Structural Study of Semaphorins, Neuropilins and Plexins

描述（由申请人提供）：脑信号蛋白是一大组细胞外蛋白，参与发育过程中的各种过程，包括神经元迁移和轴突导向。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作为化学引诱剂。脑信号蛋白受体是多蛋白复合物，其中包括作为信号转导亚基的丛蛋白分子。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。在这个建议的研究重点是详细的结构特征的semaphorins，neuropilins，plexins，以及它们之间的相互作用。对semaphorins和neuropilins的初步研究已经确定了它们的相互作用域。在2.8 A分辨率下测定脑信号蛋白-3A受体结合模块的晶体结构，揭示了意想不到的β螺旋桨分子结构。接下来将使用X射线晶体学来确定全长Semaphorin-3A的结构和从其他类别中选择的semaphorin的结构。这些结构的分析将集中在确定重要的结构元素定义的受体和辅助受体的特异性信号蛋白。神经纤毛蛋白和丛蛋白的相互作用域的晶体结构也将被确定。最后，一系列的脑信号蛋白/神经纤毛蛋白，神经纤毛蛋白/丛蛋白，脑信号蛋白/丛蛋白，和脑信号蛋白/神经纤毛蛋白/丛蛋白复合物的结构将被确定，照亮的分子事件，导致启动脑信号蛋白信号。的结构数据将补充生物物理，生物化学和荧光/FRET为基础的研究semaphorin/neuropilin/丛蛋白的相互作用。结合的结构和生物物理信息将提供基本的见解semaphorins，neuropilins和plexin的生物学功能的分子机制，并可能有显着的应用在开发治疗剂治疗脑和脊髓损伤。

DESCRIPTION (provided by applicant): 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 fluorescence/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.