Structural Study of Semaphorins, Neuropilins and Plexins

信号素是一大组细胞外蛋白质，参与了细胞外的各种过程。 发育，包括神经元迁移和轴突引导。它们的作用是化学抵抗剂 引导轴突远离由其表达标记的组织，但在某些情况下，也可以起到 化学诱导剂。信号素受体是多蛋白复合体，其中包括一个丛蛋白分子。 作为信号转导的亚单位。此外，一些信号素受体还包括一种神经纤毛素 配体结合亚基。本提案中的研究重点是详细的结构表征 信号素、神经粘连蛋白、丛状蛋白及其相互作用。信号素及其受体的初步研究 神经匹林已经确定了它们的相互作用区域。受体结合模块的晶体结构 信号素-3A在2.8A分辨率下被测定，揭示了一个意想不到的β推进器分子 建筑。接下来将使用X射线结晶学来确定全长的结构 信号素-3A和从其他类别选择的信号素的结构。对这些问题的分析 结构将侧重于识别对确定受体和辅受体重要的结构元素 信号素的特殊性。神经粘连蛋白和神经丛蛋白相互作用区域的晶体结构将 也要有决心。最后，对一系列信号素/神经粘连蛋白，神经粘连蛋白/丛状蛋白， 将测定信号素/丛状蛋白和信号素/神经粘连蛋白/丛状蛋白复合体，从而阐明 导致信号素信号启动的分子事件。结构数据将是 辅以生物物理、生化和基于荧光/FRET的研究 信号素/神经粘连蛋白/丛状蛋白相互作用。综合的结构和生物物理信息将提供 对信号素生物功能潜在的分子机制的基本见解， 和丛状蛋白，并可能在开发治疗药物方面有重要应用 脑和脊髓损伤的治疗。

The semaphorins are a large group of extracellular proteins involved in a variety of processes during development, including neuronal migration and axon guidance. They function as chemorepellents that direct axons away from tissues marked by their expression, but in some cases can also act as chemoattractants. The semaphorin receptors are multiprotein complexes, which include a plexin molecule serving as the signal-transducing subunit. In addition, some semaphorin receptors include a neuropilin ligand-binding subunit. Research in this proposal focuses on detailed structural characterization of the semaphorins, neuropilins, plexins, and their interactions. Preliminary studies of semaphorins and neuropilins have identified their interacting domains. The crystal structure of the receptor-binding module of Semaphorin-3A was determined at 2.8 A resolution, revealing an unexpected beta propeller molecular architecture. X-ray crystallography will be used next to determine the structure of full-length Semaphorin-3A and structures of selected semaphorins from other classes. The analysis of these structures will focus on identifying structural elements important for defining the receptor and co-receptor specificities of semaphorins. The crystal structures of the interacting domains of neuropilins and plexins will also be determined. Finally, the structures of a series of semaphorin/neuropilin, neuropilin/plexin, semaphorin/plexin, and semaphorin/neuropilin/plexin complexes will be determined, illuminating the molecular events leading to the initiation of semaphorin signaling. The structural data will be complemented by biophysical, biochemical and flourescence/FRET-based studies of the semaphorin/neuropilin/plexin interactions. The combined structural and biophysical information will provide fundamental insights into the molecular mechanisms underlying the biological functions of semaphorins, neuropilins, and plexin, and could have significant applications in development of therapeutic agents for treatment of brain and spinal cord injuries.