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INSIGHTS INTO THE MOLECULAR MECHANISMS OF PROTEIN FOLDING AND MISFOLDING. Sheena E. Radford, University of Leeds, Leeds, UK, LS2 9JT. Email s.e.radford@leeds.ac.uk; FAX + (113) 233 3167 Recent innovations in protein engineering, protein expression and methods for monitoring protein folding in real time, have now placed scientists at the exciting point of being able to make real progress towards understanding protein folding. For a complete understanding of folding, we also need not only to consider the problem of protein folding in vitro, but also how this process occurs in vivo. This is an exciting field involving topical areas such as chaperone-assisted folding and protein misfolding diseases. We are investigating all of these aspects of protein folding in my research group, using a wide variety of biochemical and biophysical methods and a variety of different proteins with a range of topologies. In this lecture I will describe recent insights into the folding mechanisms of some of these proteins. I will also highlight some of the recent results we have obtained which suggest that the molecular chaperone GroEL can bind substrates ranging from unstable early intermediates, to protein conformations resembling closely the ultimate native-state. Another important, and currently, very topical aspect of protein folding, focuses on the misfolding of proteins in amyloid diseases. We are using our knowledge of protein folding mechanisms in vitro, gathered using a wide range of biochemical and biophysical methods, to investigate the mechanism of amyloidosis of human lysozyme. Our results suggest that the amyloidogenic variants of lysozyme are destabilised relative to the wild-type protein, but more significantly, they have unusual conformational dynamics that might explain their propensity to aggregate. We have investigated this further using peptides from lysozyme which are thought to be important in fibrillogenesis. We have shown that the small peptides also form fibrils, reminiscent, but much more simple in structure, than amyloid fibres. This has opened the door to a detailed investigation of the mechanism of protein fibrillogenesis, the results of which will be described. ## Back to the list of abstracts