Protein Supported Lipid Bilayers as a Mimic of Native Biological Membranes

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DESCRIPTION (provided by applicant): Protein aggregation is an extremely important subject in biology, biophysics, biotechnology, and medicine. A number of debilitating human diseases are associated with the deposition in tissue of protein aggregates known as amyloid fibrils. The primary goal of this project is to characterize the intermediates in the early stages of amyloid fibril formation. In this study, RNase Sa will be used as a model system. Recently, the Scholtz Lab has investigated the propensity of RNase Sa and two variants to form fibrils in the presence of TFE and as a function of pH. In preliminary studies, we have developed conditions in which we have identified and isolated several small molecular weight oligomers of RNase Sa in solutions that are in the process of forming amyloid fibrils. I will characterize the secondary and tertiary structure of fibril formation by near UV-CD, fluorescence, limited proteolysis, possibly by NMR, and hydrogen-exchange mass spectrometry. The overall goal is to reach a molecular understanding of the early events in amyloid fibril formation in an effort to hopefully design small molecules or treatment strategies to help prevent the devasting consequences of these protein misfolding diseases.