CAREER: Evolution of Signaling Mechanisms in Membrane Receptors

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Many biomedical processes and targets involve membrane proteins (MPs) which constitute approximately 25% of the genes in typical genomes. Since MPs are in part accessible through the outside of cells, they form an important group of proteins for potential bioengineering applications. Advancing the fundamental understanding of folding and function of MPs required for such applications is a challenge that has lagged behind that of soluble proteins for many years. Intellectual Merit.The PI proposes that microbial sensory rhodopsin has evolved into eukaryotic rhodopsin through gradual replacement of the importance of helix-helix contacts with long-range contacts to form the folded receptor in order to achieve signaling capabilities within a single receptor. It is the goal of this proposal to test this hypothesis.The PI proposes that tertiary contacts between amino acids from both helical and loop regions take place during the very early stages before the helices have formed and possibly during their association. The two-stage hypothesis was based on experimental studies of bacteriorhodopsin. Broader Impact. Advancing the understanding of signaling mechanisms in membrane receptors may provide novel ways to engineer their function.This would be important for potential uses such as:-nanobiotechnology,bioengineering or medical intervention.-useful framework to integrate study of the fundamental processes folding and signal transduction -support education of and collaboration between researchers and students with disparate backgrounds in existing courses at the University of Pittsburgh-undergraduate student and (3) with high-school students summer camp in the PIs laboratory -Create a module for SAMS (Summer Academy for Minority Students) at Carnegie Mellon University where I hold a secondary appointment. -As the Chair of the Young Protein Scientists Committee of the Protein Society, I will be able to encourage future student chapters at Universities throughout the United States and Europe to engage in similar outreach activities.