Spatial Organization of Membrane Signaling

膜信号传导的空间组织

• 批准号: 10028536
• 负责人: Xiaolei Su
• 金额: $ 41.88万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10028536
• 关键词: Address; Affect; Antigens; Basic Science; Biological Process; Cell Nucleus; Cell membrane; Cells; Charge; Cytoplasm; Disease; Environment; Foundations; Geometry; Goals; Immune response; Infection; Inner Leaflet of the Lipid Bilayer; Lipid Bilayers; Lipids; Mediating; Membrane; Mission; National Institute of General Medical Sciences; Pathway interactions; Phase; Process; Proteins; Public Health; Receptor Activation; Receptor Signaling; Research; Signal Transduction; Signaling Molecule; Stimulus; System; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Work; cell killing; extracellular; pathogen; protein protein interaction; self assembly; three dimensional structure; tumor progression

Project Summary The overall goal of this project is to understand how the spatial organization of signaling molecules on the cell membrane regulates signal transduction. Extracellular stimuli are transduced across the plasma membrane, processed, and amplified along the inner leaflet of the lipid bilayer, and then further delivered into the cytoplasm and nucleus. It has been shown that proteins and lipids are organized into membrane domains to mediate signal transduction though the underlying mechanisms are not fully understood. The T cell receptor (TCR) pathway represents an ideal system for studying this phenomenon. Dozens of the components of the TCR pathway are enriched in the T cell microcluster, a membrane-associated micron-sized domain that is essential for TCR signaling. Our recent work suggested that T cell microclusters are phase-separated condensates driven by multivalent protein-protein interactions. What is lacking, however, is an understanding of how the formation of these microclusters is regulated by the local membrane environment, where significant changes occur in both lipid composition and membrane geometry upon TCR activation. Therefore, this proposal aims to determine the mechanism by which lipids and membrane geometry regulate the assembly of T cell microclusters and the associated functional consequences during T cell activation. The following questions will be addressed: How do charged lipids modulate T cell microcluster formation? How does membrane geometry influence microcluster function? How do microclusters affect T cells’ killing activity? Answering these questions will significantly impact the field because it will reveal how the protein machineries and lipid bilayers coordinate to process and amplify the signal from antigen stimuli to cell activation. Moreover, the majority of currently identified phase-separated structures are 3-D droplets located in the nucleus or cytoplasm whereas T cell microclusters are 2-D domains on the membrane. Understanding the functional relationship between T cell microclusters and lipid bilayers is expected to create a new research interface between the field of protein self-assembly and membrane signaling.

项目摘要 该项目的总体目标是了解细胞上信号分子的空间组织如何 膜调节信号转导。细胞外刺激在质膜上翻译 加工并沿着脂质双层的内部传单膨胀，然后进一步递送到细胞质中 和核。已经表明，蛋白质和脂质被组织到膜结构域中以介导信号 尽管基本机制尚未完全理解，但转导。 T细胞受体（TCR）途径 代表研究这种现象的理想系统。 TCR途径的数十个组件是 富含T细胞微簇，这是一种与膜相关的微米大小的结构域，对TCR至关重要 信号。我们最近的工作表明，T细胞微量群体是相位分离的冷凝物。 多价蛋白质 - 蛋白质相互作用。但是，缺乏的是对如何形成的理解 这些微簇受到局部膜环境的调节，在这些环境中，这两者都发生了重大变化 TCR激活后的脂质组成和膜几何形状。因此，该建议旨在确定 脂质和膜几何形状调节T细胞微量群体和膜的几何形状的机制和 在T细胞激活过程中相关的功能后果。将解决以下问题：如何 带电的脂质调节T细胞微簇的形成？膜几何形状如何影响微簇 功能？微量群体如何影响T细胞的杀伤活性？回答这些问题将显着影响 该领域，因为它将揭示蛋白质机和脂质双层如何协调和放大 从抗原刺激到细胞激活的信号。此外，大多数当前确定的相位分隔 结构是位于细胞核或细胞质中的3-D液滴 在膜上。了解T细胞微簇和脂质双层之间的功能关系是 预计将在蛋白质自组装和膜信号传导领域之间建立新的研究界面。