Annexins and Membrane Organization

膜联蛋白和膜组织

• 批准号: 6414291
• 负责人: ANNE HINDERLITER
• 金额: $ 13.08万
• 依托单位: NORTH DAKOTA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6414291
• 关键词: anions; annexins; artificial membranes; biological signal transduction; calcium ion; calorimetry; chemical structure function; computer simulation; diacylglycerols; gene mutation; intermolecular interaction; mathematical model; membrane lipids; membrane model; membrane structure; model design /development; molecular assembly /self assembly; molecular site; phosphatidylethanolamines; protein localization; protein purification; protein structure function; spectrometry; statistics /biometry; yeasts

DESCRIPTION (provided by applicant): Propagation of signal transduction events usually involves protein-protein interactions, (eg protein phosphorylation and substrate-enzyme reactions). Such events are highly enhanced in magnitude and specificity if the proteins involved are associated with and concentrated in the same membrane domain, rather than distributed over a large number of disconnected domains (Thompson et al., 1995). We believe that membrane lipid domains can impart a magnifying or quenching effect on membrane associated cascading reactions. For this contention to be valid, regulation of domains is necessary to prevent random modulation of a cascade reaction by the mere presence of domains. Fluid lipid domains are dynamic structures (in model membrane systems) whose differences in interaction energies between different lipid species are quite small, on the order of hundreds of calories per mole (Sugar et al., 1994, 1999, Jerala et al., 1996). The large number of lipids present in membranes magnifies such lipid-lipid interactions, leading to domain formation. In contrast, protein-lipid interactions are usually on the order of kcal/mol of protein and vary with lipid composition. Differential protein-lipid interactions that vary with lipid composition may then enhance formation or disintegration of domains. Annexins are an abundant family of membrane-associated proteins with diverse distribution in organisms, which bind anionic phospholipids and Ca2+ and do not have any apparent enzymatic function. The present grant proposal is based on a fundamental concept; that annexins have a general organizational function on cell membranes. The manner in which this function is achieved is through binding and consequent stabilization of lipid domains. We will approach this hypothesis using an integrative approach that combines experimental work (spectroscopy, calorimetry and molecular biology) with Monte Carlo computer simulation in the study of a protein-lipid bilayer model system. The approach is iterative, building in complexity of the model lipid system and type of annexin with each step.

描述（由申请人提供）：信号转导事件的传播 通常涉及蛋白质 - 蛋白质相互作用（例如蛋白质磷酸化和 底物 - 酶反应）。此类事件的幅度高度增强， 特异性如果涉及的蛋白质与并集中在 相同的膜域，而不是在大量上分布 断开的域（Thompson等，1995）。我们相信膜脂质 域可以对相关的膜产生放大或淬火效应 级联反应。对于此论点有效，域的调节是 防止单纯调制级联反应的必要条件 域的存在。流体脂质结构域是动态结构（在模型中 膜系统），其在不同的相互作用能量之间的差异 脂质物种很小，每摩尔的卡路里数百卡路里 （Sugar等，1994，1999； Jerala等，1996）。大量脂质 膜中的存在会放大这种脂质脂质相互作用，导致结构域 形成。相反，蛋白质脂质相互作用通常在 蛋白质的kcal/mol随脂质组成而变化。差异蛋白脂 然后，随着脂质成分变化的相互作用可能会增强形成或 域的分解。附属蛋白是一个丰富的家族 膜相关的蛋白质在生物体中具有不同分布的蛋白质，它们结合 阴离子磷脂和Ca2+，并且没有任何明显的酶促功能。 目前的赠款提案基于一个基本概念；那个附件 在细胞膜上具有一般的组织功能。方式 该功能是通过结合和随之而来的稳定 脂质域。我们将使用综合方法来解决这一假设 结合了实验工作（光谱，量热法和分子 生物学）与蒙特卡洛计算机模拟有关蛋白质脂质的研究 双层模型系统。这种方法是迭代的，建立在复杂性 每个步骤都模型脂质系统和膜联蛋白的类型。