With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Emily Smith from Iowa State University to investigate the chemical species that allow a class of membrane proteins to function, and to develop a detailed understanding of how the proteins organize and move in a cell membrane. Proteins in the cell membrane have a critical role in how cells get information about their surroundings as well as respond to their environment. One way these proteins function is by moving throughout the cell membrane to facilitate interactions with other proteins and cells. This project is providing information, through optical spectroscopy and microscopy measurements that would advance the understanding of two important membrane proteins associated with many aspects of cellular function. Broader impact activities target middle school, high school, undergraduate and graduate students to meet the societal goals of cultivating a scientifically literate public; increasing the number of students pursuing science degrees including students from underrepresented groups in science; and promoting a strong, diverse and capable scientific workforce to increase America's global competitiveness. These activities are being accomplished in partnership with Science Bound, a pre-college program to increase the number of ethnically diverse Iowa students who pursue science degrees, and the local American Chemical Society SEED program that provides summer research opportunities for economically disadvantaged students.
The overarching objective of this work is to measure the clustering, diffusion, and nanoscale organization of a class of cell membrane proteins termed pattern recognition receptors (PRRs). These receptors are part of the innate immune system that recognizes several pathogen-associated molecular patterns and damage-associated molecular patterns. The molecular mechanism of clustering and diffusion within the membrane upon chemically-defined ligand binding events will be measured for two PRRs: receptor for advanced glycation endproducts (RAGE) and Toll-like receptor 4 (TLR4). Both PRRs share a subset of ligands, and have been shown to exhibit receptor "cross talk," as evidenced by downstream protein phosphorylation (i.e., signaling). The project is using single particle tracking methods to measure the diffusion of TLR4 and elucidate the role of chemically-characterized ligands in affecting the diffusion of RAGE and TLR4. The RAGE and TLR4 association in the cell membrane is measured by fluorescence resonance energy transfer. Evidence for an association of these two receptors within the membrane has not been reported. It is hypothesized that a direct interaction between RAGE and TLR4 may be an important mechanism of their function, and that diffusion is an important regulator of these interactions. The proposed work is generating a foundation for understanding the molecular biophysical aspects of PRRs' molecular function that will add to the available data on the downstream signaling of these receptors.
