Sheena E. Radford, University of Leeds, Leeds, UK, LS2 9JT.
Email; 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