Structural Mechanisms in Semaphorin Signaling

描述（由申请人提供）：信号蛋白信号在神经、免疫和心血管系统的发育和稳态中起寻径控制作用。信号素的多效性功能是由其细胞表面受体丛蛋白介导的，在许多情况下由共受体神经肽辅助。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王国中是保守的。信号蛋白信号的失调与许多病理状况有关，包括肿瘤血管生成和进展、神经退行性疾病和多发性硬化症。Semaphorin信号的调节具有治疗潜力，但由于缺乏有关Semaphorin受体识别和Semaphorin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信号素信号传导的分子机制：1)描述类特异性信号素-丛蛋白识别的基础；2)阐明Neuropilins在3类Semaphorin信号复合物组装中的作用；3)了解丛蛋白自抑制模式和信号蛋白结合引起的丛蛋白构象改变。重组蛋白表达和工程、x射线晶体学、等温滴定量热法（ITC）以及生物物理和细胞分析将用于实现这些特定目标。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，如抗血管生成和抗肿瘤治疗中的转移，以及损伤部位的定向神经生长。我们的研究团队经验丰富，在类似于这项研究的项目中有着良好的记录。该研究的结构信息将是高度新颖的，并可能为信号蛋白领域的新生化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.