MPECDeveloping & Applying Innovative Expression Methods
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Dr. Jonathan Weissman


To ensure proper folding, cells have evolved a sophisticated and essential machinery of proteins called molecular chaperones that assist the folding of newly made polypeptides. The importance of proper protein folding is underscored by the fact that a number of diseases, including Alzheimer's and those involving infectious proteins (prions), result from protein-misfolding events. My research focuses on identifying and understanding the machinery necessary for efficient folding, as well as studying the mechanism and consequences of protein misfolding. We are also developing experimental and analytical approaches for exploring the organizational principles of complex biological systems. Mechanism of Amyloid Formation and Propagation In contrast to the more frequently observed disordered aggregates, some proteins form ordered aggregates, termed amyloid fibrils, that accumulate in a number of human diseases. Our goal is to provide a mechanistic understanding of how amyloid fibers propagate, to elucidate how molecular chaperones control amyloid growth in vivo, and to determine the role of amyloid formation in both disease and normal physiology. Efforts to understand amyloid propagation have been hampered by the lack of a facile genetic or biochemical system for studying this process. This situation has improved greatly with the finding that the [URE3] and [PSI+] states of yeast result from the prion-like aggregation of endogenous proteins. My laboratory has taken advantage of the PSI phenomenon to identify and characterize properties of the protein Sup35p that allow it to propagate a b-sheet rich prion form. These efforts have been greatly aided by our development of strategies that let us create distinct synthetic prion conformations of Sup35p (the protein determinant of [PSI+]) and introduce them into yeast. This has provided the first demonstration of the "protein-only" hypothesis, identified amyloid as the infectious conformation, and enabled mechanistic investigations into several of the most perplexing features of prion biology in terms of the structural and biophysical properties of amyloids and cellular factors that act on such forms. These features include the ubiquitous presence of "species barriers" which inhibit transmission between even closely related prion proteins, and prion strains wherein infectious particles composed of the same protein give rise to a range of different heritable prion states.

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