Mechanisms of signal transduction revealed through unique chemistry of xenobiotic metal ions
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With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Tatyana Igumenova from Texas A&M University to investigate molecular pathways of calcium-dependent signaling processes at the cell membrane surface. The life of cells depends on their response to their environment. Cells need to get information about the environment and react to it. The communication of this information takes place through the cell membrane by what are called signaling processes. These signaling processes are aided by a specialized set of proteins that bind calcium. Many aspects of the calcium-mediated protein binding to membranes remain unknown. The research experiments focus on the understanding the structure and dynamics of a class of these proteins, namely C2 domains, by an innovative experimental approach that takes advantage of the binding of unnatural (non-native) metal ions to the protein. The objective of the research is to obtain insight into the fundamental biological chemistry and biophysics of the interactions between the protein and metal ions and between the protein and membrane because these interactions determine the transmission of information into the cell. Professor Igumenova organizes a 2-day summer workshop for high-school students from under-represented and under-privileged groups through an educational partnership with a Title 1 high school in which student population is more than 90% minority and 64% qualifies as economically disadvantaged. During this experience, the high school students learn through lectures, use of Wikipedia webpages constructed by Dr. Igumenova and her students, and hands-on activities about the important role of metal ions in biology as well as about the toxicity of some metal ions. This project is focused on C2 domains, a class of Ca2+-dependent peripheral membrane proteins. The C2 domains chosen for this study belong to two proteins that are of paramount importance in human biology, Protein Kinase C and Synaptotagmin I. The experimental approach, which integrates NMR and EPR spectroscopies and quantum chemical calculations, is applied to the complexes of C2 domains with xenobiotic (i.e. non-native) metal ions to investigate the conformational preferences of the Ca2+-sensing region of Synaptotagmin I, the role of protein dynamics in C2 interactions with metal ions, and the structural basis of the metal-ion dependent recruitment of C2 domains to lipid membranes. The impact of the proposed work goes beyond the two protein systems under study because the C2 domains are found in more than 100 signaling proteins. In addition to uncovering the mechanisms of signal transduction, information from this study provides new insight into the biological chemistry of xenobiotic metal ions.This award reflects NSF''s statutory mission and has been deemed worthy of support through evaluation using the Foundation''s intellectual merit and broader impacts review criteria.