STRUCTURAL STUDIES ON NEURORECEPTORS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 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. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.