STRUCTURAL STUDIES ON NEURORECEPTORS

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 我所在小组的研究旨在了解参与神经传递的整体膜受体、酶和离子通道的生物学活性和物理性质的分子基础。为了实现我们的目标，主要通过X射线结晶学来确定三维结构，并通过基于结构的定点突变结合包括电生理在内的生物物理和生化技术来评估目标蛋白的功能性质。 具体地说，我们重点关注在介导神经元活动中发挥关键作用的三类整膜蛋白：NMDA受体，一个配体门控的阳离子通道，它与谷氨酸和甘氨酸结合后打开，并介导兴奋性突触传递；低密度脂蛋白受体相关蛋白(LRP)，一个与NMDA受体相关的脂蛋白受体，调节突触传递的强度；以及伽马分泌酶，一种膜内裂解酶(ICLIPs)，它介导淀粉样前体蛋白(APP)的受控膜内蛋白分解(RIP)，以调节淀粉样β蛋白的产生，淀粉样β蛋白是阿尔茨海默病的致病产物。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The research in my group is aimed at understanding molecular basis for biological activity and physical properties of integral membrane receptors, enzymes and ion channels involved in neurotransmission. To achieve our goals, three-dimensional structures are determined primarily by x-ray crystallography and functional properties of target proteins are assessed by structure-based site-directed mutagenesis in combination with biophysical and biochemical techniques including electrophysiology. Specifically, we are focusing on three classes of integral membrane proteins, which play key roles in mediating neuronal activities: NMDA receptors, a ligand-gated cation channel that opens upon binding to glutamate and glycine and mediate excitatory synaptic transmission; LDL receptor related protein (LRP), a lipoprotein receptor that associate with NMDA receptors and regulate the strength of synaptic transmission; and gamma-secretase, an intramembrane cleaving protease (iCLIPs) that mediate regulated intramembrane proteolysis (RIP) of amyloid precursor protein (APP) to regulate the production of amyloid beta, a pathogenic product for Alzheimer's disease.