RUI: G Protein-Coupled Receptor Kinase 2: Structure and Function

人体的各个细胞通过荷尔蒙和神经递质相互交流，这些激素和神经递质由一个细胞产生，然后作用于目标细胞。激素或神经递质与特定受体的相互作用在细胞内引发了信号级联反应。一种重要的介质是一种叫做G蛋白的分子，它与受体和下游信号分子相互作用，导致特定细胞类型的反应。例如，当我们害怕时，肾上腺素被释放到血液中，它作用于心脏中的靶细胞，导致心率加快。信号的适当强度和持续时间是如此重要，以至于已经进化出多种机制来调制这种信号。信号调节的一种机制涉及激素诱导受体失活，这种特定蛋白被称为G蛋白偶联受体激酶2(GRK2)。因此，GRK2阻断了由肾上腺素启动的信号，并允许细胞返回到基础状态，以便它能够适当地对环境做出反应。虽然GRK2最初是通过肾上腺素受体来调节信号的能力，但现在人们知道GRK2调节许多受体，称为G蛋白偶联受体，这些受体实际上代表了人类基因组中最大的一类蛋白质。此外，除了改变受体，GRK2还与G蛋白结合。因此，GRK2“多任务”地调节激素信号。这个项目的目标是了解GRK2如何执行激素刺激的功能，如受体失活和与G蛋白的相互作用。由于GRK2的形状在原子细节上是已知的，公共数据库和文献可以用来预测GRK2如何与受体相互作用。下一步是使用分子生物学技术来替代单个氨基酸，以评估GRK2的哪些部分对受体相互作用是重要的。这些研究不仅将深入了解GRK2调节受体的机制，而且还将确定这一新的蛋白质家族的激活机制。确定受体识别位点将最终导致可能具有治疗价值的GRK2抑制剂的合理设计。这个项目将在一个以本科生为主的机构进行，并将允许许多学生参与现代结构、分子和细胞研究。与研究密集型大学的研究人员广泛合作，将确保最新技术的注入，这将反映在这所规模较小的文理学院的细胞生物学、分子生物学和生物化学课程中。首席研究员将保持吸引本科生参与研究(特别是那些来自代表性不足群体的本科生)和培养职业科学家的良好记录。

Individual cells of the body communicate with each other via hormones and neurotransmitters that are produced by one cell and then act on a target cell. The interaction of the hormone or neurotransmitter with a specific receptor sets off a signaling cascade within the cell. An essential mediator is a molecule called a G protein that interacts with both receptor and downstream signaling molecules leading to a response that is specific to the cell type. For example, when we are frightened, adrenalin is released into the bloodstream and it acts on target cells in the heart resulting in an increase in heart-rate. The appropriate intensity and duration of the signal are so important that multiple mechanisms have evolved which modulate such a signal. One mechanism of signal modulation involves hormone-induced inactivation of the receptor by a specific protein called G protein-coupled receptor kinase 2 (GRK2). Thus, GRK2 blocks the signal initiated by adrenalin and allows the cell to return to a basal state so that it can appropriately respond to the environment. Although GRK2 was first identified by its ability to modulate signaling by the adrenalin receptor, it is now known that GRK2 regulates many receptors, called G protein-coupled receptors, and these receptors in fact represent the largest class of proteins in the human genome. Furthermore, in addition to altering the receptor, GRK2 also binds the G protein. Thus, GRK2 "multi-tasks" to regulate hormone signaling. The goal of this project is to understand how GRK2 carries out hormone-stimulated functions such as inactivation of the receptor and interaction with the G protein. Since the shape of GRK2 is known in atomic detail, public databases and the literature can be used to predict, for example, how GRK2 interacts with receptors. The next step is to use molecular biological techniques to substitute individual amino acids to assess which portions of GRK2 are important for receptor interaction. These studies will not only provide insight into the mechanism of receptor regulation by GRK2 but also define a mechanism of activation for this novel family of proteins. Defining receptor recognition sites will ultimately lead to the rational design of GRK2 inhibitors that may have therapeutic value. This project will be carried out at a predominantly undergraduate institution and will allow many students to participate in modern structural, molecular and cellular research. Extensive collaborations with investigators at research-intensive universities will ensure the infusion of the latest technology and this will be reflected in the cell biology, molecular biology and biochemistry curricula at this small liberal arts college. The principal investigator will maintain a strong record of engaging undergraduates in research (especially those from under-represented groups), and producing career scientists.