭示关键的见解， 多种受体类型下游的PLC-β同工酶的功能和调节。这些研究还将 推进我们的总体目标，即更深入，但更简约地理解生物学中的信号传导。 膜。

ABSTRACT Biological membranes create compartments within cells and demarcate the outsides of cells from their insides. Beyond their role as physical barriers, lipid membranes also are used as platforms to organize biological processes essential for life: Membrane surfaces are unique for the exceptional ability to coalesce, organize, and regulate biological complexes necessary to transmit information between cells and among cellular compartments. Certain of these biological complexes are core nodes that coordinate diverse inputs into conserved outputs. One such core node is organized and orchestrated by the phospholipase C gamma (PLC-) isozymes in response to diverse transmembrane receptors including a host of receptor tyrosine kinases and immune receptors. We will study this core node as a “Rosetta Stone” to learn the inherent and emergent properties of signaling at biological membranes. By systematically and quantitatively comparing how properties of this core node and associated cellular responses are altered for different classes of input receptors and in different cell types, we will derive fundamental and guiding principles about how cells and tissues execute precise signaling within the physical-chemical constraints of their biological membranes. This goal will be accomplished using a highly collaborative and interdisciplinary approach: Detailed structural, biophysical, and biochemical studies of purified proteins and complexes will guide complementary studies of reconstituted nodes on self- assembled lipid bilayers or re-engineered in cells to be controlled and imaged with light. Data from these studies will inform computational models based on a newly-developed frameworks describing core nodes operating at membranes that will be used to predict signaling kinetics, efficiency, and dynamics in response to changes in core components, inputs, and feedback regulation. Together, these studies will reveal critical insights into the function and regulation of the PLC- isozymes downstream of multiple receptor types. These studies will also advance our overall goal of a deeper, yet more parsimonious, understanding of signaling at biological membranes.