The Rho-family of small guanosine triphosphatase (GTPase) proteins are essential for many basic physiological processes, including cell differentiation, division, chemotaxis, axonal development, and polarity. GTPases act as binary "on/off" switches and control communication within a cell. Guanine nucleotide exchange factors (GEFs) tightly control the active state of GTPases and coordinate their function. However, the fundamental mechanisms for how GEF proteins are regulated and how they direct GTPase signaling remain poorly understood. This project is focused on Tiam1, a large, modular GEF that specifically activates a GTPase (Rac1) that regulates cell polarity, adhesion, and migration. Under normal conditions Tiam1 GEF inhibits its own activity by protein-protein interactions and/or by phosphorylation. Upon activation, Tiam1 is capable of interacting with multiple protein targets and influencing many cell processes. In this study a combination of structural, biophysical, and biochemical approaches will be used to define the molecular basis of Tiam1 auto-inhibition, its activation, and its signaling specificity. The basic concepts learned from this project will enhance our understanding of signal transduction and provide new insights into the coordinated regulation of modular signaling proteins. In addition, this research will contribute to our understanding of diverse fields including protein allostery and dynamics, and promote the rational design of artificial scaffold proteins with desired regulatory features and functions.
Broader Impacts: The major educational goal of this CAREER project is to expose faculty and students from primarily undergraduate institutions (PUI) to cutting-edge biophysics research. The PI will conduct a yearly "Biophysics Workshop" to establish research and education collaborations with PUI faculty throughout Iowa. These workshops will introduce PUI faculty and their students to modern experimental biophysics and provide access to the infrastructure necessary for them to expand their research capabilities. In addition, the PI will design an "Honors Tutorial Series" to introduce advanced high school and undergraduate students to web-based protein and gene analysis tools to enhance their summer research experience. The audience for this series will be drawn from ~100 high school and undergraduate students that participate in summer research programs across campus, including the SROP/McNair Scholars Program, Iowa Biosciences Advantage Program, Iowa First Nations Summer Program, and Secondary Student Training Program for high school students. Collectively, these activities will engage faculty and students, including members of minorities under-represented in science, in advanced biophysical research.
This project is jointly supported by the Cellular Systems Cluster of the Molecular and Cellular Biosciences Division and the NSF EPSCoR Office
