Integrin alpha(V)beta(8) structure and bidirectional signaling

This project seeks to understand how receptor proteins at the surface of cells communicate with other cells. One class of these receptor proteins, called “integrins” transmit signals both into and out of the cell at the same time (these proteins “integrate” signals). Integrin signaling is essential for human cells to communicate with other cells and the environment to carry out immune responses, growth and development of the creatures, and prevent cells from forming carcinogenic tumors. The results from the proposed research will look at a specific type of integrin that will serve as a model for understanding the structure of activated integrin molecules. In addition to publication of the research, the results will be disseminated through oral and poster presentations at national and international conferences and at local, state, national and international science fairs. The project will train undergraduate and graduate students at Louisiana State University, as well as high school students at East Baton Rouge Parish in a range of methods taught by the PI and collaborators who have complementary expertise. The proposed experiments are designed to attract and retain high school, undergraduate, and graduate students, and involve them in interdisciplinary projects of fundamental importance to Biology and Chemistry. Through vigorous research activities and group meeting presentations, students will learn the methods of conducting research and, more importantly, develop the analytical thinking skills and work ethic that are crucial for success in scientific careers in academia, government, or industry. Typical integrin dimers are believed to adopt a bent, low-affinity conformation under physiological conditions, and undergo conformational change during ligand binding and signaling. Integrin αvβ8, however, shows high affinity for ligand binding at all times. This integrin dimer plays a critical role in the development of the central and peripheral nervous system. The PIs propose that the high affinity of integrin αvβ8 is closely related to its high affinity for ligand binding, anchoring nerve cells to the extracellular matrix. In this project, various methods will be used to study the structure, function, and signaling pathways of integrin αvβ8. The PI speculates that this integrin dimer provides a unique, innovative model to study a variant mechanism of integrin bidirectional signaling across the plasma membrane. The high affinity of αvβ8 is hypothesized to be the result of a stable structure “fixed” in the extended conformation, which will allow the dimer to be crystallized in the extended form. The project will combine biochemical, spectroscopic, and genetic approaches to test the hypothesis that the integrin adopts an atypical extended closed conformation with high affinity for ligands under physiological conditions. This project should lead to new understanding of how integrins interact with ligands in the extended, open conformation. This knowledge can then be used for the development of the next generation of antagonists targeting specific integrin conformation with improved therapeutic profiles. The multidisciplinary methods used in this study are also easily applicable to research fields of other proteins. This research is funded by the Cellular Dynamics and Function cluster in the Division of Molecular and Cellular Biosciences in the Directorate of Biological Sciences. 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.