Structural Dynamics of Presynaptic Membrane Fusion

突触前膜融合的结构动力学

• 批准号: 7596916
• 负责人: LUKAS K TAMM
• 金额: $ 94.41万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7596916
• 关键词: Structural; Dynamics; Presynaptic; Membrane; Fusion

DESCRIPTION (provided by applicant): The goal of this interdisciplinary program is to elucidate the mechanism of presynaptic membrane fusion from a mostly structural-biophysical perspective. Fusions of intracellular membranes in the secretory pathway are mediated by supramolecular machines that are assembled on demand and disassembled when the task is completed. At the core of presynaptic (and other intracellular) membrane fusion is the assembly of the SNARE core complex. The most prevalent model in the field is that the assembly of the SNARE core complex drives the membrane merger by a mechanism that is still poorly understood. The assembly and disassembly of SNAREs is believed to be regulated and catalyzed by numerous accessory proteins including SM-proteins, NSF, and alpha-SNAP. Although structures of soluble domains of many of these proteins and even of some complexes between them are known and have enormously contributed to our current understanding of their possible roles in membrane fusion, their precise sites of action at different steps of membrane docking and fusion have not yet been determined. Likewise, the site of action of the calcium sensor synaptotagmin in synaptic fusion is still poorly understood at the molecular level. Therefore, the main focus of this program is to shift attention to studying spatial relationships and interactions of these membrane proteins in the context of membranes. The three major program components will address how these fusion machines assemble/disassemble on membranes and work on membranes to eventually convert them to form productive fusion pores. To accomplish this goal, new biophysical techniques will be developed and used.

描述（由申请人提供）：该跨学科计划的目的是从大多数结构性生物物理学的角度阐明突触前膜融合的机制。分泌途径中细胞内膜的融合是由超分子机器介导的，这些机器按需按需组装并在任务完成时拆卸。突触前（和其他细胞内）膜融合的核心是SNARE CORE络合物的组装。该领域中最普遍的模型是，SNARE CORE络合物的组装通过仍然知之甚少的机制驱动膜合并。据信，网罗的组装和拆卸是由许多辅助蛋白（包括Sm-蛋白质，NSF和Alpha-SNAP）调节和催化的。尽管许多此类蛋白质甚至它们之间的某些复合物的可溶性结构域的结构是已知的，并且已经有助于我们当前对它们在膜融合中可能作用的理解，但尚未确定它们在膜对接和融合的不同步骤中的精确作用位点。同样，在分子水平上，钙传感器突触素蛋白在突触融合中的作用部位仍然很差。因此，该程序的主要重点是将注意力转移到膜上研究这些膜蛋白的空间关系和相互作用。这三个主要程序组件将解决这些融合机在膜上如何组装/拆卸膜，并在膜上工作以最终将其转换为形成生产融合孔。为了实现这一目标，将开发和使用新的生物物理技术。