Structural Study of Semaphorins, Neuropilins and Plexins

脑信号蛋白是一大类细胞外蛋白，参与细胞内多种过程， 发育，包括神经元迁移和轴突引导。它们作为化学排斥剂， 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充当 化学引诱物脑信号蛋白受体是一种多蛋白复合物，其中包括一个丛蛋白分子 作为信号转导亚单位。此外，一些脑信号蛋白受体包括神经纤毛蛋白， 配体结合亚基。本提案的研究重点是详细的结构表征， semaphorins，neuropilins，plexins和它们的相互作用。对脑信号蛋白和 神经纤毛蛋白已经确定了它们的相互作用域。的受体结合模块的晶体结构 Semaphorin-3A在2.8 A分辨率下测定，揭示了一种意想不到的β螺旋桨分子 架构接下来将使用X射线晶体学来确定全长 Semaphorin-3A和来自其他类别的选择的semaphorins的结构。分析这些 结构将侧重于识别对定义受体和辅助受体重要的结构元件 semaphorins的特点神经纤毛蛋白和丛蛋白的相互作用域的晶体结构将 也要坚决。最后，对一系列semaphorin/neuropilin，neuropilin/plexin， 脑信号蛋白/丛蛋白和脑信号蛋白/神经纤毛蛋白/丛蛋白复合物将被确定，阐明了 导致脑信号蛋白信号传导起始的分子事件。结构数据将是 辅以生物物理、生物化学和荧光/FRET研究， semaphorin/neuropilin/plexin相互作用。结合结构和生物物理信息将提供 对脑信号蛋白生物学功能的分子机制的基本见解， 神经毡蛋白和丛蛋白，并且可以在开发用于以下疾病的治疗剂中具有重要的应用： 治疗脑和脊髓损伤。

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.