MAGI2介导的蛋白复合物在神经突触发育与信号转导中的结构与功能研究

神经系统的正常发育及信号传导是人类完成各项生理活动的基础。神经信号的精确传导受到神经突触后膜附近的突触后致密区（PSD）的精密调控。研究表明，MAGUK家族蛋白在建立与维持神经突触连接、调节PSD的动态组成过程中发挥着重要的作用，其功能失调会导致一系列精神疾病的发生。MAGUK家族成员MAGI2介导的蛋白复合物（MAGI2/SAPAP/Shank）能够将神经信号从受体传导到细胞骨架，调控神经信号转导可塑性。该蛋白复合物功能的缺失将导致精神分裂症、躁郁症、自闭症及强迫症的发生。目前MAGI2介导的蛋白复合物的分子组装机制尚不明确。本项目计划研究该蛋白复合物的相互作用机制、解析其三维结构，并利用小鼠海马神经元细胞研究其在树突棘形态变化及信号转导过程中的作用机理。研究成果将为全面了解MAGUK家族蛋白在调控神经信号传导过程中的作用提供结构信息并为治疗相关神经疾病的药物的设计与开发提供理论基础。

Synaptic development and signalling transduction are essential for various biological processes in human being.The postsynaptic density (PSD) is located at the postsynaptic side of excitatory synapse, which has pivotal roles in orchestrating synaptic structure and function. Membrane-associated guanylate kinases (MAGUKs) are a family of scaffold proteins that are highly enriched in synapses and are responsible for organizing the numerous protein complexes required for synaptic development and plasticity. Mutations in genes encoding MAGUKs and their interacting proteins can cause a broad spectrum of human psychiatric disorders. MAGI, one of the most important members of MAGUK family scaffold protein, mediates signalling pathway in PSD via protein complex MAGI2/SAPAP/Shank, which is essential for the plasticity of synapse. However, little is known about how MAGI2-mediated complex assembles. Here, we plan to systematically study the molecular details of MAGI2-mediated protein complex using biochemical and structural tools. In addition, we will study the function of MAGI2-mediated protein complex in regulating the formation and dynamic changes in PSD in vivo. We hope that our biochemical and structural discoveries will largely improve our understanding the molecular basis of PSD assembly and dynamics and provide valuable information for the drug design for psychiatric disorders.