Uncovering Biophysical Mechanisms of Crosstalk in Pattern Recognition Receptors

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With this award, the Chemistry of Life Processes Program is funding Professor Emily Smith at Iowa State University to reveal mechanisms of membrane protein crosstalk that involve receptor clustering and diffusion in pattern recognition receptors (PRRs). Cells must produce an immune response when they encounter outside organisms and other invaders. Critical to the immune response are proteins in the cell membrane. These membrane proteins not only detect the invader, but they also control how the cell produces a response. The immune response must be very carefully balanced to fight the outside invader while not producing extensive inflammation, which is itself harmful. Professor Emily Smith and her research group at Iowa State University are using optical microscopy to study the involvement of two important membrane proteins in this immune response, and to answer the critical question of how these two membrane proteins work together to generate a response to chemically-characterized invading species. A set of integrated activities provides outreach to high school students from low-income families, as well as undergraduate and graduate student training in research and science policy. The overarching goal of these activities is to impart the skills necessary to pursue outstanding science while acquiring specialized skills in protein chemistry and biophysical measurement science.This project involves state-of-the-art biophysical studies of membrane protein crosstalk and clustering and diffusion patterns associated with the immune response. The two receptors that are the focus of this work are the Receptor for Advanced Glycation Endproducts (RAGE) and Toll-like Receptor 4 (TLR4). Both receptors are part of the inflammatory response in the presence of heterogeneously diverse ligands containing damage associated molecule patterns (DAMPs) and pathogen associated molecular patterns (PAMPs). Crosstalk results when the function of one receptor influences the other receptor. RAGE and TLR4 are known to share common ligands and signaling pathways, but the details of their crosstalk are poorly understood. An important aspect of this work is the use of chemically-characterized ligands to study RAGE isomers and differentially phosphorylated forms of the receptor. Receptor nanoscale organization and diffusion are being measured with single molecule localization microscopy and single particle tracking. The research objectives are integrated with the educational objectives of advancing the scientific literacy of high school students from low-income families, as well as training undergraduate and graduate students in chemical physics and data-driven science policy.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.