Sema-Plexin信号通路中FARP2的结构与功能研究

神经系统的精确发育发展离不开轴突导向。神经细胞生长椎上的受体接受环境中的轴突导向因子传递的信号，经过一系列蛋白的传递，最后作用于细胞骨架蛋白，从而影响生长椎的走向。Semaphorin-Plexin 通路是其中重要的信号通路之一，我们的研究重点是这一通路中plexin的下游互作蛋白FARP2。FARP2 N端的FERM结构域介导它与Plexin之间的相互作用，但是二者之间的互作模式与分子机制还不清楚。本项目将利用晶体生物学，生物化学，细胞生物学等手段，在结构与功能上研究FARP2及其与Plexin的互作关系和分子调控机制，为进一步理解Sema-Plexin通路下游信号传导机制提供分子依据。我们之前的结构生物学研究发现FARP2 的DH-PH-PH结构域是一种以自我抑制构象存在的小GTP酶的鸟核苷酸交换因子(GEF)，本项目将进一步探讨如何激活FARP2的GEF活性。

英文摘要.The correct wiring of the nervous system relies on the precise axon guidance. During development of the nervous system, axons are guided to their proper targets by sensing a variety of extracellular cues in the local environment. The receptor protein on the neuronal growth cones which is located at the tip of the growing axon, recognizes guidance cues. The signal finally selectively alters the stability of the actin cytoskeleton and microtubules that determine the rate and direction of axon extension. Semaphorin-Plexin is one of the classic ligand/receptor systems involved in this process， and we will focus on FARP2, which is a downstream partner of Plexin A1. FARP2 interacts with Plexin A1 though its N terminal FERM domain, but how they bind is still not clear. We are using the combination of protein X-ray crystallography, biochemical techniques and cell based assay to study the structure and function of FARP2 and its interaction and regulation with Plexin A1. Our research will help us to understand the molecular regulation mechanisms of downstream signal transduction of Sema-plexin pathway. C terminal domain DH-PH-PH of FARP2 is an auto-inhibited Guanine nucleotide exchange factor (GEF) based on our previous studies, and we will study how to active GEF activity further.