Structural Mechanisms in Semaphorin Signaling

描述（由申请人提供）：脑信号蛋白信号传导作为神经、免疫和心血管系统发育和稳态的寻路控制。脑信号蛋白的多效性功能由其细胞表面受体丛蛋白介导，并且在许多情况下由共受体神经纤毛蛋白辅助。脑信号蛋白及其受体是糖蛋白的大家族，其各自的结构和功能在动物界中是保守的。脑信号蛋白信号传导的失调与许多病理状况相关，包括肿瘤血管生成和进展、神经退行性疾病和多发性硬化。脑信号蛋白信号传导的调节具有治疗潜力，但由于缺乏脑信号蛋白受体识别和脑信号蛋白受体激活的结构信息而受到限制。我们提出了三个具体的目标来阐明脑信号蛋白信号传导的分子机制：1）描述类别特异性脑信号蛋白-丛状蛋白识别的基础; 2）阐明神经纤毛蛋白在3类脑信号蛋白信号传导复合物组装中的作用; 3）理解丛状蛋白自身抑制的模式和由脑信号蛋白结合诱导的丛状蛋白构象变化。重组蛋白表达和工程，X射线晶体学，等温滴定量热法（ITC），生物物理和细胞分析将用于实现这些特定的目标。脑信号蛋白及其受体的结构信息可以作为设计潜在应用的基础，例如癌症治疗中的抗血管生成和抗转移，以及损伤部位的定向神经生长。我们的研究团队经验丰富，在类似于这项拟议研究的项目中有着良好的记录。这项研究的结构信息将是非常新颖的，并可能为Semaphorin领域的新生物化学和细胞生物学研究奠定基础。

DESCRIPTION (provided by applicant): Semaphorins signaling serves as a path-finding control for the development and homeostasis of the nervous, immune, and cardiovascular systems. The pleiotropic functions of Semaphorins are mediated by their cell surface receptors Plexins, and in many cases aided by the co-receptors Neuropilins. Semaphorins and their receptors are large families of glycoproteins whose respective structures and functions are conserved across the animal kingdom. Dysregulation of Semaphorin signaling has been associated with many pathological conditions, including tumor angiogenesis and progression, neurodegenerative diseases, and multiple sclerosis. The modulation of Semaphorin signaling has therapeutic potential, but is limited by the lack of structural information on Semaphorin-receptor recognition and the activation of Semaphorin receptors. We propose three specific aims to elucidate the molecular mechanisms in Semaphorin signaling: 1) Delineate the basis of class-specific Semaphorin- Plexin recognition; 2) Elucidate the role of Neuropilins in the assembly of class 3 Semaphorin signaling complexes; 3) Understand the mode of Plexin auto-inhibition and the Plexin conformational change induced by Semaphorin binding. Recombinant protein expression and engineering, X-ray crystallography, isothermal titration calorimetry (ITC), and biophysical and cellular assays will be used to accomplish these specific aims. The structural information about Semaphorins and their receptors can serve as a basis for designing potential applications such as anti-angiogenesis and anti- metastasis in cancer treatments, and directional nerve growth at the injury sites. Our research team is highly experienced and has a track record in projects similar to this proposed study. The structural information from this study will be highly novel, and likely will lay the groundwork for novel biochemical and cell biological research in the Semaphorin field.