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

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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.