Some proteins can acquire stable unconventional conformations and pass them on to newly synthesized protein molecules with the same primary sequence. These self-perpetuating protein conformations are called prions. For years, prions were considered to be a rare abnormality. However, recent identification of prions as benign epigenetic modifiers of cellular functions in fungi suggests that prions play a role in normal cellular physiology and evolutionary adaptation. Consequently, there are indications of the existence of molecular mechanisms governing the formation and elimination of self-perpetuating protein conformations. The long-term goal of the PI's research is to understand these mechanisms and the biological role of prions. The major objective of this project is to explore a novel scientific concept of epigenetic control of the appearance of protein-based hereditary traits. Genetic analysis in yeast is the major approach. It is hypothesized that there are two different ways for proteins to attain a prion state. The first mechanism is by direct seeding involving imperfect templating of novel prions by pre-existing ones. Aim 1 will provide material and data for elucidating this mechanism. The second mechanism does not involve a pre-existing template - the prion conformation is a result of spontaneous misfolding. Aim 2 is to determine protein characteristics and cellular factors that facilitate such spontaneous prionization. Because discovery of ubiquitous functional prions is likely to impact many fundamental cellular processes, these studies are expected to impact various fields of modern biology and our understanding of regulation, heredity and evolution. Obtained results may also contribute to agricultural and environmental sciences by explaining yet another mechanism of attaining phenotypic variability. The research will be integrated with education. The lab relies heavily on graduate students - two graduate research assistants are expected to work full time on this project and perform most of experimental work. Also, the S. cerevisiae experimental system provides a unique opportunity to engage undergraduate and even high school students in prion research. Undergraduate students are involved through the NYU Summer Undergraduate Research Program; high school students - through the Intel Science Talent Search project. Results will be presented to diverse audiences.
