Membrane shape transition control in cellular membrane trafficking phenomena

细胞膜运输现象中的膜形状转变控制

• 批准号: 10167604
• 负责人: Tobias Baumgart
• 金额: $ 9.24万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10167604
• 关键词: Actins; Adaptor Signaling Protein; Address; Alzheimer' s Disease; Area; Automobile Driving; Binding; Calcium; Cell membrane; Cell physiology; Cells; Cellular Membrane; Cellular Structures; Centronuclear myopathy; Clathrin Adaptors; Communicable Diseases; Crowding; Data; Descriptor; Disease; Endocytosis; Evaluation; Filopodia; Fluorescence; Generations; Goals; Human; Huntington Disease; In Vitro; Inflammatory; Ions; Laboratories; Lead; Lipids; Mammalian Cell; Membrane; Membrane Proteins; Metabolic Diseases; Micromanipulation; Molecular; Molecular Motors; Mutation; Organelles; Parkinson Disease; Pathologic; Pathway interactions; Peripheral; Phase; Phosphorylation; Problem Solving; Process; Proteins; Regulation; Research; Shapes; Signal Transduction; Tertiary Protein Structure; Testing; Therapeutic; Yeasts; alpha synuclein; amphiphysin; apical membrane; biophysical model; cancer type; design; epsin; experience; experimental study; human disease; improved; insight; interest; membrane model; neglect; nervous system disorder; pathogen; polymerization; protein function; protein protein interaction; receptor; scaffold; synergism; tool; trafficking

Membrane shape transition control in cellular membrane trafficking phenomena Tobias Baumgart, PI PROJECT SUMMARY Membrane shape is important not only as a static aspect of size and structure of cells and organelles, but dynamically changes in numerous processes such as membrane signaling and trafficking. At the plasma membrane, the formation of in- and exvaginations, in processes such as endocytosis and the generation of filopodia, respectively, are some of the most important phenomena where membrane curvature is modulated. The discovery of a class of proteins which contain crescent shaped scaffolds called BAR (Bin/amphiphysin/Rvs) domain proteins, has prompted a growing interest in understanding how proteins couple with membrane curvature. BAR domains are found in numerous proteins implicated in human disease, and many contain disease driving mutations and/or show altered expression levels under pathological conditions. Additional peripheral proteins that are related to membrane curvature include intrinsically disordered proteins such as α-synuclein, as well as ENTH domain-containing proteins such as epsin, both of which are believed to be involved in membrane trafficking phenomena. Endocytosis is the primary mechanism by which pathogens enter cells. To improve the understanding of the mechanism and regulation of this process therefore is a matter of primary biomedical relevance. However, despite the fact that more than 90000 research contributions have investigated endocytosis alone, the mechanisms for initiation of this process are not understood. This is due in part to the fact that in cells numerous endocytic mechanisms operate in parallel and that the degree for experimental control of key parameters in cells is limited. The goal of this project is to understand how membrane shape transitions are regulated in processes such as endocytosis. In order to achieve this goal, we have developed an experimental biophysical model membrane approach that allows us to determine the conditions under which membranes undergo shape transitions. With the help of this tool, which consists of a combined micro- manipulation/fluorescence approach that is presently used exclusively in our laboratory, we will investigate mechanisms of the function of the many proteins involved in endocytosis, and isolate key modulators of membrane shape transitions. We already have developed a theoretical framework that will facilitate mechanistic interpretation of our findings. While plasma membranes experience significant asymmetry with respect to transmembrane ion and lipid distributions, model membrane research has largely focused on symmetric membranes. We will overcome this limitation and determine to what extent membrane asymmetry, which will include cytoskeletal interactions, contributes to the function of peripheral proteins in shaping membranes. Overall this project will provide far- reaching insight into the mechanisms by which peripheral proteins deform membranes under healthy and pathological conditions.

细胞膜运输现象中的膜形状转变控制 Tobias Baumgart，PI 项目摘要 膜的形状不仅是细胞和细胞器的大小和结构的静态方面， 在许多过程中动态变化，如膜信号传导和运输。在等离子体 膜，形成的in-and exvaginations，在过程中，如内吞作用和产生的 丝状伪足分别是调节膜曲率的一些最重要的现象。 发现了一类含有新月形支架的蛋白质，称为BAR (Bin/amphiphysin/Rvs）结构域蛋白，已经促使人们对理解蛋白质如何偶联的兴趣越来越大 膜曲率。BAR结构域存在于许多与人类疾病有关的蛋白质中， 许多含有疾病驱动突变和/或在病理条件下显示改变的表达水平。 其他与膜弯曲相关的外周蛋白包括内在无序蛋白 如α-突触核蛋白，以及含有ENTH结构域的蛋白质如epsin，据信这两者都 参与膜运输现象。 内吞作用是病原体进入细胞的主要机制。增进了解 因此，这一过程的机制和调控是一个主要的生物医学相关问题。然而，在这方面， 尽管有超过90000篇研究论文仅研究了内吞作用， 启动该过程的机制尚不清楚。这部分是因为在细胞中 许多内吞机制并行运作，实验控制的关键程度 细胞中的参数是有限的。这个项目的目标是了解如何膜形状的转变是 调节过程，如内吞作用。为了实现这一目标，我们开发了一种实验性的 生物物理模型膜的方法，使我们能够确定的条件下，膜 经历形状转变。在这个工具的帮助下，它包括一个组合的微型， 操纵/荧光方法，目前只在我们的实验室使用，我们将调查 参与内吞作用的许多蛋白质的功能机制，并分离出关键的调节剂。 膜形状过渡。我们已经建立了一个理论框架， 对我们发现的机械解释。 而质膜经历相对于跨膜离子和脂质的显著不对称性， 由于膜的分布，模型膜的研究主要集中在对称膜上。我们会克服的 限制并确定膜不对称的程度，这将包括细胞骨架相互作用， 有助于外周蛋白质在形成膜中的功能。总的来说，该项目将提供远- 深入了解外周蛋白质在健康和 病理条件。