Dr. Stephen Fried from Johns Hopkins University at 4:00pm

Though protein folding has been at the heart of biophysical research for several decades, our knowledge of the topic is deep but narrow – we “know” a lot about a sparse set of “model” proteins that conform to Anfinsen’s thermodynamic hypothesis.  Leveraging the power of structural proteomics, work in our lab has endeavored to interrogate protein folding and refolding globally, sensitively, and (for some applications) in vivo.  We found that many E. coli proteins cannot efficiently return to their native structures following complete denaturation, and nonrefoldable proteins over-represent a particular set of biophysical and topological features that have been traditionally excluded from folding research.  Proteins from yeast are strikingly more refoldable than E. coli proteins despite their greater size and complexity, a difference that we find can be attributed to the higher levels of intrinsic disorder in yeast proteins and their requirement for facile retrieval from biomolecular condensates.  Nonrefoldability is connected to and explains a broad range of phenomena, such as the requirement of certain proteins to fold cotranslationally, kinetic stability, and may explain – in part – the molecular basis of cognitive decline associated with aging.